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The kids may not be alright, but psychiatry can help
When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.
Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.
The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.
Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.
For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.
The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.
Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.
In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:
- During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
- A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
- The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
- Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).
In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.
Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”
In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.
Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.
Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.
Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.
Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.
When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.
Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.
The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.
Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.
For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.
The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.
Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.
In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:
- During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
- A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
- The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
- Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).
In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.
Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”
In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.
Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.
Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.
Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.
Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.
When I was growing up, I can remember experiencing “duck and cover” drills at school. If a flash appeared in our peripheral vision, we were told we should not look at it but crawl under our desks. My classmates and I were being taught how to protect ourselves in case of a nuclear attack.
Clearly, had there been such an attack, ducking under our desks would not have saved us. Thankfully, such a conflict never occurred – and hopefully never will. Still, the warning did penetrate our psyches. In those days, families and children in schools were worried, and some were scared.
The situation is quite different today. Our children and grandchildren are being taught to protect themselves not from actions overseas – that never happened – but from what someone living in their community might do that has been occurring in real time. According to my daughter-in-law, her young children are taught during “lockdowns” to hide in their classrooms’ closets. During these drills, some children are directed to line up against a wall that would be out of sight of a shooter, and to stay as still as possible.
Since 2017, the number of intentional shootings in U.S. kindergarten through grade 12 schools increased precipitously (Prev Med. 2022 Dec. doi: 10.1016/j.ypmed.2022.107280). Imagine the psychological impact that the vigilance required to deal with such impending threats must be having on our children, as they learn to fear injury and possible death every day they go to school. I’ve talked with numerous parents about this, including my own adult children, and this is clearly a new dimension of life that is on everyone’s minds. Schools, once bastions of safety, are no longer that safe.
For many years, I’ve written about the need to destigmatize mental illness so that it is treated on a par with physical illness. As we look at the challenges faced by young people, reframing mental illness is more important now than ever. This means finding ways to increase the funding of studies that help us understand young people with mental health issues. It also means encouraging patients to pursue treatment from psychiatrists, psychologists, or mental health counselors who specialize in short-term therapy.
The emphasis here on short-term therapy is not to discourage longer-term care when needed, but clearly short-term care strategies, such as cognitive-behavioral therapies, not only work for problem resolution, they also help in the destigmatization of mental health care – as the circumscribed treatment with a clear beginning, middle, and end is consistent with CBT and consistent with much of medical care for physical disorders.
Furthermore, as we aim to destigmatize mental health care, it’s important to equate it with physical care. For example, taking a day or two from school or work for a sprained ankle, seeing a dentist, or an eye exam, plus a myriad of physical issues is quite acceptable. Why is it not also acceptable for a mental health issue and evaluation, such as for anxiety or PTSD, plus being able to talk about it without stigma? Seeing the “shrink” needs to be removed as a negative but viewed as a very positive move toward care for oneself.
In addition, children and adolescents are battling countless other health challenges that could have implications for mental health professionals, for example:
- During the height of the coronavirus pandemic, pediatric endocrinologists reportedly saw a surge of referrals for girls experiencing early puberty. Puberty should never be medicalized, but early maturation has been linked to numerous psychiatric disorders such as depression, anxiety, and eating disorders (J Pediatr Adolec Gynecol. 2022 Oct. doi: 10.1016/j.jpag.2022.05.005).
- A global epidemiologic study of children estimates that nearly 8 million youth lost a parent or caregiver because of a pandemic-related cause between Jan. 1, 2020, and May 1, 2022. An additional 2.5 million children were affected by the loss of secondary caregivers such as grandparents (JAMA Pediatr. 2022 Sept. doi: 10.1001/jamapediatrics.2022.3157).
- The inpatient and outpatient volume of adolescents and young adults receiving care for eating disorders skyrocketed before and after the pandemic, according to the results of case study series (JAMA Pediatrics. 2022 Nov 7. doi: 10.1001/jamapediatrics.2022.4346).
- Children and adolescents who developed COVID-19 suffered tremendously during the height of the pandemic. A nationwide analysis shows that COVID-19 nearly tripled children’s risks of developing new mental health illnesses, such as attention-deficit/hyperactivity disorder, anxiety, trauma, or stress disorder (Psychiatric Services. 2022 Jun 2. doi: 10.1176/appi.ps.202100646).
In addition to those challenges, young children are facing an increase in respiratory syncytial virus (RSV) infection. We were told the “flu” would be quite bad this year and to beware of monkeypox. However, very little mention is made of the equally distressing “epidemic” of mental health issues, PTSD, anxiety, and depression as we are still in the midst of the COVID pandemic in the United States with almost 400 deaths a day – a very unacceptable number.
Interestingly, we seem to have abandoned the use of masks as protection against COVID and other respiratory diseases, despite their effectiveness. A study in Boston that looked at children in two school districts that did not lift mask mandates demonstrated that mask wearing does indeed lead to significant reductions in the number of pediatric COVID cases. In addition to societal violence and school shootings – which certainly exacerbate anxiety – the fear of dying or the death of a loved one, tied to COVID, may lead to epidemic proportions of PTSD in children. As an article in WebMD noted, “pediatricians are imploring the federal government to declare a national emergency as cases of pediatric respiratory illnesses continue to soar.”
In light of the acknowledged mental health crisis in children, which appears epidemic, I would hope the psychiatric and psychological associations would publicly sound an alarm so that resources could be brought to bear to address this critical issue. I believe doing so would also aid in destigmatizing mental disorders, and increase education and treatment.
Layered on top of those issues are natural disasters, such as the fallout from Tropical Storm Nicole when it recently caused devastation across western Florida. The mental health trauma caused by recent tropical storms seems all but forgotten – except for those who are still suffering. All of this adds up to a society-wide mental health crisis, which seems far more expansive than monkeypox, for example. Yet monkeypox, which did lead to thousands of cases and approximately 29 deaths in the United States, was declared a national public health emergency.
Additionally, RSV killed 100-500 U.S. children under age 5 each year before the pandemic, according to the Centers for Disease Control and Prevention, and currently it appears even worse. Yet despite the seriousness of RSV, it nowhere matches the emotional toll COVID has taken on children globally.
Let’s make it standard practice for children – and of course, adults – to be taught that anxiety is a normal response at times. We should teach that, in some cases, feeling “down” or in despair and even experiencing symptoms of PTSD based on what’s going on personally and within our environment (i.e., COVID, school shootings, etc.) are triggers and responses that can be addressed and often quickly treated by talking with a mental health professional.
Dr. London is a practicing psychiatrist and has been a newspaper columnist for 35 years, specializing in and writing about short-term therapy, including cognitive-behavioral therapy and guided imagery. He is author of “Find Freedom Fast” (New York: Kettlehole Publishing, 2019). He has no conflicts of interest.
Immune dysregulation may drive long-term postpartum depression
Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.
These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.
“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”
To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.
Sixteen of the 33 women had clinically significant mood disturbances. and significantly reduced activation of genes associated with viral response.
“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
Findings draw skepticism
“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.
In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.
“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”
Only prospective studies can answer these questions, she said.
Dr. Nicoloro-SantaBarbara agreed that further research is needed.
“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”
The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.
Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.
These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.
“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”
To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.
Sixteen of the 33 women had clinically significant mood disturbances. and significantly reduced activation of genes associated with viral response.
“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
Findings draw skepticism
“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.
In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.
“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”
Only prospective studies can answer these questions, she said.
Dr. Nicoloro-SantaBarbara agreed that further research is needed.
“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”
The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.
Postpartum depression, anxiety, and posttraumatic stress disorder that persist 2-3 years after birth are associated with a dysregulated immune system that is characterized by increased inflammatory signaling, according to investigators.
These findings suggest that mental health screening for women who have given birth should continue beyond the first year post partum, reported lead author Jennifer M. Nicoloro-SantaBarbara, PhD, of Brigham and Women’s Hospital, Harvard Medical School, Boston, and colleagues.
“Delayed postpartum depression, also known as late-onset postpartum depression, can affect women up to 18 months after delivery,” the investigators wrote in the American Journal of Reproductive Immunology. “It can appear even later in some women, depending on the hormonal changes that occur after having a baby (for example, timing of weaning). However, the majority of research on maternal mental health focuses on the first year post birth, leaving a gap in research beyond 12 months post partum.”
To address this gap, the investigators enrolled 33 women who were 2-3 years post partum. Participants completed self-guided questionnaires on PTSD, depression, and anxiety, and provided blood samples for gene expression analysis.
Sixteen of the 33 women had clinically significant mood disturbances. and significantly reduced activation of genes associated with viral response.
“The results provide preliminary evidence of a mechanism (e.g., immune dysregulation) that might be contributing to mood disorders and bring us closer to the goal of identifying targetable biomarkers for mood disorders,” Dr. Nicoloro-SantaBarbara said in a written comment. “This work highlights the need for standardized and continual depression and anxiety screening in ob.gyn. and primary care settings that extends beyond the 6-week maternal visit and possibly beyond the first postpartum year.”
Findings draw skepticism
“The authors argue that mothers need to be screened for depression/anxiety longer than the first year post partum, and this is true, but it has nothing to do with their findings,” said Jennifer L. Payne, MD, an expert in reproductive psychiatry at the University of Virginia, Charlottesville.
In a written comment, she explained that the cross-sectional design makes it impossible to know whether the mood disturbances were linked with delivery at all.
“It is unclear if the depression/anxiety symptoms began after delivery or not,” Dr. Payne said. “In addition, it is unclear if the findings are causative or a result of depression/anxiety symptoms (the authors admit this in the limitations section). It is likely that the findings are not specific or even related to having delivered a child, but rather reflect a more general process related to depression/anxiety outside of the postpartum time period.”
Only prospective studies can answer these questions, she said.
Dr. Nicoloro-SantaBarbara agreed that further research is needed.
“Our findings are exciting, but still need to be replicated in larger samples with diverse women in order to make sure they generalize,” she said. “More work is needed to understand why inflammation plays a role in postpartum mental illness for some women and not others.”
The study was supported by a Cedars-Sinai Precision Health Grant, the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, and the National Institute of Mental Health. The investigators and Dr. Payne disclosed no relevant conflicts of interest.
FROM THE AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY
‘Striking’ rate of mental health comorbidities in epilepsy
NASHVILLE, TENN. – , new research reveals.
“We hope these results inspire epileptologists and neurologists to both recognize and screen for suicide ideation and behaviors in their adolescent patients,” said study investigator Hadley Greenwood, a third-year medical student at New York University.
The new data should also encourage providers “to become more comfortable” providing support to patients, “be that by increasing their familiarity with prescribing different antidepressants or by being well versed in how to connect patients to resources within their community,” said Mr. Greenwood.
The findings were presented here at the annual meeting of the American Epilepsy Society.
Little research
Previous studies have reported on the prevalence of suicidality as well as depression and anxiety among adults with epilepsy. “We wanted to look at adolescents because there’s much less in the literature out there about psychiatric comorbidity, and specifically suicidality, in this population,” said Mr. Greenwood.
Researchers used data from the Human Epilepsy Project, a study that collected data from 34 sites in the United States, Canada, Europe, and Australia from 2012 to 2017.
From a cohort of more than 400 participants, researchers identified 67 patients aged 11-17 years who were enrolled within 4 months of starting treatment for focal epilepsy.
Participants completed the Columbia–Suicide Severity Rating Scale (C-SSRS) at enrollment and at follow-ups over 36 months. The C-SSRS measures suicidal ideation and severity, said Mr. Greenwood.
“It’s scaled from passive suicide ideation, such as thoughts of ‘I wish I were dead’ without active intent, all the way up to active suicidal ideation with a plan and intent.”
Researchers were able to distinguish individuals with passive suicide ideation from those with more serious intentions, said Mr. Greenwood. They used medical records to evaluate the prevalence of suicidal ideation and behavior.
The investigators found that more than one in five (20.9%) teens endorsed any lifetime suicide ideation. This, said Mr. Greenwood, is “roughly equivalent” to the prevalence reported earlier in the adult cohort of the Human Epilepsy Project (21.6%).
‘Striking’ rate
The fact that one in five adolescents had any lifetime suicide ideation is “definitely a striking number,” said Mr. Greenwood.
Researchers found that 15% of patients experienced active suicide ideation, 7.5% exhibited preparatory or suicidal behaviors, and 3% had made a prior suicide attempt.
All of these percentages increased at 3 years: Thirty-one percent for suicide ideation; 25% for active suicide behavior, 15% for preparatory or suicide behaviors, and 5% for prior suicide attempt.
The fact that nearly one in three adolescents endorsed suicide ideation at 3 years is another “striking” finding, said Mr. Greenwood.
Of the 53 adolescents who had never had suicide ideation at the time of enrollment, 7 endorsed new-onset suicide ideation in the follow-up period. Five of 14 who had had suicide ideation at some point prior to enrollment continued to endorse it.
“The value of the study is identifying the prevalence and identifying the significant number of adolescents with epilepsy who are endorsing either suicide ideation or suicidal behaviors,” said Mr. Greenwood.
The researchers found that among younger teens (aged 11–14 years) rates of suicide ideation were higher than among their older counterparts (aged 15–17 years).
The study does not shed light on the biological connection between epilepsy and suicidality, but Mr. Greenwood noted that prior research has suggested a bidirectional relationship.
“Depression and other psychiatric comorbidities might exist prior to epileptic activity and actually predispose to epileptic activity.”
Mr. Greenwood noted that suicide ideation has “spiked” recently across the general population, and so it’s difficult to compare the prevalence in her study with “today’s prevalence.”
However, other research generally shows that the suicide ideation rate in the general adolescent population is much lower than in teens with epilepsy.
Unique aspects of the current study are that it reports suicide ideation and behaviors at around the time of an epilepsy diagnosis and documents how suicidality progresses or resolves over time, said Mr. Greenwood.
Underdiagnosed, undertreated
Commenting on the research, Elizabeth Donner, MD, director of the comprehensive epilepsy program, Hospital for Sick Children, and associate professor, department of pediatrics, University of Toronto, said a “key point” from the study is that the suicidality rate among teens with epilepsy exceeds that of children not living with epilepsy.
“We are significantly underdiagnosing and undertreating the mental health comorbidities in epilepsy,” said Dr. Donner. “Epilepsy is a brain disease and so are mental health disorders, so it shouldn’t come as any surprise that they coexist in individuals with epilepsy.”
The new results contribute to what is already known about the significant mortality rates among persons with epilepsy, said Dr. Donner. She referred to a 2018 study that showed that people with epilepsy were 3.5 times more likely to die by suicide.
Other research has shown that people with epilepsy are 10 times more likely to die by drowning, mostly in the bathtub, said Dr. Donner.
“You would think that we’re educating these people about risks related to their epilepsy, but either the messages don’t get through, or they don’t know how to keep themselves safe,” she said.
“This needs to be seen in a bigger picture, and the bigger picture is we need to recognize comorbid mental health issues; we need to address them once recognized; and then we need to counsel and support people to live safely with their epilepsy.
The study received funding from the Epilepsy Study Consortium, Finding a Cure for Epilepsy and Seizures (FACES) and other related foundations, UCB, Pfizer, Eisai, Lundbeck, and Sunovion. Mr. Greenwood and Dr. Donner report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – , new research reveals.
“We hope these results inspire epileptologists and neurologists to both recognize and screen for suicide ideation and behaviors in their adolescent patients,” said study investigator Hadley Greenwood, a third-year medical student at New York University.
The new data should also encourage providers “to become more comfortable” providing support to patients, “be that by increasing their familiarity with prescribing different antidepressants or by being well versed in how to connect patients to resources within their community,” said Mr. Greenwood.
The findings were presented here at the annual meeting of the American Epilepsy Society.
Little research
Previous studies have reported on the prevalence of suicidality as well as depression and anxiety among adults with epilepsy. “We wanted to look at adolescents because there’s much less in the literature out there about psychiatric comorbidity, and specifically suicidality, in this population,” said Mr. Greenwood.
Researchers used data from the Human Epilepsy Project, a study that collected data from 34 sites in the United States, Canada, Europe, and Australia from 2012 to 2017.
