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Microdosing psychedelics: Untapped potential in psychiatry?
In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.
Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.
Although psychedelics remain illegal for both recreational and therapeutic use, they are increasingly being studied at academic centers, and there is hope that they will offer something that our traditional medications might not. However, these are not “micro” doses, but full doses of psychedelic agents that induce clinically-monitored “trips” in order to treat conditions such as depression, anorexia nervosa, or for smoking cessation, to name just a few.
Yet
Because these drugs are illegal under most circumstances, many of the studies involve surveys of users in their natural environments who are already microdosing in an uncontrolled manner. In a 2019 study published in PLOS One, Vince Polito and Richard Stevenson, from Macquarie University, Sydney, gave daily surveys of psychological functioning to 98 microdosers over 6 weeks. Several participants were excluded for using doses that were too high or for concurrent use of other illicit substances.
Whereas the authors found that many people claimed to have positive experiences, there was an increase in neuroticism in some of the subjects. There was no control group and no uniformity to what the subject claimed to be ingesting with regard to dose, frequency, substance, or verification of the chemical content.
University of Chicago neuroscientist Harriet De Wit, PhD, leads one of the few laboratories that conducts controlled, double-blind studies looking at microdosing LSD.
“With microdosing there are expectations, and we don’t know if it’s the expectation or the agent that is making a difference,” she explained. And when asked who in her experience is experimenting with microdosing psychedelics, she expounded “Everybody under the sun!”
Dr. De Wit notes that people microdose to increase their creativity, productivity, focus, and energy, to heighten their spiritual awareness, improve empathy and social relational skills, and to improve their mood – all purported benefits of low-dose psychedelics.
Her group published a study in Addiction Biology, in which 39 subjects were administered low doses of LSD four times over 2 weeks. To address the issues of expectation, the subjects were not told they were participating in a study of hallucinogens specifically but were instead given a list of pharmaceuticals in different classes that they might be given. Microdoses of LSD did not improve either mood or performance, but they did appear to be safe, and they produced no adverse effects.
To date, studies on microdosing have looked at their effects on healthy populations, and the practice has been associated with “Silicon Valley techies” looking for performance enhancement. Ms. Waldman, however, is different.
She is open about her diagnosis of bipolar disorder, and her long history with therapy and medications. As she describes herself in the beginning of her book, she is emotionally uncomfortable, and both irritable and reactive to the point that her life is propelled by interpersonal chaos. In her uncontrolled ‘study,’ she is an N of 1, and she is pleased with the results. Microdosing, she believes, helped her become less irritable, more resilient, and in fact, have some very good days.
By the end of her memoir, she was looking for a way to continue microdosing but was unsure how to safely obtain more LSD and be certain of its purity. Her experience does raise the possibility that microdoses may have therapeutic benefits in people with certain psychiatric conditions, but this has yet to be studied.
J. Raymond DePaulo Jr., MD, is the chair of the National Network of Depression Centers and a distinguished service professor at Johns Hopkins Hospital, Baltimore. “Microdosing of psychedelics is very problematic for two equally serious reasons,” he cautioned. “There is no control over what it is that people are actually taking, it is completely unstudied scientifically, and there is no agreement on what a ‘micro’ dose is.”
He noted that one of his patients thought he was taking psilocybin. A chemical analysis was done that revealed the agent to contain a combination of THC, a stimulant, morphine, and fluoxetine. There wasn’t a trace of psilocybin. “Mislabeling is the rule, not the exception,” Dr. DePaulo has concluded.
He also believes the placebo effect has a powerful role with microdosing. “It’s not working because of what is in the pill, more likely it is working because of what is advertised to be in it.”
Ms. De Wit noted that when she started her study, she tried to find people who were elevated on measures of depression or anxiety, but she was not looking for a specific clinical population of patients with these clinical diagnoses. “We found a handful of people, and they improved, but so did those in the placebo group; they all got better.”
Psychedelic agents interact with antidepressants, so subjects in controlled studies need to go off their medications before enrolling – this is a limiting factor in studies of both macro- and microdosing. Ms. De Wit also notes that there are logistical and practical obstacles – it is difficult to get approval to use these agents, and the patients have to remain in the lab and be observed for several hours after they are administered, just as with standard doses.
As might be expected, data collection and anecdotal microdosing experiences are rampant on the internet. The social media forum Reddit alone boasts 192,000 members in its microdosing group, while Imperial College London invites microdosers to take part in surveys intended to add to the body of knowledge. But despite its popularity, there is little in the way of prospective, agent-verified, placebo-controlled research exploring whether or not microdosing is truly beneficial beyond just anecdotal evidence.
Perhaps microdosing is a fad, or perhaps it offers some benefits to some people. Given the current interest in the therapeutic uses of psychedelics, it would be useful to have controlled studies of lower doses that don’t carry the risk of “bad trips.”
Certainly, psychiatry could use more agents to address mental health issues, and society might benefit from the use of agents that are proven to be evidence-based options for improving creativity and productivity. Anything that has potential to reduce psychiatric suffering seems worthy of further study to delineate which populations could be helped or harmed.
Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.
A version of this article first appeared on Medscape.com.
In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.
Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.
Although psychedelics remain illegal for both recreational and therapeutic use, they are increasingly being studied at academic centers, and there is hope that they will offer something that our traditional medications might not. However, these are not “micro” doses, but full doses of psychedelic agents that induce clinically-monitored “trips” in order to treat conditions such as depression, anorexia nervosa, or for smoking cessation, to name just a few.
Yet
Because these drugs are illegal under most circumstances, many of the studies involve surveys of users in their natural environments who are already microdosing in an uncontrolled manner. In a 2019 study published in PLOS One, Vince Polito and Richard Stevenson, from Macquarie University, Sydney, gave daily surveys of psychological functioning to 98 microdosers over 6 weeks. Several participants were excluded for using doses that were too high or for concurrent use of other illicit substances.
Whereas the authors found that many people claimed to have positive experiences, there was an increase in neuroticism in some of the subjects. There was no control group and no uniformity to what the subject claimed to be ingesting with regard to dose, frequency, substance, or verification of the chemical content.
University of Chicago neuroscientist Harriet De Wit, PhD, leads one of the few laboratories that conducts controlled, double-blind studies looking at microdosing LSD.
“With microdosing there are expectations, and we don’t know if it’s the expectation or the agent that is making a difference,” she explained. And when asked who in her experience is experimenting with microdosing psychedelics, she expounded “Everybody under the sun!”
Dr. De Wit notes that people microdose to increase their creativity, productivity, focus, and energy, to heighten their spiritual awareness, improve empathy and social relational skills, and to improve their mood – all purported benefits of low-dose psychedelics.
Her group published a study in Addiction Biology, in which 39 subjects were administered low doses of LSD four times over 2 weeks. To address the issues of expectation, the subjects were not told they were participating in a study of hallucinogens specifically but were instead given a list of pharmaceuticals in different classes that they might be given. Microdoses of LSD did not improve either mood or performance, but they did appear to be safe, and they produced no adverse effects.
To date, studies on microdosing have looked at their effects on healthy populations, and the practice has been associated with “Silicon Valley techies” looking for performance enhancement. Ms. Waldman, however, is different.
She is open about her diagnosis of bipolar disorder, and her long history with therapy and medications. As she describes herself in the beginning of her book, she is emotionally uncomfortable, and both irritable and reactive to the point that her life is propelled by interpersonal chaos. In her uncontrolled ‘study,’ she is an N of 1, and she is pleased with the results. Microdosing, she believes, helped her become less irritable, more resilient, and in fact, have some very good days.
By the end of her memoir, she was looking for a way to continue microdosing but was unsure how to safely obtain more LSD and be certain of its purity. Her experience does raise the possibility that microdoses may have therapeutic benefits in people with certain psychiatric conditions, but this has yet to be studied.
J. Raymond DePaulo Jr., MD, is the chair of the National Network of Depression Centers and a distinguished service professor at Johns Hopkins Hospital, Baltimore. “Microdosing of psychedelics is very problematic for two equally serious reasons,” he cautioned. “There is no control over what it is that people are actually taking, it is completely unstudied scientifically, and there is no agreement on what a ‘micro’ dose is.”
He noted that one of his patients thought he was taking psilocybin. A chemical analysis was done that revealed the agent to contain a combination of THC, a stimulant, morphine, and fluoxetine. There wasn’t a trace of psilocybin. “Mislabeling is the rule, not the exception,” Dr. DePaulo has concluded.
He also believes the placebo effect has a powerful role with microdosing. “It’s not working because of what is in the pill, more likely it is working because of what is advertised to be in it.”
Ms. De Wit noted that when she started her study, she tried to find people who were elevated on measures of depression or anxiety, but she was not looking for a specific clinical population of patients with these clinical diagnoses. “We found a handful of people, and they improved, but so did those in the placebo group; they all got better.”
Psychedelic agents interact with antidepressants, so subjects in controlled studies need to go off their medications before enrolling – this is a limiting factor in studies of both macro- and microdosing. Ms. De Wit also notes that there are logistical and practical obstacles – it is difficult to get approval to use these agents, and the patients have to remain in the lab and be observed for several hours after they are administered, just as with standard doses.