From a cohort of more than 400 participants, researchers identified 67 patients aged 11-17 years who were enrolled within 4 months of starting treatment for focal epilepsy.
Participants completed the Columbia–Suicide Severity Rating Scale (C-SSRS) at enrollment and at follow-ups over 36 months. The C-SSRS measures suicidal ideation and severity, said Mr. Greenwood.
“It’s scaled from passive suicide ideation, such as thoughts of ‘I wish I were dead’ without active intent, all the way up to active suicidal ideation with a plan and intent.”
Researchers were able to distinguish individuals with passive suicide ideation from those with more serious intentions, said Mr. Greenwood. They used medical records to evaluate the prevalence of suicidal ideation and behavior.
The investigators found that more than one in five (20.9%) teens endorsed any lifetime suicide ideation. This, said Mr. Greenwood, is “roughly equivalent” to the prevalence reported earlier in the adult cohort of the Human Epilepsy Project (21.6%).
‘Striking’ rate
The fact that one in five adolescents had any lifetime suicide ideation is “definitely a striking number,” said Mr. Greenwood.
Researchers found that 15% of patients experienced active suicide ideation, 7.5% exhibited preparatory or suicidal behaviors, and 3% had made a prior suicide attempt.
All of these percentages increased at 3 years: Thirty-one percent for suicide ideation; 25% for active suicide behavior, 15% for preparatory or suicide behaviors, and 5% for prior suicide attempt.
The fact that nearly one in three adolescents endorsed suicide ideation at 3 years is another “striking” finding, said Mr. Greenwood.
Of the 53 adolescents who had never had suicide ideation at the time of enrollment, 7 endorsed new-onset suicide ideation in the follow-up period. Five of 14 who had had suicide ideation at some point prior to enrollment continued to endorse it.
“The value of the study is identifying the prevalence and identifying the significant number of adolescents with epilepsy who are endorsing either suicide ideation or suicidal behaviors,” said Mr. Greenwood.
The researchers found that among younger teens (aged 11–14 years) rates of suicide ideation were higher than among their older counterparts (aged 15–17 years).
The study does not shed light on the biological connection between epilepsy and suicidality, but Mr. Greenwood noted that prior research has suggested a bidirectional relationship.
“Depression and other psychiatric comorbidities might exist prior to epileptic activity and actually predispose to epileptic activity.”
Mr. Greenwood noted that suicide ideation has “spiked” recently across the general population, and so it’s difficult to compare the prevalence in her study with “today’s prevalence.”
However, other research generally shows that the suicide ideation rate in the general adolescent population is much lower than in teens with epilepsy.
Unique aspects of the current study are that it reports suicide ideation and behaviors at around the time of an epilepsy diagnosis and documents how suicidality progresses or resolves over time, said Mr. Greenwood.
Underdiagnosed, undertreated
Commenting on the research, Elizabeth Donner, MD, director of the comprehensive epilepsy program, Hospital for Sick Children, and associate professor, department of pediatrics, University of Toronto, said a “key point” from the study is that the suicidality rate among teens with epilepsy exceeds that of children not living with epilepsy.
“We are significantly underdiagnosing and undertreating the mental health comorbidities in epilepsy,” said Dr. Donner. “Epilepsy is a brain disease and so are mental health disorders, so it shouldn’t come as any surprise that they coexist in individuals with epilepsy.”
The new results contribute to what is already known about the significant mortality rates among persons with epilepsy, said Dr. Donner. She referred to a 2018 study that showed that people with epilepsy were 3.5 times more likely to die by suicide.
Other research has shown that people with epilepsy are 10 times more likely to die by drowning, mostly in the bathtub, said Dr. Donner.
“You would think that we’re educating these people about risks related to their epilepsy, but either the messages don’t get through, or they don’t know how to keep themselves safe,” she said.
“This needs to be seen in a bigger picture, and the bigger picture is we need to recognize comorbid mental health issues; we need to address them once recognized; and then we need to counsel and support people to live safely with their epilepsy.
The study received funding from the Epilepsy Study Consortium, Finding a Cure for Epilepsy and Seizures (FACES) and other related foundations, UCB, Pfizer, Eisai, Lundbeck, and Sunovion. Mr. Greenwood and Dr. Donner report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NASHVILLE, TENN. – , new research reveals.
“We hope these results inspire epileptologists and neurologists to both recognize and screen for suicide ideation and behaviors in their adolescent patients,” said study investigator Hadley Greenwood, a third-year medical student at New York University.
The new data should also encourage providers “to become more comfortable” providing support to patients, “be that by increasing their familiarity with prescribing different antidepressants or by being well versed in how to connect patients to resources within their community,” said Mr. Greenwood.
The findings were presented here at the annual meeting of the American Epilepsy Society.
Little research
Previous studies have reported on the prevalence of suicidality as well as depression and anxiety among adults with epilepsy. “We wanted to look at adolescents because there’s much less in the literature out there about psychiatric comorbidity, and specifically suicidality, in this population,” said Mr. Greenwood.
Researchers used data from the Human Epilepsy Project, a study that collected data from 34 sites in the United States, Canada, Europe, and Australia from 2012 to 2017.
From a cohort of more than 400 participants, researchers identified 67 patients aged 11-17 years who were enrolled within 4 months of starting treatment for focal epilepsy.
Participants completed the Columbia–Suicide Severity Rating Scale (C-SSRS) at enrollment and at follow-ups over 36 months. The C-SSRS measures suicidal ideation and severity, said Mr. Greenwood.
“It’s scaled from passive suicide ideation, such as thoughts of ‘I wish I were dead’ without active intent, all the way up to active suicidal ideation with a plan and intent.”
Researchers were able to distinguish individuals with passive suicide ideation from those with more serious intentions, said Mr. Greenwood. They used medical records to evaluate the prevalence of suicidal ideation and behavior.
The investigators found that more than one in five (20.9%) teens endorsed any lifetime suicide ideation. This, said Mr. Greenwood, is “roughly equivalent” to the prevalence reported earlier in the adult cohort of the Human Epilepsy Project (21.6%).
‘Striking’ rate
The fact that one in five adolescents had any lifetime suicide ideation is “definitely a striking number,” said Mr. Greenwood.
Researchers found that 15% of patients experienced active suicide ideation, 7.5% exhibited preparatory or suicidal behaviors, and 3% had made a prior suicide attempt.
All of these percentages increased at 3 years: Thirty-one percent for suicide ideation; 25% for active suicide behavior, 15% for preparatory or suicide behaviors, and 5% for prior suicide attempt.
The fact that nearly one in three adolescents endorsed suicide ideation at 3 years is another “striking” finding, said Mr. Greenwood.
Of the 53 adolescents who had never had suicide ideation at the time of enrollment, 7 endorsed new-onset suicide ideation in the follow-up period. Five of 14 who had had suicide ideation at some point prior to enrollment continued to endorse it.
“The value of the study is identifying the prevalence and identifying the significant number of adolescents with epilepsy who are endorsing either suicide ideation or suicidal behaviors,” said Mr. Greenwood.
The researchers found that among younger teens (aged 11–14 years) rates of suicide ideation were higher than among their older counterparts (aged 15–17 years).
The study does not shed light on the biological connection between epilepsy and suicidality, but Mr. Greenwood noted that prior research has suggested a bidirectional relationship.
“Depression and other psychiatric comorbidities might exist prior to epileptic activity and actually predispose to epileptic activity.”
Mr. Greenwood noted that suicide ideation has “spiked” recently across the general population, and so it’s difficult to compare the prevalence in her study with “today’s prevalence.”
However, other research generally shows that the suicide ideation rate in the general adolescent population is much lower than in teens with epilepsy.
Unique aspects of the current study are that it reports suicide ideation and behaviors at around the time of an epilepsy diagnosis and documents how suicidality progresses or resolves over time, said Mr. Greenwood.
Underdiagnosed, undertreated
Commenting on the research, Elizabeth Donner, MD, director of the comprehensive epilepsy program, Hospital for Sick Children, and associate professor, department of pediatrics, University of Toronto, said a “key point” from the study is that the suicidality rate among teens with epilepsy exceeds that of children not living with epilepsy.
“We are significantly underdiagnosing and undertreating the mental health comorbidities in epilepsy,” said Dr. Donner. “Epilepsy is a brain disease and so are mental health disorders, so it shouldn’t come as any surprise that they coexist in individuals with epilepsy.”
The new results contribute to what is already known about the significant mortality rates among persons with epilepsy, said Dr. Donner. She referred to a 2018 study that showed that people with epilepsy were 3.5 times more likely to die by suicide.
Other research has shown that people with epilepsy are 10 times more likely to die by drowning, mostly in the bathtub, said Dr. Donner.
“You would think that we’re educating these people about risks related to their epilepsy, but either the messages don’t get through, or they don’t know how to keep themselves safe,” she said.
“This needs to be seen in a bigger picture, and the bigger picture is we need to recognize comorbid mental health issues; we need to address them once recognized; and then we need to counsel and support people to live safely with their epilepsy.
The study received funding from the Epilepsy Study Consortium, Finding a Cure for Epilepsy and Seizures (FACES) and other related foundations, UCB, Pfizer, Eisai, Lundbeck, and Sunovion. Mr. Greenwood and Dr. Donner report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT AES 2022
SSRI tied to improved cognition in comorbid depression, dementia
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.
“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.
“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.
However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.
“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.
Potential neurotransmission modulator
Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”
The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.
Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.
The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.
In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.
“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.
“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.
More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.
For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”
A third of patients had drug-related treatment-emergent adverse events.
Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.
Small trial, open-label design
In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”
She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.
The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.
A version of this article first appeared on Medscape.com.
FROM CTAD 2022
Mood stabilizers, particularly lithium, potential lifesavers in bipolar disorder
Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.
However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.
“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.
“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.
The study was published online in Acta Psychiatrica Scandinavica.
Research gap
Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.
Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”
To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.
The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”
Covariates included sex, age, employment status, comorbidities, and concomitant drugs.
Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
Cardioprotective effects?
The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).
The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).
The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.
Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.
Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).
Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.
Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).
Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.
The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.
The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.
Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.
The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.
The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
First-line treatment
Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”
But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”
The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.
This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.
However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.
“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.
“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.
The study was published online in Acta Psychiatrica Scandinavica.
Research gap
Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.
Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”
To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.
The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”
Covariates included sex, age, employment status, comorbidities, and concomitant drugs.
Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
Cardioprotective effects?
The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).
The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).
The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.
Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.
Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).
Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.
Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).
Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.
The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.
The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.
Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.
The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.
The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
First-line treatment
Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”
But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”
The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.
This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
Investigators led by Pao-Huan Chen, MD, of the department of psychiatry, Taipei Medical University Hospital, Taiwan, evaluated the association between the use of mood stabilizers and the risks for all-cause mortality, suicide, and natural mortality in more than 25,000 patients with BD and found that those with BD had higher mortality.
However, they also found that patients with BD had a significantly decreased adjusted 5-year risk of dying from any cause, suicide, and natural causes. Lithium was associated with the largest risk reduction compared with the other mood stabilizers.
“The present findings highlight the potential role of mood stabilizers, particularly lithium, in reducing mortality among patients with bipolar disorder,” the authors write.
“The findings of this study could inform future clinical and mechanistic research evaluating the multifaceted effects of mood stabilizers, particularly lithium, on the psychological and physiological statuses of patients with bipolar disorder,” they add.
The study was published online in Acta Psychiatrica Scandinavica.
Research gap
Patients with BD have an elevated risk for multiple comorbidities in addition to mood symptoms and neurocognitive dysfunction, with previous research suggesting a mortality rate due to suicide and natural causes that is at least twice as high as that of the general population, the authors write.
Lithium, in particular, has been associated with decreased risk for all-cause mortality and suicide in patients with BD, but findings regarding anticonvulsant mood stabilizers have been “inconsistent.”
To fill this research gap, the researchers evaluated 16 years of data from Taiwan’s National Health Insurance Research Database, which includes information about more than 23 million residents of Taiwan. The current study, which encompassed 25,787 patients with BD, looked at data from the 5-year period after index hospitalization.
The researchers hypothesized that mood stabilizers “would decrease the risk of mortality” among patients with BD and that “different mood stabilizers would exhibit different associations with mortality, owing to their varying effects on mood symptoms and physiological function.”
Covariates included sex, age, employment status, comorbidities, and concomitant drugs.
Of the patients with BD, 4,000 died within the 5-year period. Suicide and natural causes accounted for 19.0% and 73.7% of these deaths, respectively.
Cardioprotective effects?
The standardized mortality ratios (SMRs) – the ratios of observed mortality in the BD cohort to the number of expected deaths in the general population – were 5.26 for all causes (95% confidence interval, 5.10-5.43), 26.02 for suicide (95% CI, 24.20-27.93), and 4.68 for natural causes (95% CI, 4.51-4.85).
The cumulative mortality rate was higher among men vs. women, a difference that was even larger among patients who had died from any cause or natural causes (crude hazard ratios, .60 and .52, respectively; both Ps < .001).
The suicide risk peaked between ages 45 and 65 years, whereas the risks for all-cause and natural mortality increased with age and were highest in those older than 65 years.
Patients who had died from any cause or from natural causes had a higher risk for physical and psychiatric comorbidities, whereas those who had died by suicide had a higher risk for primarily psychiatric comorbidities.
Mood stabilizers were associated with decreased risks for all-cause mortality and natural mortality, with lithium and valproic acid tied to the lowest risk for all three mortality types (all Ps < .001).
Lamotrigine and carbamazepine were “not significantly associated with any type of mortality,” the authors report.
Longer duration of lithium use and a higher cumulative dose of lithium were both associated with lower risks for all three types of mortality (all Ps < .001).
Valproic acid was associated with dose-dependent decreases in all-cause and natural mortality risks.
The findings suggest that mood stabilizers “may improve not only psychosocial outcomes but also the physical health of patients with BD,” the investigators note.
The association between mood stabilizer use and reduced natural mortality risk “may be attributable to the potential benefits of psychiatric care” but may also “have resulted from the direct effects of mood stabilizers on physiological functions,” they add.
Some research suggests lithium treatment may reduce the risk for cardiovascular disease in patients with BD. Mechanistic studies have also pointed to potential cardioprotective effects from valproic acid.
The authors note several study limitations. Focusing on hospitalized patients “may have led to selection bias and overestimated mortality risk.” Moreover, the analyses were “based on the prescription, not the consumption, of mood stabilizers” and information regarding adherence was unavailable.
The absence of a protective mechanism of lamotrigine and carbamazepine may be attributable to “bias toward the relatively poor treatment responses” of these agents, neither of which is used as a first-line medication to treat BD in Taiwan. Patients taking these agents “may not receive medical care at a level equal to those taking lithium, who tend to receive closer surveillance, owing to the narrow therapeutic index.”
First-line treatment
Commenting on the study, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, and head of the mood disorders psychopharmacology unit, said that the data “add to a growing confluence of data from observational studies indicating that lithium especially is capable of reducing all-cause mortality, suicide mortality, and natural mortality.”
Dr. McIntyre, chairman and executive director of the Brain and Cognitive Discover Foundation, Toronto, who was not involved with the study, agreed with the authors that lamotrigine is “not a very popular drug in Taiwan, therefore we may not have sufficient assay sensitivity to document the effect.”
But lamotrigine “does have recurrence prevention effects in BD, especially bipolar depression, and it would be expected that it would reduce suicide potentially especially in such a large sample.”
The study’s take-home message “is that the extant evidence now indicates that lithium should be a first-line treatment in persons who live with BD who are experiencing suicidal ideation and/or behavior and these data should inform algorithms of treatment selection and sequencing in clinical practice guidelines,” said Dr. McIntyre.
This research was supported by grants from the Ministry of Science and Technology in Taiwan and Taipei City Hospital. The authors declared no relevant financial relationships. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China, and the Milken Institute; and speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe Pharma, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences. Dr. McIntyre is a CEO of Braxia Scientific.
A version of this article first appeared on Medscape.com.
FROM ACTA PSYCHIATRICA SCANDINAVICA
Clinical factors drive hospitalization after self-harm
Clinicians who assess suicidal patients in the emergency department setting face the challenge of whether to admit the patient to inpatient or outpatient care, and data on predictors of compulsory admission are limited, wrote Laurent Michaud, MD, of the University of Lausanne, Switzerland, and colleagues.
To better identify predictors of hospitalization after self-harm, the researchers reviewed data from 1,832 patients aged 18 years and older admitted to four emergency departments in Switzerland between December 2016 and November 2019 .
Self-harm (SH) was defined in this study as “all nonfatal intentional acts of self-poisoning or self-injury, irrespective of degree of suicidal intent or other types of motivation,” the researchers noted. The study included 2,142 episodes of self-harm.
The researchers conducted two analyses. They compared episodes followed by any hospitalization and those with outpatient follow-up (1,083 episodes vs. 1,059 episodes) and episodes followed by compulsory hospitalization (357 episodes) with all other episodes followed by either outpatient care or voluntary hospitalization (1,785 episodes).
Overall, women were significantly more likely to be referred to outpatient follow-up compared with men (61.8% vs. 38.1%), and hospitalized patients were significantly older than outpatients (mean age of 41 years vs. 36 years, P < .001 for both).
“Not surprisingly, major psychopathological conditions such as depression, mania, dementia, and schizophrenia were predictive of hospitalization,” the researchers noted.
Other sociodemographic factors associated with hospitalization included living alone, no children, problematic socioeconomic status, and unemployment. Clinical factors associated with hospitalization included physical pain, more lethal suicide attempt method, and clear intent to die.
In a multivariate analysis, independent predictors of any hospitalization included male gender, older age, assessment in the Neuchatel location vs. Lausanne, depression vs. personality disorders, substance use, or anxiety disorder, difficult socioeconomic status, a clear vs. unclear intent to die, and a serious suicide attempt vs. less serious.
Differences in hospitalization based on hospital setting was a striking finding, the researchers wrote in their discussion. These differences may be largely explained by the organization of local mental health services and specific institutional cultures; the workload of staff and availability of beds also may have played a role in decisions to hospitalize, they said.
The findings were limited by several factors including the lack of data on the realization level of a self-harm episode and significant events such as a breakup, the researchers explained. Other limitations included missing data, multiple analyses that could increase the risk of false positives, the reliance on clinical diagnosis rather than formal instruments, and the cross-sectional study design, they said.
However, the results have clinical implications, as the clinical factors identified could be used to target subgroups of suicidal populations and refine treatment strategies, they concluded.
The study was supported by institutional funding and the Swiss Federal Office of Public Health. The researchers had no financial conflicts to disclose.
Clinicians who assess suicidal patients in the emergency department setting face the challenge of whether to admit the patient to inpatient or outpatient care, and data on predictors of compulsory admission are limited, wrote Laurent Michaud, MD, of the University of Lausanne, Switzerland, and colleagues.
To better identify predictors of hospitalization after self-harm, the researchers reviewed data from 1,832 patients aged 18 years and older admitted to four emergency departments in Switzerland between December 2016 and November 2019 .
Self-harm (SH) was defined in this study as “all nonfatal intentional acts of self-poisoning or self-injury, irrespective of degree of suicidal intent or other types of motivation,” the researchers noted. The study included 2,142 episodes of self-harm.
The researchers conducted two analyses. They compared episodes followed by any hospitalization and those with outpatient follow-up (1,083 episodes vs. 1,059 episodes) and episodes followed by compulsory hospitalization (357 episodes) with all other episodes followed by either outpatient care or voluntary hospitalization (1,785 episodes).
Overall, women were significantly more likely to be referred to outpatient follow-up compared with men (61.8% vs. 38.1%), and hospitalized patients were significantly older than outpatients (mean age of 41 years vs. 36 years, P < .001 for both).
“Not surprisingly, major psychopathological conditions such as depression, mania, dementia, and schizophrenia were predictive of hospitalization,” the researchers noted.
Other sociodemographic factors associated with hospitalization included living alone, no children, problematic socioeconomic status, and unemployment. Clinical factors associated with hospitalization included physical pain, more lethal suicide attempt method, and clear intent to die.
In a multivariate analysis, independent predictors of any hospitalization included male gender, older age, assessment in the Neuchatel location vs. Lausanne, depression vs. personality disorders, substance use, or anxiety disorder, difficult socioeconomic status, a clear vs. unclear intent to die, and a serious suicide attempt vs. less serious.
Differences in hospitalization based on hospital setting was a striking finding, the researchers wrote in their discussion. These differences may be largely explained by the organization of local mental health services and specific institutional cultures; the workload of staff and availability of beds also may have played a role in decisions to hospitalize, they said.
The findings were limited by several factors including the lack of data on the realization level of a self-harm episode and significant events such as a breakup, the researchers explained. Other limitations included missing data, multiple analyses that could increase the risk of false positives, the reliance on clinical diagnosis rather than formal instruments, and the cross-sectional study design, they said.
However, the results have clinical implications, as the clinical factors identified could be used to target subgroups of suicidal populations and refine treatment strategies, they concluded.
The study was supported by institutional funding and the Swiss Federal Office of Public Health. The researchers had no financial conflicts to disclose.
Clinicians who assess suicidal patients in the emergency department setting face the challenge of whether to admit the patient to inpatient or outpatient care, and data on predictors of compulsory admission are limited, wrote Laurent Michaud, MD, of the University of Lausanne, Switzerland, and colleagues.
To better identify predictors of hospitalization after self-harm, the researchers reviewed data from 1,832 patients aged 18 years and older admitted to four emergency departments in Switzerland between December 2016 and November 2019 .
Self-harm (SH) was defined in this study as “all nonfatal intentional acts of self-poisoning or self-injury, irrespective of degree of suicidal intent or other types of motivation,” the researchers noted. The study included 2,142 episodes of self-harm.
The researchers conducted two analyses. They compared episodes followed by any hospitalization and those with outpatient follow-up (1,083 episodes vs. 1,059 episodes) and episodes followed by compulsory hospitalization (357 episodes) with all other episodes followed by either outpatient care or voluntary hospitalization (1,785 episodes).
Overall, women were significantly more likely to be referred to outpatient follow-up compared with men (61.8% vs. 38.1%), and hospitalized patients were significantly older than outpatients (mean age of 41 years vs. 36 years, P < .001 for both).
“Not surprisingly, major psychopathological conditions such as depression, mania, dementia, and schizophrenia were predictive of hospitalization,” the researchers noted.
Other sociodemographic factors associated with hospitalization included living alone, no children, problematic socioeconomic status, and unemployment. Clinical factors associated with hospitalization included physical pain, more lethal suicide attempt method, and clear intent to die.
In a multivariate analysis, independent predictors of any hospitalization included male gender, older age, assessment in the Neuchatel location vs. Lausanne, depression vs. personality disorders, substance use, or anxiety disorder, difficult socioeconomic status, a clear vs. unclear intent to die, and a serious suicide attempt vs. less serious.
Differences in hospitalization based on hospital setting was a striking finding, the researchers wrote in their discussion. These differences may be largely explained by the organization of local mental health services and specific institutional cultures; the workload of staff and availability of beds also may have played a role in decisions to hospitalize, they said.
The findings were limited by several factors including the lack of data on the realization level of a self-harm episode and significant events such as a breakup, the researchers explained. Other limitations included missing data, multiple analyses that could increase the risk of false positives, the reliance on clinical diagnosis rather than formal instruments, and the cross-sectional study design, they said.
However, the results have clinical implications, as the clinical factors identified could be used to target subgroups of suicidal populations and refine treatment strategies, they concluded.
The study was supported by institutional funding and the Swiss Federal Office of Public Health. The researchers had no financial conflicts to disclose.
FROM PSYCHIATRIC RESEARCH
Strong two-way link between epilepsy and depression
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, with implications for diagnosis and patient care. The findings “strongly support previous observations of a bidirectional association between these two brain disorders,” said Eva Bølling-Ladegaard, MD, a PhD student, department of clinical medicine (Neurology), Aarhus (Denmark) University.
“We add to the existing evidence in temporal range, showing that the increased risks of depression following epilepsy, and vice versa, are sustained over a much more extended time period than previously shown; that is, 20 years on both sides of receiving a diagnosis of the index disorder,” Ms. Bølling-Ladegaard said.
The study was published online in Neurology.
Epilepsy then depression
The researchers examined the magnitude and long-term temporal association between epilepsy and depression. They compared the risk of the two brain disorders following another chronic disorder (asthma) in a nationwide, register-based, matched cohort study.
In a population of more than 8.7 million people, they identified 139,014 persons with epilepsy (54% males; median age at diagnosis, 43 years), 219,990 with depression (37% males; median age at diagnosis, 43 years), and 358,821 with asthma (49% males; median age at diagnosis, 29 years).
The rate of developing depression was increased nearly twofold among people with epilepsy compared with the matched population who did not have epilepsy (adjusted hazard ratio, 1.88; 95% confidence interval, 1.82-1.95).
The rate of depression was highest during the first months and years after epilepsy diagnosis. It declined over time, yet remained significantly elevated throughout the 20+ years of observation.
The cumulative incidence of depression at 5 and 35 years’ follow-up in the epilepsy cohort was 1.37% and 6.05%, respectively, compared with 0.59% and 3.92% in the reference population.
The highest rate of depression after epilepsy was among individuals aged 40-59 years, and the lowest was among those aged 0-19 years at first epilepsy diagnosis.
Depression then epilepsy
The rate of developing epilepsy was increased more than twofold among patients with incident depression compared with the matched population who were without depression (aHR, 2.35; 95% CI, 2.25-2.44).
As in the opposite analysis, the rate of epilepsy was highest during the first months and years after depression diagnosis and declined over time.
The cumulative incidence of epilepsy at 5 and 35 years after depression diagnosis was 1.10% and 4.19%, respectively, compared with 0.32% and 2.06% in the reference population.
The rate of epilepsy was highest among those aged 0-19 years at time of first depression diagnosis and was lowest among those aged 80+ at first depression diagnosis.
For comparison, after asthma diagnosis, rates of depression and epilepsy were increased 1.63-fold (95% CI, 1.59-1.67) and 1.48-fold (95% CI, 1.44-1.53), respectively, compared with matched individuals without asthma.
Using admission with seizures as a proxy for treatment failure, the researchers observed an increased risk of treatment failure among people with epilepsy who were diagnosed with depression.
“Our results support previous findings indicating worse seizure outcomes in people with epilepsy and coexisting depression,” said Ms. Bølling-Ladegaard.
“Increased clinical awareness of the association between epilepsy and depression is therefore needed in order to increase the proportion of patients that receive appropriate treatment and improve outcomes for these patient groups,” she said.
Clinical implications
Reached for comment, Zulfi Haneef, MBBS, MD, associate professor of neurology, Baylor College of Medicine, Houston, noted that the link between epilepsy and depression is “well-known.”
“However, typically one thinks of epilepsy as leading to depression, not vice versa. Here they show the risk of epilepsy following depression to be high (highest of the risks given), which is thought provoking. However, association does not imply causation,” Dr. Haneef said.
“Prima facie, there is no biological rationale for depression to lead to epilepsy,” he said. He noted that some antidepressants can reduce the seizure threshold.
The findings do have implications for care, he said.
“For neurologists, this is another study that exhorts them to screen for depression and treat adequately in all patients with epilepsy,” Dr. Haneef said.
“For psychiatrists, this study may give guidance to watch more carefully for seizures in patients with depression, especially when using antidepressant medications that induce seizures.
“For the general public with either epilepsy or depression, it would help them be aware about this bidirectional association,” Dr. Haneef said.
The study was funded by the Lundbeck Foundation, the Danish Epilepsy Association, and the Novo Nordisk Foundation. Ms. Bølling-Ladegaard and Dr. Haneef have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NEUROLOGY
Psychedelics for treating psychiatric disorders: Are they safe?
Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box1), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.
Box
The legal landscape of psychedelics is rapidly evolving. Psilocybin use has been decriminalized in many cities in the United States (such as Denver), and some states (such as Oregon) have legalized it for therapeutic use.
It is important to understand the difference between decriminalization and legalization. Decriminalization means the substance is still prohibited under existing laws, but the legal system will choose not to enforce the prohibition. Legalization is the rescinding of laws prohibiting the use of the substance. In the United States, these laws may be state or federal. Despite psilocybin legalization for therapeutic use in Oregon and decriminalization in various cities, psychedelics currently remain illegal under federal law.
Source: Reference 1
There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 12,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics.
This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.
Psilocybin
Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.4 The acute effects last approximately 6 hours.5 While psilocybin has generated promising results in early clinical trials,3 the adverse effects of these agents have received less attention.
The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.6 It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.7 Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.6 Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.8 In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.11 In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,12 no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.12
A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.13 The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.
Lysergic acid diethylamide
LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.4 It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.14 Its acute effects last approximately 12 hours.15
Continue to: Like psilocybin...
Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.6 In a systematic review of the therapeutic use of LSD that included 567 participants,16 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.
Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.17 The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.
DMT/ayahuasca
Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,18 and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.19 Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.20
A recent review by Orsolini et al21 consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,20 nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.20 Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.22
MDMA
Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.23 This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.24 Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.24 MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.25 In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.26 These acute effects last approximately 2 to 4 hours.27
Continue to: A meta-analysis...
A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.28 Two trials from 2018 that were included in this meta-analysis—Mithoefer et al29 and Ot’alora et al30—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al29 found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al28); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.29 Ot’alora et al30 found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.
While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.31 Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.31 Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.32 MDMA has also been found to have moderate potential for abuse.33
Ketamine/esketamine
Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-
Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.35 In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.36
Bennett et al37 elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neurobiological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.
Continue to: A systematic review...
A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.38 Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 339). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.40
Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.41 Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.42
The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.39 Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.39A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).43 The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.43 Concerns regarding acute ketamine withdrawal have also been described in case reports.44
Other safety considerations of psychedelics
Hallucinogen persisting perception disorder
Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.45 Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.46 HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.45 HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.47
Serotonin toxicity and other serotonergic interactions
Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.48 Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.48
Boundary violations in psychedelic-assisted psychotherapy
A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al49 argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”
Continue to: Psychedelic treatment...
Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,50 given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.51
Caveats to consider
Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.
However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.52 Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.53 Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.13
There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al12: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.54 This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.55
The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.
Bottom Line
In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.
Related Resources
- American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
- Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
- Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/
Drug Brand Names
Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor
1. The current legal status of psychedelics in the United States. Investing News Network. August 23, 2022. Accessed August 26, 2022. https://investingnews.com/legal-status-of-psychedelics-in-the-united-states/
2. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177(5):391-410.
3. Nutt D, Carhart-Harris R. The current status of psychedelics in psychiatry. JAMA Psychiatry. 2021;78(2):121-122.
4. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355.
5. Hasler F, Grimberg U, Benz MA et al. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology. 2004;172:145-156.
6. Johnson MW, Hendricks PS, Barrett FS, et al. Classic psychedelics: an integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther. 2019;197:83-102.
7. Li NX, Hu YR, Chen WN, et al. Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis. J Affect Disord. 2022;296:26-34.
8. Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620.
9. Carhart-Harris RL, Nutt DJ. User perceptions of the benefits and harms of hallucinogenic drug use: a web-based questionnaire study. J Subst Use. 2010;15(4):283-300.
10. van Amsterdam J, Opperhuizen A, van den Brink W. Harm potential of magic mushroom use: a review. Regul Toxicol Pharmacol. 2011;59(3):423-429.
11. Johnson MW, Griffiths RR, Hendricks PS, et al. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 2018;142:143-166.
12. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl Med. 2021;384(15):1402-1411.
13. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant Episode of major depression. N Engl J Med. 2022;387(18):1637-1648.
14. Galvão-Coelho NL, Marx W, Gonzalez M, et al. Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology (Berl). 2021;238(2):341-354.
15. Schmid Y, Enzler F, Gasser P, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78(8):544-553.
16. Fuentes JJ, Fonseca F, Elices M, et al. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Front Psychiatry. 2020;10:943.
17. Family N, Maillet EL, Williams LTJ, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology (Berl). 2020;237(3):841-853.
18. Frecska E, Bokor P, Winkelman M. The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Front Pharmacol. 2016;7:35.
19. Domínguez-Clavé E, Solar J, Elices M, et al. Ayahuasca: pharmacology, neuroscience and therapeutic potential. Brain Res Bull. 2016;126(Pt 1):89-101.
20. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.
21. Orsolini L, Chiappini S, Papanti D, et al. How does ayahuasca work from a psychiatric perspective? Pros and cons of the entheogenic therapy. Hum Psychopharmacol: Clin Exp. 2020;35(3):e2728.
22. Durante Í, Dos Santos RG, Bouso JC, et al. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Braz J Psychiatry. 2021;43(4):362-369.
23. Sessa B, Higbed L, Nutt D. A review of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. Front Psychiatry. 2019;10:138.
24. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Progress Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):221-228.
25. Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affective Neurosc. 2014;9(11):1645-1652.
26. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001;165(7):917-928.
27. Dumont GJ, Verkes RJ. A review of acute effects of 3, 4-methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol. 2006;20(2):176-187.
28. Bahji A, Forsyth A, Groll D, et al. Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020;96:109735.
29. Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5(6):486-497.
30. Ot’alora GM, Grigsby J, Poulter B, et al. 3,4-methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295-1307.
31. Steinkellner T, Freissmuth M, Sitte HH, et al. The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and D-amphetamine. Biol Chem. 2011;392(1-2):103-115.
32. Montoya AG, Sorrentino R, Lukas SE, et al. Long-term neuropsychiatric consequences of “ecstasy” (MDMA): a review. Harvard Rev Psychiatry. 2002;10(4):212-220.
33. Yazar‐Klosinski BB, Mithoefer MC. Potential psychiatric uses for MDMA. Clin Pharmacol Ther. 2017;101(2):194-196.
34. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
35. Thase M, Connolly KR. Ketamine and esketamine for treating unipolar depression in adults: administration, efficacy, and adverse effects. Wolters Kluwer; 2019. Accessed August 26, 2022. https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
36. Dore J, Turnispeed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2):189-198.
37. Bennett R, Yavorsky C, Bravo G. Ketamine for bipolar depression: biochemical, psychotherapeutic, and psychedelic approaches. Front Psychiatry. 2022;13:867484.
38. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65-78.
39. U.S. Food and Drug Administration. SPRAVATO® (esketamine). Prescribing information. Janssen; 2020. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf
40. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affective Disord. 2021;278:542-555.
41. Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: a systematic review. Neurourol Urodyn. 2020;39(4):1049-1062.
42. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27(6):582-586.
43. Gastaldon, C, Raschi E, Kane JM, et al. Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2021;90(1):41-48.
44. Roxas N, Ahuja C, Isom J, et al. A potential case of acute ketamine withdrawal: clinical implications for the treatment of refractory depression. Am J Psychiatry. 2021;178(7):588-591.
45. Orsolini L, Papanti GD, De Berardis D, et al. The “Endless Trip” among the NPS users: psychopathology and psychopharmacology in the hallucinogen-persisting perception disorder. A systematic review. Front Psychiatry. 2017;8:240.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatry Association; 2013.
47. Martinotti G, Santacroce R, Pettorruso M, et al. Hallucinogen persisting perception disorder: etiology, clinical features, and therapeutic perspectives. Brain Sci. 2018;8(3):47.
48. Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl). 2022;239(6):1881-1891.
49. Anderson BT, Danforth AL, Grob CS. Psychedelic medicine: safety and ethical concerns. Lancet Psychiatry, 2020;7(10):829-830.
50. Goldhill O. Psychedelic therapy has a sexual abuse problem. QUARTZ. March 3, 2020. Accessed August 26, 2022. https://qz.com/1809184/psychedelic-therapy-has-a-sexual-abuse-problem-3/
51. Goldhill O. A psychedelic therapist allegedly took millions from a Holocaust survivor, highlighting worries about elders taking hallucinogens. STAT News. April 21, 2022. Accessed August 26, 2022. https://www.statnews.com/2022/04/21/psychedelic-therapist-allegedly-took-millions-from-holocaust-survivor-highlighting-worries-about-elders-taking-hallucinogens/
52. Strassman RJ. Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis. 1984;172(10):577-595.
53. Nutt D. Drugs Without the Hot Air: Minimising the Harms of Legal and Illegal Drugs. UIT Cambridge Ltd; 2012.
54. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.
55. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(6):422-424.
Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box1), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.
Box
The legal landscape of psychedelics is rapidly evolving. Psilocybin use has been decriminalized in many cities in the United States (such as Denver), and some states (such as Oregon) have legalized it for therapeutic use.
It is important to understand the difference between decriminalization and legalization. Decriminalization means the substance is still prohibited under existing laws, but the legal system will choose not to enforce the prohibition. Legalization is the rescinding of laws prohibiting the use of the substance. In the United States, these laws may be state or federal. Despite psilocybin legalization for therapeutic use in Oregon and decriminalization in various cities, psychedelics currently remain illegal under federal law.
Source: Reference 1
There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 12,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics.
This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.
Psilocybin
Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.4 The acute effects last approximately 6 hours.5 While psilocybin has generated promising results in early clinical trials,3 the adverse effects of these agents have received less attention.
The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.6 It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.7 Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.6 Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.8 In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.11 In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,12 no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.12
A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.13 The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.
Lysergic acid diethylamide
LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.4 It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.14 Its acute effects last approximately 12 hours.15
Continue to: Like psilocybin...
Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.6 In a systematic review of the therapeutic use of LSD that included 567 participants,16 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.
Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.17 The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.
DMT/ayahuasca
Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,18 and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.19 Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.20
A recent review by Orsolini et al21 consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,20 nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.20 Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.22
MDMA
Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.23 This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.24 Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.24 MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.25 In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.26 These acute effects last approximately 2 to 4 hours.27
Continue to: A meta-analysis...
A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.28 Two trials from 2018 that were included in this meta-analysis—Mithoefer et al29 and Ot’alora et al30—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al29 found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al28); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.29 Ot’alora et al30 found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.
While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.31 Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.31 Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.32 MDMA has also been found to have moderate potential for abuse.33
Ketamine/esketamine
Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-
Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.35 In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.36
Bennett et al37 elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neurobiological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.
Continue to: A systematic review...
A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.38 Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 339). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.40
Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.41 Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.42
The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.39 Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.39A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).43 The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.43 Concerns regarding acute ketamine withdrawal have also been described in case reports.44
Other safety considerations of psychedelics
Hallucinogen persisting perception disorder
Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.45 Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.46 HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.45 HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.47
Serotonin toxicity and other serotonergic interactions
Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.48 Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.48
Boundary violations in psychedelic-assisted psychotherapy
A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al49 argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”
Continue to: Psychedelic treatment...
Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,50 given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.51
Caveats to consider
Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.
However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.52 Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.53 Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.13
There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al12: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.54 This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.55
The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.
Bottom Line
In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.
Related Resources
- American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
- Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
- Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/
Drug Brand Names
Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor
Psychedelics are a class of substances known to produce alterations in consciousness and perception. In the last 2 decades, psychedelic research has garnered increasing attention from scientists, therapists, entrepreneurs, and the public. While many of these compounds remain illegal in the United States and in many parts of the world (Box1), a recent resurrection of psychedelic research has motivated the FDA to designate multiple psychedelic compounds as “breakthrough therapies,” thereby expediting the investigation, development, and review of psychedelic treatments.
Box
The legal landscape of psychedelics is rapidly evolving. Psilocybin use has been decriminalized in many cities in the United States (such as Denver), and some states (such as Oregon) have legalized it for therapeutic use.
It is important to understand the difference between decriminalization and legalization. Decriminalization means the substance is still prohibited under existing laws, but the legal system will choose not to enforce the prohibition. Legalization is the rescinding of laws prohibiting the use of the substance. In the United States, these laws may be state or federal. Despite psilocybin legalization for therapeutic use in Oregon and decriminalization in various cities, psychedelics currently remain illegal under federal law.
Source: Reference 1
There is growing evidence that psychedelics may be efficacious for treating a range of psychiatric disorders. Potential clinical indications for psychedelics include some forms of depression, posttraumatic stress disorder (PTSD), and substance use disorders (Table 12,3). In most instances, the clinical use of psychedelics is being investigated and offered in the context of psychedelic-assisted psychotherapy, though ketamine is a prominent exception. Ketamine and esketamine are already being used to treat depression, and FDA approval is anticipated for other psychedelics.
This article examines the adverse effect profile of classical (psilocybin [“mushrooms”], lysergic acid diethylamide [LSD], and N,N-dimethyltryptamine [DMT]/ayahuasca) and nonclassical (the entactogen 3,4-methylenedioxymethamphetamine [MDMA, known as “ecstasy”] and the dissociative anesthetic ketamine) psychedelics.
Psilocybin
Psilocybin is typically administered as a single dose of 10 to 30 mg and used in conjunction with preintegration and postintegration psychotherapy. Administration of psilocybin typically produces perceptual distortions and mind-altering effects, which are mediated through 5-HT2A brain receptor agonistic action.4 The acute effects last approximately 6 hours.5 While psilocybin has generated promising results in early clinical trials,3 the adverse effects of these agents have received less attention.
The adverse effect profile of psilocybin in adults appears promising but its powerful psychoactive effects necessitate cautious use.6 It has a very wide therapeutic index, and in a recent meta-analysis of psilocybin for depression, no serious adverse effects were reported in any of the 7 included studies.7 Common adverse effects in the context of clinical use include anxiety, dysphoria, confusion, and an increase in blood pressure and heart rate.6 Due to potential cardiac effects, psilocybin is contraindicated in individuals with cardiovascular and cerebrovascular disease.8 In recreational/nonclinical use, reactions such as suicidality, violence, convulsions, panic attacks, paranoia, confusion, prolonged dissociation, and mania have been reported.9,10 Animal and human studies indicate the risk of abuse and physical dependence is low. Major national surveys indicate low rates of abuse, treatment-seeking, and harm.11 In a recent 6-week randomized controlled trial (RCT) of psilocybin vs escitalopram for depression,12 no serious adverse events were reported. Adverse events reported in the psilocybin group in this trial are listed in Table 2.12
A recent phase 2 double-blind trial of single-dose psilocybin (1 mg, 10 mg, and 25 mg) for treatment-resistant depression (N = 233) sheds more light on the risk of adverse effects.13 The percentage of individuals experiencing adverse effects on Day 1 of administration was high: 61% in the 25 mg psilocybin group. Headache, nausea, fatigue, and dizziness were the most common effects. The incidence of any adverse event in the 25 mg group was 56% from Day 2 to Week 3, and 29% from Week 3 to Week 12. Suicidal ideation, suicidal behavior, or self-injury occurred in all 3 dose groups. Overall, 14% in the 25 mg group, 17% in the 10 mg group, and 9% in the 1 mg group showed worsening of suicidality from baseline to Week 3. Suicidal behavior was reported by 3 individuals in the 25 mg group after Week 3. The new-onset or worsening of preexisting suicidality with psilocybin reported in this study requires further investigation.
Lysergic acid diethylamide
LSD is similar to psilocybin in its agonistic action at the 5-HT2A brain receptors.4 It is typically administered as a single 100 to 200 μg dose and is used in conjunction with preintegration and postintegration psychotherapy.14 Its acute effects last approximately 12 hours.15
Continue to: Like psilocybin...
Like psilocybin, LSD has a wide therapeutic index. Commonly reported adverse effects of LSD are increased anxiety, dysphoria, and confusion. LSD can also lead to physiological adverse effects, such as increased blood pressure and heart rate, and thus is contraindicated in patients with severe heart disease.6 In a systematic review of the therapeutic use of LSD that included 567 participants,16 2 cases of serious adverse events were reported: a tonic-clonic seizure in a patient with a prior history of seizures, and a case of prolonged psychosis in a 21-year-old with a history of psychotic disorder.
Though few psychedelic studies have examined the adverse effects of these agents in older adults, a recent phase 1 study that recruited 48 healthy older adults (age 55 to 75) found that, compared to placebo, low doses (5 to 20 μg) of LSD 2 times a week for 3 weeks had similar adverse effects, cognitive impairment, or balance impairment.17 The only adverse effect noted to be different between the placebo group and active treatment groups was headache (50% for LSD 10 μg, 25% for LSD 20 μg, and 8% for placebo). Because the dose range (5 to 20 μg) used in this study was substantially lower than the typical therapeutic dose range of 100 to 200 μg, these results should not be interpreted as supporting the safety of LSD at higher doses in older adults.
DMT/ayahuasca
Ayahuasca is a plant-based psychedelic that contains an admixture of substances, including DMT, which acts as a 5-HT2A receptor agonist. In addition to DMT, ayahuasca also contains the alkaloid harmaline, which acts as a monoamine inhibitor. Use of ayahuasca can therefore pose a particular risk for individuals taking other serotonergic or noradrenergic medications or substances. The acute effects of DMT last approximately 4 hours,18 and acute administration of ayahuasca leads to a transient modified state of consciousness that is characterized by introspection, visions, enhanced emotions, and recall of personal memories.19 Research shows ayahuasca has been dosed at approximately 0.36 mg/kg of DMT for 1 dosing session alongside 6 2-hour therapy sessions.20
A recent review by Orsolini et al21 consolidated 40 preclinical, observational, and experimental studies of ayahuasca, and this compound appeared to be safe and well-tolerated; the most common adverse effects were transient emesis and nausea. In an RCT by Palhano-Fontes et al,20 nausea was observed in 71% of participants in the ayahuasca group (vs 26% placebo), vomiting in 57% of participants (vs 0% placebo), and restlessness in 50% of participants (vs 20% placebo). The authors noted that for some participants the ayahuasca session “was not necessarily a pleasant experience,” and was accompanied by psychological distress.20 Vomiting is traditionally viewed as an expected part of the purging process of ayahuasca religious ceremonies. Another review found that there appears to be good long-term tolerability of ayahuasca consumption among individuals who use this compound in religious ceremonies.22
MDMA
Entactogens (or empathogens) are a class of psychoactive substances that produce experiences of emotional openness and connection. MDMA is an entactogen known to release serotonin, norepinephrine, and dopamine by inhibiting reuptake.23 This process leads to the stimulation of neurohormonal signaling of oxytocin, cortisol, and other signaling molecules such as brain-derived neurotrophic factor.24 Memory reconsolidation and fear extinction may also play a therapeutic role, enabled by reduced activity in the amygdala and insula, and increased connectivity between the amygdala and hippocampus.24 MDMA has been reported to enhance feelings of well-being and increase prosocial behavior.25 In the therapeutic setting, MDMA has been generally dosed at 75 to 125 mg in 2 to 3 sessions alongside 10 therapy sessions. Administration of MDMA gives the user a subjective experience of energy and distortions in time and perception.26 These acute effects last approximately 2 to 4 hours.27
Continue to: A meta-analysis...
A meta-analysis of 5 RCTs of MDMA-assisted therapy for PTSD in adults demonstrated that MDMA was well-tolerated, and few serious adverse events were reported.28 Two trials from 2018 that were included in this meta-analysis—Mithoefer et al29 and Ot’alora et al30—illustrate the incidence of specific adverse effects. In a randomized, double-blind trial of 26 veterans and first responders with chronic PTSD, Mithoefer et al29 found the most commonly reported reactions during experimental sessions with MDMA were anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), and jaw clenching or tight jaw (50%). The most commonly reported reactions during 7 days of contact were fatigue (88%), anxiety (73%), insomnia (69%), headache (46%), muscle tension (46%), and increased irritability (46%). One instance of suicidal ideation was severe enough to require psychiatric hospitalization (this was the only instance of suicidal ideation among the 106 patients in the meta-analysis by Bahji et al28); the patient subsequently completed the trial. Transient elevation in pulse, blood pressure, and body temperature were noted during sessions that did not require medical intervention.29 Ot’alora et al30 found similar common adverse reactions: anxiety, dizziness, fatigue, headache, jaw clenching, muscle tension, and irritability. There were no serious adverse effects.