As might be expected, data collection and anecdotal microdosing experiences are rampant on the internet. The social media forum Reddit alone boasts 192,000 members in its microdosing group, while Imperial College London invites microdosers to take part in surveys intended to add to the body of knowledge. But despite its popularity, there is little in the way of prospective, agent-verified, placebo-controlled research exploring whether or not microdosing is truly beneficial beyond just anecdotal evidence.
Perhaps microdosing is a fad, or perhaps it offers some benefits to some people. Given the current interest in the therapeutic uses of psychedelics, it would be useful to have controlled studies of lower doses that don’t carry the risk of “bad trips.”
Certainly, psychiatry could use more agents to address mental health issues, and society might benefit from the use of agents that are proven to be evidence-based options for improving creativity and productivity. Anything that has potential to reduce psychiatric suffering seems worthy of further study to delineate which populations could be helped or harmed.
Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.
A version of this article first appeared on Medscape.com.
In her month-long memoir, A Really Good Day: How Microdosing Made a Mega Difference in My Mood, My Marriage, and My Life (Knopf, 2017), author Ayelet Waldman turns herself into a one-woman experiment.
Over a single month she takes one-tenth of a recreational dose of LSD every third day. She plots her emotions, her productivity, and her pain along the way. Ms. Waldman obtains the LSD in a single vial, enough for 10 doses, from a researcher, who is retiring. What she’s looking for, she tells the reader, is a really good day – something that has been elusive in her turbulent life.
Although psychedelics remain illegal for both recreational and therapeutic use, they are increasingly being studied at academic centers, and there is hope that they will offer something that our traditional medications might not. However, these are not “micro” doses, but full doses of psychedelic agents that induce clinically-monitored “trips” in order to treat conditions such as depression, anorexia nervosa, or for smoking cessation, to name just a few.
Yet
Because these drugs are illegal under most circumstances, many of the studies involve surveys of users in their natural environments who are already microdosing in an uncontrolled manner. In a 2019 study published in PLOS One, Vince Polito and Richard Stevenson, from Macquarie University, Sydney, gave daily surveys of psychological functioning to 98 microdosers over 6 weeks. Several participants were excluded for using doses that were too high or for concurrent use of other illicit substances.
Whereas the authors found that many people claimed to have positive experiences, there was an increase in neuroticism in some of the subjects. There was no control group and no uniformity to what the subject claimed to be ingesting with regard to dose, frequency, substance, or verification of the chemical content.
University of Chicago neuroscientist Harriet De Wit, PhD, leads one of the few laboratories that conducts controlled, double-blind studies looking at microdosing LSD.
“With microdosing there are expectations, and we don’t know if it’s the expectation or the agent that is making a difference,” she explained. And when asked who in her experience is experimenting with microdosing psychedelics, she expounded “Everybody under the sun!”
Dr. De Wit notes that people microdose to increase their creativity, productivity, focus, and energy, to heighten their spiritual awareness, improve empathy and social relational skills, and to improve their mood – all purported benefits of low-dose psychedelics.
Her group published a study in Addiction Biology, in which 39 subjects were administered low doses of LSD four times over 2 weeks. To address the issues of expectation, the subjects were not told they were participating in a study of hallucinogens specifically but were instead given a list of pharmaceuticals in different classes that they might be given. Microdoses of LSD did not improve either mood or performance, but they did appear to be safe, and they produced no adverse effects.
To date, studies on microdosing have looked at their effects on healthy populations, and the practice has been associated with “Silicon Valley techies” looking for performance enhancement. Ms. Waldman, however, is different.
She is open about her diagnosis of bipolar disorder, and her long history with therapy and medications. As she describes herself in the beginning of her book, she is emotionally uncomfortable, and both irritable and reactive to the point that her life is propelled by interpersonal chaos. In her uncontrolled ‘study,’ she is an N of 1, and she is pleased with the results. Microdosing, she believes, helped her become less irritable, more resilient, and in fact, have some very good days.
By the end of her memoir, she was looking for a way to continue microdosing but was unsure how to safely obtain more LSD and be certain of its purity. Her experience does raise the possibility that microdoses may have therapeutic benefits in people with certain psychiatric conditions, but this has yet to be studied.
J. Raymond DePaulo Jr., MD, is the chair of the National Network of Depression Centers and a distinguished service professor at Johns Hopkins Hospital, Baltimore. “Microdosing of psychedelics is very problematic for two equally serious reasons,” he cautioned. “There is no control over what it is that people are actually taking, it is completely unstudied scientifically, and there is no agreement on what a ‘micro’ dose is.”