While the use of MDMA in controlled interventional settings has resulted in relatively few adverse events, robust literature describes the risks associated with the nonclinical/recreational use of MDMA. In cases of MDMA toxicity, death has been reported.31 Acutely, MDMA may lead to sympathomimetic effects, including serotonin syndrome.31 Longer-term studies of MDMA users have found chronic recreational use to be associated with worse sleep, poor mood, anxiety disturbances, memory deficits, and attention problems.32 MDMA has also been found to have moderate potential for abuse.33
Ketamine/esketamine
Ketamine is a dissociative anesthetic with some hallucinogenic effects. It is an N-methyl-
Esketamine, the S(+)-enantiomer of ketamine, is also an NDMA antagonist. It has been developed as an intranasal formulation, typically dosed between 56 and 84 mg 2 times a week for 1 month, once a week for the following month, and once every 1 to 2 weeks thereafter.35 In most ketamine and esketamine trials, these compounds have been used without psychotherapy, although some interventions have integrated psychotherapy with ketamine treatment.36
Bennett et al37 elaborated on 3 paradigms for ketamine treatment: biochemical, psychotherapeutic, and psychedelic. The biochemical model examines the neurobiological effects of the medication. The psychotherapeutic model views ketamine as a way of assisting the psychotherapy process. The psychedelic model utilizes ketamine’s dissociative and psychedelic properties to induce an altered state of consciousness for therapeutic purposes and psychospiritual exploration.
Continue to: A systematic review...
A systematic review of the common adverse effects associated with ketamine use in clinical trials for depression reported dissociation, sedation, perceptual disturbances, anxiety, agitation, euphoria, hypertension, tachycardia, headache, and dizziness.38 Adverse effects experienced with esketamine in clinical trials include dissociation, dizziness, sedation, hypertension, hypoesthesia, gastrointestinal symptoms, and euphoric mood (Table 339). A recent systemic review found both ketamine and esketamine demonstrated higher adverse events than control conditions. IV ketamine also demonstrated lower dropouts and adverse events when compared to intranasal esketamine.40
Nonclinical/recreational use of ketamine is notable for urinary toxicity; 20% to 30% of frequent users of ketamine experience urinary problems that can range from ketamine-induced cystitis to hydronephrosis and kidney failure.41 Liver toxicity has also been reported with chronic use of high-dose ketamine. Ketamine is liable to abuse, dependence, and tolerance. There is evidence that nonclinical use of ketamine may lead to morbidity; impairment of memory, cognition, and attention; and urinary, gastric, and hepatic pathology.42
The FDA prescribing information for esketamine lists aneurysmal vascular disease, arteriovenous malformation, and intracerebral hemorrhage as contraindications.39 Patients with cardiovascular and cerebrovascular conditions and risk factors may be at increased risk of adverse effects due to an increase in blood pressure. Esketamine can impair attention, judgment, thinking, reaction speed, and motor skills. Other adverse effects of esketamine noted in the prescribing information include dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, vomiting, feeling drunk, and euphoric mood.39A study of postmarketing safety concerns with esketamine using reports submitted to the FDA Adverse Event Reporting System (FAERS) revealed signals for suicidal ideation (reporting odds ratio [ROR] 24.03; 95% CI, 18.72 to 30.84), and completed suicide (ROR 5.75; 95% CI, 3.18 to 10.41).43 The signals for suicidal and self-injurious ideation remained significant when compared to venlafaxine in the FAERS database, while suicide attempts and fatal suicide attempts were no longer significant.43 Concerns regarding acute ketamine withdrawal have also been described in case reports.44
Other safety considerations of psychedelics
Hallucinogen persisting perception disorder
Hallucinogen persisting perception disorder (HPPD) is a rare condition associated with hallucinogen use. It is characterized by the recurrence of perceptual disturbances that an individual experienced while using hallucinogenic substances that creates significant distress or impairment.45 Because HPPD is a rare disorder, the exact prevalence is not well characterized, but DSM-5 suggests it is approximately 4.2%.46 HPPD is associated with numerous psychoactive substances, including psilocybin, ayahuasca, MDMA, and ketamine, but is most associated with LSD.45 HPPD is more likely to arise in individuals with histories of psychiatric illness or substance use disorders.47
Serotonin toxicity and other serotonergic interactions
Serotonin toxicity is a risk of serotonergic psychedelics, particularly when such agents are used in combination with serotonergic psychotropic medications. The most severe manifestation of serotonin toxicity is serotonin syndrome, which manifests as a life-threatening condition characterized by myoclonus, rigidity, agitation, delirium, and unstable cardiovascular functioning. Many psychedelic compounds have transient serotonin-related adverse effects, but serotonin toxicity due to psychedelic use is rare.48 Due to their mechanism of action, classical psychedelics are relatively safe in combination with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors. MDMA is a serotonin-releasing agent that has a higher risk of serotonin syndrome or hypertensive crisis when used in combination with MAOIs.48
Boundary violations in psychedelic-assisted psychotherapy
A key task facing psychedelic research is to establish parameters for the safe and ethical use of these agents. This is particularly relevant given the hype that surrounds the psychedelic resurgence and what we know about the controversial history of these substances. Anderson et al49 argued that “psychedelics can have lingering effects that include increased suggestibility and affective instability, as well as altered ego structure, social behaviour, and philosophical worldview. Stated simply, psychedelics can induce a vulnerable state both during and after treatment sessions.”
Continue to: Psychedelic treatment...
Psychedelic treatments such as psilocybin and MDMA are typically offered within the context of psychedelic-assisted psychotherapy, and some researchers have raised concerns regarding boundary violations,50 given the patients’ particularly vulnerable states. In addition to concerns about sexual harassment, the financial exploitation of older adults is also a possible risk.51
Caveats to consider
Novel psychedelics therapies have demonstrated promising preliminary results for a broad range of psychiatric indications, including depression, end-of-life distress, substance use disorders, PTSD, and improving well-being. To date, psychedelics are generally well-tolerated in adults in clinical trials.
However, when it comes to adverse effects, there are challenges in regards to interpreting the psychedelic state.52 Some consider any unpleasant or unsettling psychedelic experience as an adverse reaction, while others consider it part of the therapeutic process. This is exemplified by the case of vomiting during ayahuasca ceremonies, which is generally considered part of the ritual. In such instances, it is essential to obtain informed consent and ensure participants are aware of these aspects of the experience. Compared to substances such as alcohol, opioids, and cocaine, psychedelics are remarkably safe from a physiological perspective, especially with regards to the risks of toxicity, mortality, and dependence.53 Their psychological safety is less established, and more caution and research is needed. The high incidence of adverse effects and suicidality noted in the recent phase 2 trial of psilocybin in treatment resistant depression are a reminder of this.13
There is uncertainty regarding the magnitude of risk in real-world clinical practice, particularly regarding addiction, suicidality, and precipitation or worsening of psychotic disorders. For example, note the extensive exclusion criteria used in the psilocybin vs escitalopram RCT by Carhart-Harris et al12: currently or previously diagnosed psychotic disorder, immediate family member with a diagnosed psychotic disorder, significant medical comorbidity (eg, diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure), history of suicide attempts requiring hospitalization, history of mania, pregnancy, and abnormal QT interval prolongation, among others. It would be prudent to keep these contraindications in mind regarding the clinical use of psychedelics in the future. This is particularly important in older adults because such patients often have substantial medical comorbidities and are at greater risk for adverse effects. For ketamine, research has implicated the role of mu opioid agonism in mediating ketamine’s antidepressant effects.54 This raises concerns about abuse, dependence, and addiction, especially with long-term use. There are also concerns regarding protracted withdrawal symptoms and associated suicidality.55
The therapeutic use of psychedelics is an exciting and promising avenue, with ongoing research and a rapidly evolving literature. An attitude of cautious optimism is warranted, but efficacy and safety should be demonstrated in well-designed and rigorous trials with adequate long-term follow-up before routine clinical use is recommended.
Bottom Line
In clinical trials for psychiatric disorders, psychedelics have been associated with a range of cognitive, psychiatric, and psychoactive adverse effects but generally have been well-tolerated, with a low incidence of serious adverse effects.
Related Resources
- American Psychiatric Association. Position Statement on the Use of Psychedelic and Empathogenic Agents for Mental Health Conditions. Updated July 2022. Accessed October 24, 2022. https://www.psychiatry.org/getattachment/d5c13619-ca1f-491f-a7a8-b7141c800904/Position-Use-of-Psychedelic-Empathogenic-Agents.pdf
- Johns Hopkins Center for Psychedelic & Consciousness Research. https://hopkinspsychedelic.org/
- Multidisciplinary Association for Psychedelic Studies (MAPS). https://maps.org/
Drug Brand Names
Esketamine • Spravato
Ketamine • Ketalar
Venlafaxine • Effexor
1. The current legal status of psychedelics in the United States. Investing News Network. August 23, 2022. Accessed August 26, 2022. https://investingnews.com/legal-status-of-psychedelics-in-the-united-states/
2. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177(5):391-410.
3. Nutt D, Carhart-Harris R. The current status of psychedelics in psychiatry. JAMA Psychiatry. 2021;78(2):121-122.
4. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355.
5. Hasler F, Grimberg U, Benz MA et al. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology. 2004;172:145-156.
6. Johnson MW, Hendricks PS, Barrett FS, et al. Classic psychedelics: an integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther. 2019;197:83-102.
7. Li NX, Hu YR, Chen WN, et al. Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis. J Affect Disord. 2022;296:26-34.
8. Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620.
9. Carhart-Harris RL, Nutt DJ. User perceptions of the benefits and harms of hallucinogenic drug use: a web-based questionnaire study. J Subst Use. 2010;15(4):283-300.
10. van Amsterdam J, Opperhuizen A, van den Brink W. Harm potential of magic mushroom use: a review. Regul Toxicol Pharmacol. 2011;59(3):423-429.
11. Johnson MW, Griffiths RR, Hendricks PS, et al. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 2018;142:143-166.
12. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl Med. 2021;384(15):1402-1411.
13. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant Episode of major depression. N Engl J Med. 2022;387(18):1637-1648.
14. Galvão-Coelho NL, Marx W, Gonzalez M, et al. Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology (Berl). 2021;238(2):341-354.
15. Schmid Y, Enzler F, Gasser P, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78(8):544-553.
16. Fuentes JJ, Fonseca F, Elices M, et al. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Front Psychiatry. 2020;10:943.
17. Family N, Maillet EL, Williams LTJ, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology (Berl). 2020;237(3):841-853.
18. Frecska E, Bokor P, Winkelman M. The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Front Pharmacol. 2016;7:35.
19. Domínguez-Clavé E, Solar J, Elices M, et al. Ayahuasca: pharmacology, neuroscience and therapeutic potential. Brain Res Bull. 2016;126(Pt 1):89-101.
20. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.
21. Orsolini L, Chiappini S, Papanti D, et al. How does ayahuasca work from a psychiatric perspective? Pros and cons of the entheogenic therapy. Hum Psychopharmacol: Clin Exp. 2020;35(3):e2728.
22. Durante Í, Dos Santos RG, Bouso JC, et al. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Braz J Psychiatry. 2021;43(4):362-369.
23. Sessa B, Higbed L, Nutt D. A review of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. Front Psychiatry. 2019;10:138.
24. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Progress Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):221-228.
25. Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affective Neurosc. 2014;9(11):1645-1652.
26. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001;165(7):917-928.
27. Dumont GJ, Verkes RJ. A review of acute effects of 3, 4-methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol. 2006;20(2):176-187.
28. Bahji A, Forsyth A, Groll D, et al. Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020;96:109735.
29. Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5(6):486-497.
30. Ot’alora GM, Grigsby J, Poulter B, et al. 3,4-methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295-1307.
31. Steinkellner T, Freissmuth M, Sitte HH, et al. The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and D-amphetamine. Biol Chem. 2011;392(1-2):103-115.
32. Montoya AG, Sorrentino R, Lukas SE, et al. Long-term neuropsychiatric consequences of “ecstasy” (MDMA): a review. Harvard Rev Psychiatry. 2002;10(4):212-220.
33. Yazar‐Klosinski BB, Mithoefer MC. Potential psychiatric uses for MDMA. Clin Pharmacol Ther. 2017;101(2):194-196.
34. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
35. Thase M, Connolly KR. Ketamine and esketamine for treating unipolar depression in adults: administration, efficacy, and adverse effects. Wolters Kluwer; 2019. Accessed August 26, 2022. https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
36. Dore J, Turnispeed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2):189-198.
37. Bennett R, Yavorsky C, Bravo G. Ketamine for bipolar depression: biochemical, psychotherapeutic, and psychedelic approaches. Front Psychiatry. 2022;13:867484.
38. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65-78.
39. U.S. Food and Drug Administration. SPRAVATO® (esketamine). Prescribing information. Janssen; 2020. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf
40. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affective Disord. 2021;278:542-555.
41. Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: a systematic review. Neurourol Urodyn. 2020;39(4):1049-1062.
42. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27(6):582-586.
43. Gastaldon, C, Raschi E, Kane JM, et al. Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2021;90(1):41-48.
44. Roxas N, Ahuja C, Isom J, et al. A potential case of acute ketamine withdrawal: clinical implications for the treatment of refractory depression. Am J Psychiatry. 2021;178(7):588-591.
45. Orsolini L, Papanti GD, De Berardis D, et al. The “Endless Trip” among the NPS users: psychopathology and psychopharmacology in the hallucinogen-persisting perception disorder. A systematic review. Front Psychiatry. 2017;8:240.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatry Association; 2013.
47. Martinotti G, Santacroce R, Pettorruso M, et al. Hallucinogen persisting perception disorder: etiology, clinical features, and therapeutic perspectives. Brain Sci. 2018;8(3):47.
48. Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl). 2022;239(6):1881-1891.
49. Anderson BT, Danforth AL, Grob CS. Psychedelic medicine: safety and ethical concerns. Lancet Psychiatry, 2020;7(10):829-830.
50. Goldhill O. Psychedelic therapy has a sexual abuse problem. QUARTZ. March 3, 2020. Accessed August 26, 2022. https://qz.com/1809184/psychedelic-therapy-has-a-sexual-abuse-problem-3/
51. Goldhill O. A psychedelic therapist allegedly took millions from a Holocaust survivor, highlighting worries about elders taking hallucinogens. STAT News. April 21, 2022. Accessed August 26, 2022. https://www.statnews.com/2022/04/21/psychedelic-therapist-allegedly-took-millions-from-holocaust-survivor-highlighting-worries-about-elders-taking-hallucinogens/
52. Strassman RJ. Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis. 1984;172(10):577-595.
53. Nutt D. Drugs Without the Hot Air: Minimising the Harms of Legal and Illegal Drugs. UIT Cambridge Ltd; 2012.
54. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.
55. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(6):422-424.
1. The current legal status of psychedelics in the United States. Investing News Network. August 23, 2022. Accessed August 26, 2022. https://investingnews.com/legal-status-of-psychedelics-in-the-united-states/
2. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiatry. 2020;177(5):391-410.
3. Nutt D, Carhart-Harris R. The current status of psychedelics in psychiatry. JAMA Psychiatry. 2021;78(2):121-122.
4. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355.
5. Hasler F, Grimberg U, Benz MA et al. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology. 2004;172:145-156.
6. Johnson MW, Hendricks PS, Barrett FS, et al. Classic psychedelics: an integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacol Ther. 2019;197:83-102.
7. Li NX, Hu YR, Chen WN, et al. Dose effect of psilocybin on primary and secondary depression: a preliminary systematic review and meta-analysis. J Affect Disord. 2022;296:26-34.
8. Johnson MW, Richards WA, Griffiths RR. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008;22(6):603-620.
9. Carhart-Harris RL, Nutt DJ. User perceptions of the benefits and harms of hallucinogenic drug use: a web-based questionnaire study. J Subst Use. 2010;15(4):283-300.
10. van Amsterdam J, Opperhuizen A, van den Brink W. Harm potential of magic mushroom use: a review. Regul Toxicol Pharmacol. 2011;59(3):423-429.
11. Johnson MW, Griffiths RR, Hendricks PS, et al. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 2018;142:143-166.
12. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl Med. 2021;384(15):1402-1411.
13. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for a treatment-resistant Episode of major depression. N Engl J Med. 2022;387(18):1637-1648.
14. Galvão-Coelho NL, Marx W, Gonzalez M, et al. Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology (Berl). 2021;238(2):341-354.
15. Schmid Y, Enzler F, Gasser P, et al. Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry. 2015;78(8):544-553.
16. Fuentes JJ, Fonseca F, Elices M, et al. Therapeutic use of LSD in psychiatry: a systematic review of randomized-controlled clinical trials. Front Psychiatry. 2020;10:943.
17. Family N, Maillet EL, Williams LTJ, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers. Psychopharmacology (Berl). 2020;237(3):841-853.
18. Frecska E, Bokor P, Winkelman M. The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Front Pharmacol. 2016;7:35.
19. Domínguez-Clavé E, Solar J, Elices M, et al. Ayahuasca: pharmacology, neuroscience and therapeutic potential. Brain Res Bull. 2016;126(Pt 1):89-101.
20. Palhano-Fontes F, Barreto D, Onias H, et al. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019;49(4):655-663.
21. Orsolini L, Chiappini S, Papanti D, et al. How does ayahuasca work from a psychiatric perspective? Pros and cons of the entheogenic therapy. Hum Psychopharmacol: Clin Exp. 2020;35(3):e2728.
22. Durante Í, Dos Santos RG, Bouso JC, et al. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Braz J Psychiatry. 2021;43(4):362-369.
23. Sessa B, Higbed L, Nutt D. A review of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. Front Psychiatry. 2019;10:138.
24. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Progress Neuropsychopharmacol Biol Psychiatry. 2018;84(Pt A):221-228.
25. Hysek CM, Schmid Y, Simmler LD, et al. MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affective Neurosc. 2014;9(11):1645-1652.
26. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001;165(7):917-928.
27. Dumont GJ, Verkes RJ. A review of acute effects of 3, 4-methylenedioxymethamphetamine in healthy volunteers. J Psychopharmacol. 2006;20(2):176-187.
28. Bahji A, Forsyth A, Groll D, et al. Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: a systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2020;96:109735.
29. Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5(6):486-497.
30. Ot’alora GM, Grigsby J, Poulter B, et al. 3,4-methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295-1307.
31. Steinkellner T, Freissmuth M, Sitte HH, et al. The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’), methamphetamine and D-amphetamine. Biol Chem. 2011;392(1-2):103-115.
32. Montoya AG, Sorrentino R, Lukas SE, et al. Long-term neuropsychiatric consequences of “ecstasy” (MDMA): a review. Harvard Rev Psychiatry. 2002;10(4):212-220.
33. Yazar‐Klosinski BB, Mithoefer MC. Potential psychiatric uses for MDMA. Clin Pharmacol Ther. 2017;101(2):194-196.
34. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74(4):399-405.
35. Thase M, Connolly KR. Ketamine and esketamine for treating unipolar depression in adults: administration, efficacy, and adverse effects. Wolters Kluwer; 2019. Accessed August 26, 2022. https://www.uptodate.com/contents/ketamine-and-esketamine-for-treating-unipolar-depression-in-adults-administration-efficacy-and-adverse-effects
36. Dore J, Turnispeed B, Dwyer S, et al. Ketamine assisted psychotherapy (KAP): patient demographics, clinical data and outcomes in three large practices administering ketamine with psychotherapy. J Psychoactive Drugs. 2019;51(2):189-198.
37. Bennett R, Yavorsky C, Bravo G. Ketamine for bipolar depression: biochemical, psychotherapeutic, and psychedelic approaches. Front Psychiatry. 2022;13:867484.
38. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65-78.
39. U.S. Food and Drug Administration. SPRAVATO® (esketamine). Prescribing information. Janssen; 2020. Accessed August 26, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf
40. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affective Disord. 2021;278:542-555.
41. Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: a systematic review. Neurourol Urodyn. 2020;39(4):1049-1062.
42. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27(6):582-586.
43. Gastaldon, C, Raschi E, Kane JM, et al. Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System. Psychother Psychosom. 2021;90(1):41-48.
44. Roxas N, Ahuja C, Isom J, et al. A potential case of acute ketamine withdrawal: clinical implications for the treatment of refractory depression. Am J Psychiatry. 2021;178(7):588-591.
45. Orsolini L, Papanti GD, De Berardis D, et al. The “Endless Trip” among the NPS users: psychopathology and psychopharmacology in the hallucinogen-persisting perception disorder. A systematic review. Front Psychiatry. 2017;8:240.
46. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatry Association; 2013.
47. Martinotti G, Santacroce R, Pettorruso M, et al. Hallucinogen persisting perception disorder: etiology, clinical features, and therapeutic perspectives. Brain Sci. 2018;8(3):47.
48. Malcolm B, Thomas K. Serotonin toxicity of serotonergic psychedelics. Psychopharmacology (Berl). 2022;239(6):1881-1891.
49. Anderson BT, Danforth AL, Grob CS. Psychedelic medicine: safety and ethical concerns. Lancet Psychiatry, 2020;7(10):829-830.
50. Goldhill O. Psychedelic therapy has a sexual abuse problem. QUARTZ. March 3, 2020. Accessed August 26, 2022. https://qz.com/1809184/psychedelic-therapy-has-a-sexual-abuse-problem-3/
51. Goldhill O. A psychedelic therapist allegedly took millions from a Holocaust survivor, highlighting worries about elders taking hallucinogens. STAT News. April 21, 2022. Accessed August 26, 2022. https://www.statnews.com/2022/04/21/psychedelic-therapist-allegedly-took-millions-from-holocaust-survivor-highlighting-worries-about-elders-taking-hallucinogens/
52. Strassman RJ. Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis. 1984;172(10):577-595.
53. Nutt D. Drugs Without the Hot Air: Minimising the Harms of Legal and Illegal Drugs. UIT Cambridge Ltd; 2012.
54. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205-1215.
55. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176(6):422-424.
Optimal psychiatric treatment: Target the brain and avoid the body
Pharmacotherapy for psychiatric disorders is a mixed blessing. The advent of psychotropic medications since the 1950s (antipsychotics, antidepressants, anxiolytics, mood stabilizers) has revolutionized the treatment of serious psychiatric brain disorders, allowing certain patients to be discharged to the community after a lifetime of institutionalization.
However, like all medications, psychotropic agents are often associated with various potentially intolerable symptoms (Table 1) or safety complications (Table 2) because they interact with every organ in the body besides their intended target, the brain, and its neurochemical circuitry.
Imagine if we could treat our psychiatric patients while bypassing the body and achieve response, remission, and ultimately recovery without any systemic adverse effects. Adherence would dramatically improve, our patients’ quality of life would be enhanced, and the overall effectiveness (defined as the complex package of efficacy, safety, and tolerability) would be superior to current pharmacotherapies. This is important because most psychiatric medications must be taken daily for years, even a lifetime, to avoid a relapse of the illness. Psychiatrists frequently must manage adverse effects or switch the patient to a different medication if a tolerability or safety issue emerges, which is very common in psychiatric practice. A significant part of psychopharmacologic management includes ordering various laboratory tests to monitor adverse reactions in major organs, especially the liver, kidney, and heart. Additionally, psychiatric physicians must be constantly cognizant of medications prescribed by other clinicians for comorbid medical conditions to successfully navigate the turbulent seas of pharmacokinetic interactions.
I am sure you have noticed that whenever you watch a direct-to-consumer commercial for any medication, 90% of the advertisement is a background voice listing the various tolerability and safety complications of the medication as required by the FDA. Interestingly, these ads frequently contain colorful scenery and joyful clips, which I suspect are cleverly designed to distract the audience from focusing on the list of adverse effects.
Benefits of nonpharmacologic treatments
No wonder I am a fan of psychotherapy, a well-established psychiatric treatment modality that completely avoids body tissues. It directly targets the brain without needlessly interacting with any other organ. Psychotherapy’s many benefits (improving insight, enhancing adherence, improving self-esteem, reducing risky behaviors, guiding stress management and coping skills, modifying unhealthy beliefs, and ultimately relieving symptoms such as anxiety and depression) are achieved without any somatic adverse effects! Psychotherapy has also been shown to induce neuroplasticity and reduce inflammatory biomarkers.1 Unlike FDA-approved medications, psychotherapy does not include a “package insert,” 10 to 20 pages (in small print) that mostly focus on warnings, precautions, and sundry physical adverse effects. Even the dosing of psychotherapy is left entirely up to the treating clinician!
Although I have had many gratifying results with pharmacotherapy in my practice, especially in combination with psychotherapy,2 I also have observed excellent outcomes with nonpharmacologic approaches, especially neuromodulation therapies. The best antidepressant I have ever used since my residency training days is electroconvulsive therapy (ECT). My experience is consistent with a large meta-analysis3showing a huge effect size (Cohen d = .91) in contrast to the usual effect size of .3 to .5 for standard antidepressants (except IV ketamine). A recent study showed ECT is even better than the vaunted rapid-acting ketamine,4 which is further evidence of its remarkable efficacy in depression. Neuroimaging studies report that ECT rapidly increases the volume of the hippocampus,5,6 which shrinks in size in patients with unipolar or bipolar depression.
Neuromodulation may very well be the future of psychiatric therapeutics. It targets the brain and avoids the body, thus achieving efficacy with minimal systemic tolerability (ie, patient complaints) (Table 1) or safety (abnormal laboratory test results) issues (Table 2). This sounds ideal, and it is arguably an optimal approach to repairing the brain and healing the mind.
Continue to: ECT is the oldest...
ECT is the oldest neuromodulation technique (developed almost 100 years ago and significantly refined since then). Newer FDA-approved neuromodulation therapies include repetitive transcranial magnetic stimulation (rTMS), which was approved for depression in 2013, obsessive-compulsive disorder (OCD) in 2018, smoking cessation in 2020, and anxious depression in 2021.7 Vagus nerve stimulation (VNS) is used for drug-resistant epilepsy and was later approved for treatment-resistant depression,8,9 but some studies report it can be helpful for fear and anxiety in autism spectrum disorder10 and primary insomnia.11
There are many other neuromodulation therapies in development12 that have not yet been FDA approved (Table 3). The most prominent of these is deep brain stimulation (DBS), which is approved for Parkinson disease and has been reported in many studies to improve treatment-resistant depression13,14 and OCD.15 Another promising neuromodulation therapy is transcranial direct current stimulation (tDCS), which has promising results in schizophrenia16 similar to ECT’s effects in treatment-resistant schizophrenia.17
A particularly exciting neuromodulation approach published by Stanford University researchers is Stanford accelerated intelligent neuromodulation therapy (SAINT),18 which uses intermittent theta-burst stimulation (iTBS) daily for 5 days, targeted at the subgenual anterior cingulate gyrus (Brodman area 25). Remarkably, efficacy was rapid, with a very high remission rate (absence of symptoms) in approximately 90% of patients with severe depression.18
The future is bright for neuromodulation therapies, and for a good reason. Why send a chemical agent to every cell and organ in the body when the brain can be targeted directly? As psychiatric neuroscience advances to a point where we can localize the abnormal neurologic circuit in a specific brain region for each psychiatric disorder, it will be possible to treat almost all psychiatric disorders without burdening patients with the intolerable symptoms or safety adverse effects of medications. Psychiatrists should modulate their perspective about the future of psychiatric treatments. And finally, I propose that psychotherapy should be reclassified as a “verbal neuromodulation” technique.
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Bipolar disorder: clinical questions beg for answers. Current Psychiatry. 2006;5(12):11-12.
3. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799-808.
4. Rhee TG, Shim SR, Forester BP, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry. 2022:e223352. doi:10.1001/jamapsychiatry.2022.3352
5. Nuninga JO, Mandl RCW, Boks MP, et al. Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T. Mol Psychiatry. 2020;25(7):1559-1568.
6. Joshi SH, Espinoza RT, Pirnia T, et al. Structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy in major depression. Biol Psychiatry. 2016;79(4):282-292.
7. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715.
8. Hilz MJ. Transcutaneous vagus nerve stimulation - a brief introduction and overview. Auton Neurosci. 2022;243:103038. doi:10.1016/j.autneu.2022.103038
9. Pigato G, Rosson S, Bresolin N, et al. Vagus nerve stimulation in treatment-resistant depression: a case series of long-term follow-up. J ECT. 2022. doi:10.1097/YCT.0000000000000869
10. Shivaswamy T, Souza RR, Engineer CT, et al. Vagus nerve stimulation as a treatment for fear and anxiety in individuals with autism spectrum disorder. J Psychiatr Brain Sci. 2022;7(4):e220007. doi:10.20900/jpbs.20220007
11. Wu Y, Song L, Wang X, et al. Transcutaneous vagus nerve stimulation could improve the effective rate on the quality of sleep in the treatment of primary insomnia: a randomized control trial. Brain Sci. 2022;12(10):1296. doi:10.3390/brainsci12101296
12. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37(1):102-116.
13. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.
14. Choi KS, Mayberg H. Connectomic DBS in major depression. In: Horn A, ed. Connectomic Deep Brain Stimulation. Academic Press; 2022:433-447.
15. Cruz S, Gutiérrez-Rojas L, González-Domenech P, et al. Deep brain stimulation in obsessive-compulsive disorder: results from meta-analysis. Psychiatry Res. 2022;317:114869. doi:10.1016/j.psychres.2022.114869
16. Lisoni J, Baldacci G, Nibbio G, et al. Effects of bilateral, bipolar-nonbalanced, frontal transcranial direct current stimulation (tDCS) on negative symptoms and neurocognition in a sample of patients living with schizophrenia: results of a randomized double-blind sham-controlled trial. J Psychiatr Res. 2022;155:430-442.
17. Sinclair DJ, Zhao S, Qi F, et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3(3):CD011847. doi:10.1002/14651858.CD011847.pub2
18. Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.
Pharmacotherapy for psychiatric disorders is a mixed blessing. The advent of psychotropic medications since the 1950s (antipsychotics, antidepressants, anxiolytics, mood stabilizers) has revolutionized the treatment of serious psychiatric brain disorders, allowing certain patients to be discharged to the community after a lifetime of institutionalization.
However, like all medications, psychotropic agents are often associated with various potentially intolerable symptoms (Table 1) or safety complications (Table 2) because they interact with every organ in the body besides their intended target, the brain, and its neurochemical circuitry.
Imagine if we could treat our psychiatric patients while bypassing the body and achieve response, remission, and ultimately recovery without any systemic adverse effects. Adherence would dramatically improve, our patients’ quality of life would be enhanced, and the overall effectiveness (defined as the complex package of efficacy, safety, and tolerability) would be superior to current pharmacotherapies. This is important because most psychiatric medications must be taken daily for years, even a lifetime, to avoid a relapse of the illness. Psychiatrists frequently must manage adverse effects or switch the patient to a different medication if a tolerability or safety issue emerges, which is very common in psychiatric practice. A significant part of psychopharmacologic management includes ordering various laboratory tests to monitor adverse reactions in major organs, especially the liver, kidney, and heart. Additionally, psychiatric physicians must be constantly cognizant of medications prescribed by other clinicians for comorbid medical conditions to successfully navigate the turbulent seas of pharmacokinetic interactions.
I am sure you have noticed that whenever you watch a direct-to-consumer commercial for any medication, 90% of the advertisement is a background voice listing the various tolerability and safety complications of the medication as required by the FDA. Interestingly, these ads frequently contain colorful scenery and joyful clips, which I suspect are cleverly designed to distract the audience from focusing on the list of adverse effects.
Benefits of nonpharmacologic treatments
No wonder I am a fan of psychotherapy, a well-established psychiatric treatment modality that completely avoids body tissues. It directly targets the brain without needlessly interacting with any other organ. Psychotherapy’s many benefits (improving insight, enhancing adherence, improving self-esteem, reducing risky behaviors, guiding stress management and coping skills, modifying unhealthy beliefs, and ultimately relieving symptoms such as anxiety and depression) are achieved without any somatic adverse effects! Psychotherapy has also been shown to induce neuroplasticity and reduce inflammatory biomarkers.1 Unlike FDA-approved medications, psychotherapy does not include a “package insert,” 10 to 20 pages (in small print) that mostly focus on warnings, precautions, and sundry physical adverse effects. Even the dosing of psychotherapy is left entirely up to the treating clinician!