He noted that one of his patients thought he was taking psilocybin. A chemical analysis was done that revealed the agent to contain a combination of THC, a stimulant, morphine, and fluoxetine. There wasn’t a trace of psilocybin. “Mislabeling is the rule, not the exception,” Dr. DePaulo has concluded.
He also believes the placebo effect has a powerful role with microdosing. “It’s not working because of what is in the pill, more likely it is working because of what is advertised to be in it.”
Ms. De Wit noted that when she started her study, she tried to find people who were elevated on measures of depression or anxiety, but she was not looking for a specific clinical population of patients with these clinical diagnoses. “We found a handful of people, and they improved, but so did those in the placebo group; they all got better.”
Psychedelic agents interact with antidepressants, so subjects in controlled studies need to go off their medications before enrolling – this is a limiting factor in studies of both macro- and microdosing. Ms. De Wit also notes that there are logistical and practical obstacles – it is difficult to get approval to use these agents, and the patients have to remain in the lab and be observed for several hours after they are administered, just as with standard doses.
As might be expected, data collection and anecdotal microdosing experiences are rampant on the internet. The social media forum Reddit alone boasts 192,000 members in its microdosing group, while Imperial College London invites microdosers to take part in surveys intended to add to the body of knowledge. But despite its popularity, there is little in the way of prospective, agent-verified, placebo-controlled research exploring whether or not microdosing is truly beneficial beyond just anecdotal evidence.
Perhaps microdosing is a fad, or perhaps it offers some benefits to some people. Given the current interest in the therapeutic uses of psychedelics, it would be useful to have controlled studies of lower doses that don’t carry the risk of “bad trips.”
Certainly, psychiatry could use more agents to address mental health issues, and society might benefit from the use of agents that are proven to be evidence-based options for improving creativity and productivity. Anything that has potential to reduce psychiatric suffering seems worthy of further study to delineate which populations could be helped or harmed.
Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is assistant professor of psychiatry and behavioral sciences at Johns Hopkins in Baltimore. Dr. Miller has no conflicts of interest.
A version of this article first appeared on Medscape.com.
Psychotropic med use tied to ‘striking’ post-COVID dementia risk
, new research suggests.
Results from a large study of more than 1,700 patients who had been hospitalized with COVID showed a greater than twofold increased risk for post-COVID dementia in those taking antipsychotics and mood stabilizers/anticonvulsants – medications often used to treat schizophrenia, psychosis, bipolar disorder, and seizures.
“We know that pre-existing psychiatric illness is associated with poor COVID-19 outcomes, but our study is the first to show an association with certain psychiatric medications and dementia,” co-investigator Liron Sinvani, MD, the Feinstein Institutes for Medical Research, Manhasset, New York, said in an interview.
“Our study highlights the potential interaction between baseline neuropsychiatric disease, psychotropic medications, COVID-19, and dementia,” Dr. Sinvani added.
The findings were published online March 18 in Frontiers in Medicine.
‘Striking’ dementia rate
Using electronic health records, the researchers evaluated pre-COVID psychotropic medication use and post-COVID dementia onset in 1,755 adults aged 65 and older. All were hospitalized with COVID-19 at Northwell Health between March 1 and April 20, 2020.
A “striking” 13% of the participants (n = 223) developed dementia within 1-year of follow-up, the investigators report.
Among the 438 patients (25%) exposed to at least one psychotropic medication before COVID-19, 105 (24%) developed dementia in the year following COVID versus 118 of 1,317 (9%) patients with no pre-COVID exposure to psychotropic medication (odds ratio, 3.2; 95% confidence interval, 2.37-4.32).
Both pre-COVID psychotropic medication use (OR, 2.7; 95% CI, 1.8-4.0, P < .001) and delirium (OR, 3.0; 95% CI, 1.9-4.6, P < .001) were significantly associated with post-COVID dementia at 1 year.
In a sensitivity analysis in the subset of 423 patients with at least one documented neurologic or psychiatric diagnosis at the time of COVID admission, and after adjusting for confounding factors, pre-COVID psychotropic medication use remained significantly linked to post-COVID dementia onset (OR, 3.09; 95% CI, 1.5-6.6, P = .002).
Drug classes most strongly associated with 1-year post-COVID dementia onset were antipsychotics (OR, 2.8, 95% CI, 1.7-4.4, P < .001) and mood stabilizers/anticonvulsants (OR, 2.4, 95% CI, 1.39-4.02, P = .001).