Although I have had many gratifying results with pharmacotherapy in my practice, especially in combination with psychotherapy,2 I also have observed excellent outcomes with nonpharmacologic approaches, especially neuromodulation therapies. The best antidepressant I have ever used since my residency training days is electroconvulsive therapy (ECT). My experience is consistent with a large meta-analysis3showing a huge effect size (Cohen d = .91) in contrast to the usual effect size of .3 to .5 for standard antidepressants (except IV ketamine). A recent study showed ECT is even better than the vaunted rapid-acting ketamine,4 which is further evidence of its remarkable efficacy in depression. Neuroimaging studies report that ECT rapidly increases the volume of the hippocampus,5,6 which shrinks in size in patients with unipolar or bipolar depression.
Neuromodulation may very well be the future of psychiatric therapeutics. It targets the brain and avoids the body, thus achieving efficacy with minimal systemic tolerability (ie, patient complaints) (Table 1) or safety (abnormal laboratory test results) issues (Table 2). This sounds ideal, and it is arguably an optimal approach to repairing the brain and healing the mind.
Continue to: ECT is the oldest...
ECT is the oldest neuromodulation technique (developed almost 100 years ago and significantly refined since then). Newer FDA-approved neuromodulation therapies include repetitive transcranial magnetic stimulation (rTMS), which was approved for depression in 2013, obsessive-compulsive disorder (OCD) in 2018, smoking cessation in 2020, and anxious depression in 2021.7 Vagus nerve stimulation (VNS) is used for drug-resistant epilepsy and was later approved for treatment-resistant depression,8,9 but some studies report it can be helpful for fear and anxiety in autism spectrum disorder10 and primary insomnia.11
There are many other neuromodulation therapies in development12 that have not yet been FDA approved (Table 3). The most prominent of these is deep brain stimulation (DBS), which is approved for Parkinson disease and has been reported in many studies to improve treatment-resistant depression13,14 and OCD.15 Another promising neuromodulation therapy is transcranial direct current stimulation (tDCS), which has promising results in schizophrenia16 similar to ECT’s effects in treatment-resistant schizophrenia.17
A particularly exciting neuromodulation approach published by Stanford University researchers is Stanford accelerated intelligent neuromodulation therapy (SAINT),18 which uses intermittent theta-burst stimulation (iTBS) daily for 5 days, targeted at the subgenual anterior cingulate gyrus (Brodman area 25). Remarkably, efficacy was rapid, with a very high remission rate (absence of symptoms) in approximately 90% of patients with severe depression.18
The future is bright for neuromodulation therapies, and for a good reason. Why send a chemical agent to every cell and organ in the body when the brain can be targeted directly? As psychiatric neuroscience advances to a point where we can localize the abnormal neurologic circuit in a specific brain region for each psychiatric disorder, it will be possible to treat almost all psychiatric disorders without burdening patients with the intolerable symptoms or safety adverse effects of medications. Psychiatrists should modulate their perspective about the future of psychiatric treatments. And finally, I propose that psychotherapy should be reclassified as a “verbal neuromodulation” technique.
Pharmacotherapy for psychiatric disorders is a mixed blessing. The advent of psychotropic medications since the 1950s (antipsychotics, antidepressants, anxiolytics, mood stabilizers) has revolutionized the treatment of serious psychiatric brain disorders, allowing certain patients to be discharged to the community after a lifetime of institutionalization.
However, like all medications, psychotropic agents are often associated with various potentially intolerable symptoms (Table 1) or safety complications (Table 2) because they interact with every organ in the body besides their intended target, the brain, and its neurochemical circuitry.
Imagine if we could treat our psychiatric patients while bypassing the body and achieve response, remission, and ultimately recovery without any systemic adverse effects. Adherence would dramatically improve, our patients’ quality of life would be enhanced, and the overall effectiveness (defined as the complex package of efficacy, safety, and tolerability) would be superior to current pharmacotherapies. This is important because most psychiatric medications must be taken daily for years, even a lifetime, to avoid a relapse of the illness. Psychiatrists frequently must manage adverse effects or switch the patient to a different medication if a tolerability or safety issue emerges, which is very common in psychiatric practice. A significant part of psychopharmacologic management includes ordering various laboratory tests to monitor adverse reactions in major organs, especially the liver, kidney, and heart. Additionally, psychiatric physicians must be constantly cognizant of medications prescribed by other clinicians for comorbid medical conditions to successfully navigate the turbulent seas of pharmacokinetic interactions.
I am sure you have noticed that whenever you watch a direct-to-consumer commercial for any medication, 90% of the advertisement is a background voice listing the various tolerability and safety complications of the medication as required by the FDA. Interestingly, these ads frequently contain colorful scenery and joyful clips, which I suspect are cleverly designed to distract the audience from focusing on the list of adverse effects.
Benefits of nonpharmacologic treatments
No wonder I am a fan of psychotherapy, a well-established psychiatric treatment modality that completely avoids body tissues. It directly targets the brain without needlessly interacting with any other organ. Psychotherapy’s many benefits (improving insight, enhancing adherence, improving self-esteem, reducing risky behaviors, guiding stress management and coping skills, modifying unhealthy beliefs, and ultimately relieving symptoms such as anxiety and depression) are achieved without any somatic adverse effects! Psychotherapy has also been shown to induce neuroplasticity and reduce inflammatory biomarkers.1 Unlike FDA-approved medications, psychotherapy does not include a “package insert,” 10 to 20 pages (in small print) that mostly focus on warnings, precautions, and sundry physical adverse effects. Even the dosing of psychotherapy is left entirely up to the treating clinician!
Although I have had many gratifying results with pharmacotherapy in my practice, especially in combination with psychotherapy,2 I also have observed excellent outcomes with nonpharmacologic approaches, especially neuromodulation therapies. The best antidepressant I have ever used since my residency training days is electroconvulsive therapy (ECT). My experience is consistent with a large meta-analysis3showing a huge effect size (Cohen d = .91) in contrast to the usual effect size of .3 to .5 for standard antidepressants (except IV ketamine). A recent study showed ECT is even better than the vaunted rapid-acting ketamine,4 which is further evidence of its remarkable efficacy in depression. Neuroimaging studies report that ECT rapidly increases the volume of the hippocampus,5,6 which shrinks in size in patients with unipolar or bipolar depression.
Neuromodulation may very well be the future of psychiatric therapeutics. It targets the brain and avoids the body, thus achieving efficacy with minimal systemic tolerability (ie, patient complaints) (Table 1) or safety (abnormal laboratory test results) issues (Table 2). This sounds ideal, and it is arguably an optimal approach to repairing the brain and healing the mind.
Continue to: ECT is the oldest...
ECT is the oldest neuromodulation technique (developed almost 100 years ago and significantly refined since then). Newer FDA-approved neuromodulation therapies include repetitive transcranial magnetic stimulation (rTMS), which was approved for depression in 2013, obsessive-compulsive disorder (OCD) in 2018, smoking cessation in 2020, and anxious depression in 2021.7 Vagus nerve stimulation (VNS) is used for drug-resistant epilepsy and was later approved for treatment-resistant depression,8,9 but some studies report it can be helpful for fear and anxiety in autism spectrum disorder10 and primary insomnia.11
There are many other neuromodulation therapies in development12 that have not yet been FDA approved (Table 3). The most prominent of these is deep brain stimulation (DBS), which is approved for Parkinson disease and has been reported in many studies to improve treatment-resistant depression13,14 and OCD.15 Another promising neuromodulation therapy is transcranial direct current stimulation (tDCS), which has promising results in schizophrenia16 similar to ECT’s effects in treatment-resistant schizophrenia.17
A particularly exciting neuromodulation approach published by Stanford University researchers is Stanford accelerated intelligent neuromodulation therapy (SAINT),18 which uses intermittent theta-burst stimulation (iTBS) daily for 5 days, targeted at the subgenual anterior cingulate gyrus (Brodman area 25). Remarkably, efficacy was rapid, with a very high remission rate (absence of symptoms) in approximately 90% of patients with severe depression.18
The future is bright for neuromodulation therapies, and for a good reason. Why send a chemical agent to every cell and organ in the body when the brain can be targeted directly? As psychiatric neuroscience advances to a point where we can localize the abnormal neurologic circuit in a specific brain region for each psychiatric disorder, it will be possible to treat almost all psychiatric disorders without burdening patients with the intolerable symptoms or safety adverse effects of medications. Psychiatrists should modulate their perspective about the future of psychiatric treatments. And finally, I propose that psychotherapy should be reclassified as a “verbal neuromodulation” technique.
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Bipolar disorder: clinical questions beg for answers. Current Psychiatry. 2006;5(12):11-12.
3. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799-808.
4. Rhee TG, Shim SR, Forester BP, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry. 2022:e223352. doi:10.1001/jamapsychiatry.2022.3352
5. Nuninga JO, Mandl RCW, Boks MP, et al. Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T. Mol Psychiatry. 2020;25(7):1559-1568.
6. Joshi SH, Espinoza RT, Pirnia T, et al. Structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy in major depression. Biol Psychiatry. 2016;79(4):282-292.
7. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715.
8. Hilz MJ. Transcutaneous vagus nerve stimulation - a brief introduction and overview. Auton Neurosci. 2022;243:103038. doi:10.1016/j.autneu.2022.103038
9. Pigato G, Rosson S, Bresolin N, et al. Vagus nerve stimulation in treatment-resistant depression: a case series of long-term follow-up. J ECT. 2022. doi:10.1097/YCT.0000000000000869
10. Shivaswamy T, Souza RR, Engineer CT, et al. Vagus nerve stimulation as a treatment for fear and anxiety in individuals with autism spectrum disorder. J Psychiatr Brain Sci. 2022;7(4):e220007. doi:10.20900/jpbs.20220007
11. Wu Y, Song L, Wang X, et al. Transcutaneous vagus nerve stimulation could improve the effective rate on the quality of sleep in the treatment of primary insomnia: a randomized control trial. Brain Sci. 2022;12(10):1296. doi:10.3390/brainsci12101296
12. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37(1):102-116.
13. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.
14. Choi KS, Mayberg H. Connectomic DBS in major depression. In: Horn A, ed. Connectomic Deep Brain Stimulation. Academic Press; 2022:433-447.
15. Cruz S, Gutiérrez-Rojas L, González-Domenech P, et al. Deep brain stimulation in obsessive-compulsive disorder: results from meta-analysis. Psychiatry Res. 2022;317:114869. doi:10.1016/j.psychres.2022.114869
16. Lisoni J, Baldacci G, Nibbio G, et al. Effects of bilateral, bipolar-nonbalanced, frontal transcranial direct current stimulation (tDCS) on negative symptoms and neurocognition in a sample of patients living with schizophrenia: results of a randomized double-blind sham-controlled trial. J Psychiatr Res. 2022;155:430-442.
17. Sinclair DJ, Zhao S, Qi F, et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3(3):CD011847. doi:10.1002/14651858.CD011847.pub2
18. Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.
1. Nasrallah HA. Repositioning psychotherapy as a neurobiological intervention. Current Psychiatry. 2013;12(12):18-19.
2. Nasrallah HA. Bipolar disorder: clinical questions beg for answers. Current Psychiatry. 2006;5(12):11-12.
3. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. Lancet. 2003;361(9360):799-808.
4. Rhee TG, Shim SR, Forester BP, et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: a systematic review and meta-analysis. JAMA Psychiatry. 2022:e223352. doi:10.1001/jamapsychiatry.2022.3352
5. Nuninga JO, Mandl RCW, Boks MP, et al. Volume increase in the dentate gyrus after electroconvulsive therapy in depressed patients as measured with 7T. Mol Psychiatry. 2020;25(7):1559-1568.
6. Joshi SH, Espinoza RT, Pirnia T, et al. Structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy in major depression. Biol Psychiatry. 2016;79(4):282-292.
7. Rhee TG, Olfson M, Nierenberg AA, et al. 20-year trends in the pharmacologic treatment of bipolar disorder by psychiatrists in outpatient care settings. Am J Psychiatry. 2020;177(8):706-715.
8. Hilz MJ. Transcutaneous vagus nerve stimulation - a brief introduction and overview. Auton Neurosci. 2022;243:103038. doi:10.1016/j.autneu.2022.103038
9. Pigato G, Rosson S, Bresolin N, et al. Vagus nerve stimulation in treatment-resistant depression: a case series of long-term follow-up. J ECT. 2022. doi:10.1097/YCT.0000000000000869
10. Shivaswamy T, Souza RR, Engineer CT, et al. Vagus nerve stimulation as a treatment for fear and anxiety in individuals with autism spectrum disorder. J Psychiatr Brain Sci. 2022;7(4):e220007. doi:10.20900/jpbs.20220007
11. Wu Y, Song L, Wang X, et al. Transcutaneous vagus nerve stimulation could improve the effective rate on the quality of sleep in the treatment of primary insomnia: a randomized control trial. Brain Sci. 2022;12(10):1296. doi:10.3390/brainsci12101296
12. Rosa MA, Lisanby SH. Somatic treatments for mood disorders. Neuropsychopharmacology. 2012;37(1):102-116.
13. Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45(5):651-660.
14. Choi KS, Mayberg H. Connectomic DBS in major depression. In: Horn A, ed. Connectomic Deep Brain Stimulation. Academic Press; 2022:433-447.
15. Cruz S, Gutiérrez-Rojas L, González-Domenech P, et al. Deep brain stimulation in obsessive-compulsive disorder: results from meta-analysis. Psychiatry Res. 2022;317:114869. doi:10.1016/j.psychres.2022.114869
16. Lisoni J, Baldacci G, Nibbio G, et al. Effects of bilateral, bipolar-nonbalanced, frontal transcranial direct current stimulation (tDCS) on negative symptoms and neurocognition in a sample of patients living with schizophrenia: results of a randomized double-blind sham-controlled trial. J Psychiatr Res. 2022;155:430-442.
17. Sinclair DJ, Zhao S, Qi F, et al. Electroconvulsive therapy for treatment-resistant schizophrenia. Cochrane Database Syst Rev. 2019;3(3):CD011847. doi:10.1002/14651858.CD011847.pub2
18. Cole EJ, Stimpson KH, Bentzley BS, et al. Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry. 2020;177(8):716-726.
Should residents be taught how to prescribe monoamine oxidase inhibitors?
What else can I offer this patient?
This thought passed through my mind as the patient’s desperation grew palpable. He had experienced intractable major depressive disorder (MDD) for years and had exhausted multiple classes of antidepressants, trying various combinations without any relief.
The previous resident had arranged for intranasal ketamine treatment, but the patient was unable to receive it due to lack of transportation. As I combed through the list of the dozens of medications the patient previously had been prescribed, I noticed the absence of a certain class of agents: monoamine oxidase inhibitors (MAOIs).
My knowledge of MAOIs stemmed from medical school, where the dietary restrictions, potential for hypertensive crisis, and capricious drug-drug interactions were heavily emphasized while their value was minimized. I did not have any practical experience with these medications, and even the attending physician disclosed he had not prescribed an MAOI in more than 30 years. Nonetheless, both the attending physician and patient agreed that the patient would try one.
Following a washout period, the patient began tranylcypromine. After taking tranylcypromine 40 mg/d for 3 months, he reported he felt like a weight had been lifted off his chest. He felt less irritable and depressed, more energetic, and more hopeful for the future. He also felt that his symptoms were improving for the first time in many years.
An older but still potentially helpful class of medications
MDD is one of the leading causes of disability in the United States, affecting millions of people. Its economic burden is estimated to be more than $200 billion, with a large contingent consisting of direct medical cost and suicide-related costs.1 MDD is often recurrent—60% of patients experience another episode within 5 years.2 Most of these patients are classified as having treatment-resistant depression (TRD), which typically is defined as the failure to respond to 2 different medications given at adequate doses for a sufficient duration.3 The Sequenced Treatment Alternatives to Relieve Depression trial suggested that after each medication failure, depression becomes increasingly difficult to treat, with many patients developing TRD.4 For some patients with TRD, MAOIs may be a powerful and beneficial option.5,6 Studies have shown that MAOIs (at adequate doses) can be effective in approximately one-half of patients with TRD. Patients with anxious, endogenous, or atypical depression may also respond to MAOIs.7
MAOIs were among the earliest antidepressants on the market, starting in the late 1950s with isocarboxazid, phenelzine, tranylcypromine, and selegiline. The use of MAOIs as a treatment for depression was serendipitously discovered when iproniazid, a tuberculosis drug, was observed to have mood-elevating adverse effects that were explained by its monoamine oxidase (MAO) inhibitory properties.8 This sparked the hypothesis that a deficiency in serotonin, norepinephrine, and dopamine played a central role in depressive disorders. MAOs encompass a class of enzymes that metabolize catecholamines, which include the previously mentioned neurotransmitters and the trace amine tyramine. The MAO isoenzymes also inhabit many tissues, including the central and peripheral nervous system, liver, and intestines.
There are 2 subtypes of MAOs: MAO-A and MAO-B. MAO-A inhibits tyramine, serotonin, norepinephrine, and dopamine. MAO-B is mainly responsible for the degradation of dopamine, which makes MAO-B inhibitors (ie, rasagiline) useful in treating Parkinson disease.9
Continue to: For most psychiatrists...
For most psychiatrists, MAOIs have fallen out of favor due to their discomfort with their potential adverse effects and drug-drug interactions, the dietary restrictions patients must face, and the perception that newer medications have fewer adverse effects.10 Prescribing an MAOI requires the clinician to remain vigilant of any new medication the patient is taking that may potentiate intrasynaptic serotonin, which may include certain antibiotics or analgesics, causing serotonin syndrome. Close monitoring of the patient’s diet also is necessary so the patient avoids foods rich in tyramine that may trigger a hypertensive crisis. This is because excess tyramine can precipitate an increase in catecholamine release, causing a dangerous increase in blood pressure. However, many foods have safe levels of tyramine (<6 mg/serving), although the perception of tyramine levels in modern foods remains overestimated.5
Residents need to know how to use MAOIs
Psychiatrists should weigh the risks and benefits prior to prescribing any new medication, and MAOIs should be no exception. A patient’s enduring pain is often overshadowed by the potential for adverse effects, which occasionally is overemphasized. Other treatments for severe psychiatric illnesses (such as lithium and clozapine) are also declining due to these agents’ requirement for cumbersome monitoring and potential for adverse effects despite evidence of their superior efficacy and antisuicidal properties.11,12
Fortunately, there are many novel therapies available that can be effective for patients with TRD, including transcranial magnetic stimulation, ketamine, and vagal nerve stimulation. However, as psychiatrists, especially during training, our armamentarium should be equipped with all modalities of psychopharmacology. Training and teaching residents to prescribe MAOIs safely and effectively may add a glimmer of hope for an otherwise hopeless patient.
1. Greenberg PE, Fournier AA, Sisitsky T, et al. The economic burden of adults with major depressive disorder in the United States (2010 and 2018). Pharmacoeconomics. 2021;39(6):653-665.
2. Hardeveld F, Spijker J, De Graaf R, et al. Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand. 2010;122(3):184-191.
3. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134-145.
4. 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.
5. Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10(4):239-248.
6. Amsterdam JD, Shults J. MAOI efficacy and safety in advanced stage treatment-resistant depression--a retrospective study. J Affect Disord. 2005;89(1-3):183-188.
7. Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):371-386.
8. Ramachandraih CT, Subramanyam N, Bar KJ, et al. Antidepressants: from MAOIs to SSRIs and more. Indian J Psychiatry. 2011;53(2):180-182.
9. Tipton KF. 90 years of monoamine oxidase: some progress and some confusion. J Neural Transm (Vienna). 2018;125(11):1519-1551.
10. Gillman PK, Feinberg SS, Fochtmann LJ. Revitalizing monoamine oxidase inhibitors: a call for action. CNS Spectr. 2020;25(4):452-454.
11. Kelly DL, Wehring HJ, Vyas G. Current status of clozapine in the United States. Shanghai Arch Psychiatry. 2012;24(2):110-113.
12. Tibrewal P, Ng T, Bastiampillai T, et al. Why is lithium use declining? Asian J Psychiatr. 2019;43:219-220.
What else can I offer this patient?
This thought passed through my mind as the patient’s desperation grew palpable. He had experienced intractable major depressive disorder (MDD) for years and had exhausted multiple classes of antidepressants, trying various combinations without any relief.
The previous resident had arranged for intranasal ketamine treatment, but the patient was unable to receive it due to lack of transportation. As I combed through the list of the dozens of medications the patient previously had been prescribed, I noticed the absence of a certain class of agents: monoamine oxidase inhibitors (MAOIs).
My knowledge of MAOIs stemmed from medical school, where the dietary restrictions, potential for hypertensive crisis, and capricious drug-drug interactions were heavily emphasized while their value was minimized. I did not have any practical experience with these medications, and even the attending physician disclosed he had not prescribed an MAOI in more than 30 years. Nonetheless, both the attending physician and patient agreed that the patient would try one.
Following a washout period, the patient began tranylcypromine. After taking tranylcypromine 40 mg/d for 3 months, he reported he felt like a weight had been lifted off his chest. He felt less irritable and depressed, more energetic, and more hopeful for the future. He also felt that his symptoms were improving for the first time in many years.
An older but still potentially helpful class of medications
MDD is one of the leading causes of disability in the United States, affecting millions of people. Its economic burden is estimated to be more than $200 billion, with a large contingent consisting of direct medical cost and suicide-related costs.1 MDD is often recurrent—60% of patients experience another episode within 5 years.2 Most of these patients are classified as having treatment-resistant depression (TRD), which typically is defined as the failure to respond to 2 different medications given at adequate doses for a sufficient duration.3 The Sequenced Treatment Alternatives to Relieve Depression trial suggested that after each medication failure, depression becomes increasingly difficult to treat, with many patients developing TRD.4 For some patients with TRD, MAOIs may be a powerful and beneficial option.5,6 Studies have shown that MAOIs (at adequate doses) can be effective in approximately one-half of patients with TRD. Patients with anxious, endogenous, or atypical depression may also respond to MAOIs.7
MAOIs were among the earliest antidepressants on the market, starting in the late 1950s with isocarboxazid, phenelzine, tranylcypromine, and selegiline. The use of MAOIs as a treatment for depression was serendipitously discovered when iproniazid, a tuberculosis drug, was observed to have mood-elevating adverse effects that were explained by its monoamine oxidase (MAO) inhibitory properties.8 This sparked the hypothesis that a deficiency in serotonin, norepinephrine, and dopamine played a central role in depressive disorders. MAOs encompass a class of enzymes that metabolize catecholamines, which include the previously mentioned neurotransmitters and the trace amine tyramine. The MAO isoenzymes also inhabit many tissues, including the central and peripheral nervous system, liver, and intestines.
There are 2 subtypes of MAOs: MAO-A and MAO-B. MAO-A inhibits tyramine, serotonin, norepinephrine, and dopamine. MAO-B is mainly responsible for the degradation of dopamine, which makes MAO-B inhibitors (ie, rasagiline) useful in treating Parkinson disease.9
Continue to: For most psychiatrists...
For most psychiatrists, MAOIs have fallen out of favor due to their discomfort with their potential adverse effects and drug-drug interactions, the dietary restrictions patients must face, and the perception that newer medications have fewer adverse effects.10 Prescribing an MAOI requires the clinician to remain vigilant of any new medication the patient is taking that may potentiate intrasynaptic serotonin, which may include certain antibiotics or analgesics, causing serotonin syndrome. Close monitoring of the patient’s diet also is necessary so the patient avoids foods rich in tyramine that may trigger a hypertensive crisis. This is because excess tyramine can precipitate an increase in catecholamine release, causing a dangerous increase in blood pressure. However, many foods have safe levels of tyramine (<6 mg/serving), although the perception of tyramine levels in modern foods remains overestimated.5
Residents need to know how to use MAOIs
Psychiatrists should weigh the risks and benefits prior to prescribing any new medication, and MAOIs should be no exception. A patient’s enduring pain is often overshadowed by the potential for adverse effects, which occasionally is overemphasized. Other treatments for severe psychiatric illnesses (such as lithium and clozapine) are also declining due to these agents’ requirement for cumbersome monitoring and potential for adverse effects despite evidence of their superior efficacy and antisuicidal properties.11,12
Fortunately, there are many novel therapies available that can be effective for patients with TRD, including transcranial magnetic stimulation, ketamine, and vagal nerve stimulation. However, as psychiatrists, especially during training, our armamentarium should be equipped with all modalities of psychopharmacology. Training and teaching residents to prescribe MAOIs safely and effectively may add a glimmer of hope for an otherwise hopeless patient.
What else can I offer this patient?
This thought passed through my mind as the patient’s desperation grew palpable. He had experienced intractable major depressive disorder (MDD) for years and had exhausted multiple classes of antidepressants, trying various combinations without any relief.
The previous resident had arranged for intranasal ketamine treatment, but the patient was unable to receive it due to lack of transportation. As I combed through the list of the dozens of medications the patient previously had been prescribed, I noticed the absence of a certain class of agents: monoamine oxidase inhibitors (MAOIs).
My knowledge of MAOIs stemmed from medical school, where the dietary restrictions, potential for hypertensive crisis, and capricious drug-drug interactions were heavily emphasized while their value was minimized. I did not have any practical experience with these medications, and even the attending physician disclosed he had not prescribed an MAOI in more than 30 years. Nonetheless, both the attending physician and patient agreed that the patient would try one.
Following a washout period, the patient began tranylcypromine. After taking tranylcypromine 40 mg/d for 3 months, he reported he felt like a weight had been lifted off his chest. He felt less irritable and depressed, more energetic, and more hopeful for the future. He also felt that his symptoms were improving for the first time in many years.
An older but still potentially helpful class of medications
MDD is one of the leading causes of disability in the United States, affecting millions of people. Its economic burden is estimated to be more than $200 billion, with a large contingent consisting of direct medical cost and suicide-related costs.1 MDD is often recurrent—60% of patients experience another episode within 5 years.2 Most of these patients are classified as having treatment-resistant depression (TRD), which typically is defined as the failure to respond to 2 different medications given at adequate doses for a sufficient duration.3 The Sequenced Treatment Alternatives to Relieve Depression trial suggested that after each medication failure, depression becomes increasingly difficult to treat, with many patients developing TRD.4 For some patients with TRD, MAOIs may be a powerful and beneficial option.5,6 Studies have shown that MAOIs (at adequate doses) can be effective in approximately one-half of patients with TRD. Patients with anxious, endogenous, or atypical depression may also respond to MAOIs.7
MAOIs were among the earliest antidepressants on the market, starting in the late 1950s with isocarboxazid, phenelzine, tranylcypromine, and selegiline. The use of MAOIs as a treatment for depression was serendipitously discovered when iproniazid, a tuberculosis drug, was observed to have mood-elevating adverse effects that were explained by its monoamine oxidase (MAO) inhibitory properties.8 This sparked the hypothesis that a deficiency in serotonin, norepinephrine, and dopamine played a central role in depressive disorders. MAOs encompass a class of enzymes that metabolize catecholamines, which include the previously mentioned neurotransmitters and the trace amine tyramine. The MAO isoenzymes also inhabit many tissues, including the central and peripheral nervous system, liver, and intestines.
There are 2 subtypes of MAOs: MAO-A and MAO-B. MAO-A inhibits tyramine, serotonin, norepinephrine, and dopamine. MAO-B is mainly responsible for the degradation of dopamine, which makes MAO-B inhibitors (ie, rasagiline) useful in treating Parkinson disease.9
Continue to: For most psychiatrists...
For most psychiatrists, MAOIs have fallen out of favor due to their discomfort with their potential adverse effects and drug-drug interactions, the dietary restrictions patients must face, and the perception that newer medications have fewer adverse effects.10 Prescribing an MAOI requires the clinician to remain vigilant of any new medication the patient is taking that may potentiate intrasynaptic serotonin, which may include certain antibiotics or analgesics, causing serotonin syndrome. Close monitoring of the patient’s diet also is necessary so the patient avoids foods rich in tyramine that may trigger a hypertensive crisis. This is because excess tyramine can precipitate an increase in catecholamine release, causing a dangerous increase in blood pressure. However, many foods have safe levels of tyramine (<6 mg/serving), although the perception of tyramine levels in modern foods remains overestimated.5
Residents need to know how to use MAOIs
Psychiatrists should weigh the risks and benefits prior to prescribing any new medication, and MAOIs should be no exception. A patient’s enduring pain is often overshadowed by the potential for adverse effects, which occasionally is overemphasized. Other treatments for severe psychiatric illnesses (such as lithium and clozapine) are also declining due to these agents’ requirement for cumbersome monitoring and potential for adverse effects despite evidence of their superior efficacy and antisuicidal properties.11,12
Fortunately, there are many novel therapies available that can be effective for patients with TRD, including transcranial magnetic stimulation, ketamine, and vagal nerve stimulation. However, as psychiatrists, especially during training, our armamentarium should be equipped with all modalities of psychopharmacology. Training and teaching residents to prescribe MAOIs safely and effectively may add a glimmer of hope for an otherwise hopeless patient.
1. Greenberg PE, Fournier AA, Sisitsky T, et al. The economic burden of adults with major depressive disorder in the United States (2010 and 2018). Pharmacoeconomics. 2021;39(6):653-665.
2. Hardeveld F, Spijker J, De Graaf R, et al. Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand. 2010;122(3):184-191.
3. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134-145.
4. 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.
5. Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10(4):239-248.
6. Amsterdam JD, Shults J. MAOI efficacy and safety in advanced stage treatment-resistant depression--a retrospective study. J Affect Disord. 2005;89(1-3):183-188.
7. Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):371-386.
8. Ramachandraih CT, Subramanyam N, Bar KJ, et al. Antidepressants: from MAOIs to SSRIs and more. Indian J Psychiatry. 2011;53(2):180-182.
9. Tipton KF. 90 years of monoamine oxidase: some progress and some confusion. J Neural Transm (Vienna). 2018;125(11):1519-1551.
10. Gillman PK, Feinberg SS, Fochtmann LJ. Revitalizing monoamine oxidase inhibitors: a call for action. CNS Spectr. 2020;25(4):452-454.
11. Kelly DL, Wehring HJ, Vyas G. Current status of clozapine in the United States. Shanghai Arch Psychiatry. 2012;24(2):110-113.
12. Tibrewal P, Ng T, Bastiampillai T, et al. Why is lithium use declining? Asian J Psychiatr. 2019;43:219-220.
1. Greenberg PE, Fournier AA, Sisitsky T, et al. The economic burden of adults with major depressive disorder in the United States (2010 and 2018). Pharmacoeconomics. 2021;39(6):653-665.
2. Hardeveld F, Spijker J, De Graaf R, et al. Prevalence and predictors of recurrence of major depressive disorder in the adult population. Acta Psychiatr Scand. 2010;122(3):184-191.
3. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020;37(2):134-145.
4. 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.
5. Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10(4):239-248.
6. Amsterdam JD, Shults J. MAOI efficacy and safety in advanced stage treatment-resistant depression--a retrospective study. J Affect Disord. 2005;89(1-3):183-188.
7. Amsterdam JD, Hornig-Rohan M. Treatment algorithms in treatment-resistant depression. Psychiatr Clin North Am. 1996;19(2):371-386.
8. Ramachandraih CT, Subramanyam N, Bar KJ, et al. Antidepressants: from MAOIs to SSRIs and more. Indian J Psychiatry. 2011;53(2):180-182.
9. Tipton KF. 90 years of monoamine oxidase: some progress and some confusion. J Neural Transm (Vienna). 2018;125(11):1519-1551.
10. Gillman PK, Feinberg SS, Fochtmann LJ. Revitalizing monoamine oxidase inhibitors: a call for action. CNS Spectr. 2020;25(4):452-454.
11. Kelly DL, Wehring HJ, Vyas G. Current status of clozapine in the United States. Shanghai Arch Psychiatry. 2012;24(2):110-113.
12. Tibrewal P, Ng T, Bastiampillai T, et al. Why is lithium use declining? Asian J Psychiatr. 2019;43:219-220.