In a further exploratory analysis, the psychotropics valproic acid (multiple brands) and haloperidol (Haldol) had the largest association with post-COVID dementia.
Antidepressants as a class were not associated with post-COVID dementia, but the potential effects of two commonly prescribed antidepressants in older adults, mirtazapine (Remeron) and escitalopram (Lexapro), “warrant further investigation,” the researchers note.
Predictive risk marker?
“This research shows that psychotropic medications can be considered a predictive risk marker for post-COVID dementia. In patients taking psychotropic medications, COVID-19 could have accelerated progression of dementia after hospitalization,” lead author Yun Freudenberg-Hua, MD, the Feinstein Institutes, said in a news release.
It is unclear why psychotropic medications may raise the risk for dementia onset after COVID, the investigators note.
“It is intuitive that psychotropic medications indicate pre-existing neuropsychiatric conditions in which COVID-19 occurs. It is possible that psychotropic medications may potentiate the neurostructural changes that have been found in the brain of those who have recovered from COVID-19,” they write.
The sensitivity analysis in patients with documented neurologic and psychiatric diagnoses supports this interpretation.
COVID-19 may also accelerate the underlying brain disorders for which psychotropic medications were prescribed, leading to the greater incidence of post-COVID dementia, the researchers write.
“It is important to note that this study is in no way recommending people should stop taking antipsychotics but simply that clinicians need to factor in a patient’s medication history while considering post-COVID aftereffects,” Dr. Freudenberg-Hua said.
“Given that the number of patients with dementia is projected to triple in the next 30 years, these findings have significant public health implications,” Dr. Sinvani added.
She noted that “care partners and health care professionals” should look for early signs of dementia, such as forgetfulness and depressive symptoms, in their patients.
“Future studies must continue to evaluate these associations, which are key for potential future interventions to prevent dementia,” Dr. Sinvani said.
The study was funded by the National Institutes of Health. Dr. Freudenberg-Hua co-owns stock and stock options from Regeneron Pharmaceuticals. Dr. Sinvani has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a large study of more than 1,700 patients who had been hospitalized with COVID showed a greater than twofold increased risk for post-COVID dementia in those taking antipsychotics and mood stabilizers/anticonvulsants – medications often used to treat schizophrenia, psychosis, bipolar disorder, and seizures.
“We know that pre-existing psychiatric illness is associated with poor COVID-19 outcomes, but our study is the first to show an association with certain psychiatric medications and dementia,” co-investigator Liron Sinvani, MD, the Feinstein Institutes for Medical Research, Manhasset, New York, said in an interview.
“Our study highlights the potential interaction between baseline neuropsychiatric disease, psychotropic medications, COVID-19, and dementia,” Dr. Sinvani added.
The findings were published online March 18 in Frontiers in Medicine.
‘Striking’ dementia rate
Using electronic health records, the researchers evaluated pre-COVID psychotropic medication use and post-COVID dementia onset in 1,755 adults aged 65 and older. All were hospitalized with COVID-19 at Northwell Health between March 1 and April 20, 2020.
A “striking” 13% of the participants (n = 223) developed dementia within 1-year of follow-up, the investigators report.
Among the 438 patients (25%) exposed to at least one psychotropic medication before COVID-19, 105 (24%) developed dementia in the year following COVID versus 118 of 1,317 (9%) patients with no pre-COVID exposure to psychotropic medication (odds ratio, 3.2; 95% confidence interval, 2.37-4.32).
Both pre-COVID psychotropic medication use (OR, 2.7; 95% CI, 1.8-4.0, P < .001) and delirium (OR, 3.0; 95% CI, 1.9-4.6, P < .001) were significantly associated with post-COVID dementia at 1 year.
In a sensitivity analysis in the subset of 423 patients with at least one documented neurologic or psychiatric diagnosis at the time of COVID admission, and after adjusting for confounding factors, pre-COVID psychotropic medication use remained significantly linked to post-COVID dementia onset (OR, 3.09; 95% CI, 1.5-6.6, P = .002).
Drug classes most strongly associated with 1-year post-COVID dementia onset were antipsychotics (OR, 2.8, 95% CI, 1.7-4.4, P < .001) and mood stabilizers/anticonvulsants (OR, 2.4, 95% CI, 1.39-4.02, P = .001).
In a further exploratory analysis, the psychotropics valproic acid (multiple brands) and haloperidol (Haldol) had the largest association with post-COVID dementia.
Antidepressants as a class were not associated with post-COVID dementia, but the potential effects of two commonly prescribed antidepressants in older adults, mirtazapine (Remeron) and escitalopram (Lexapro), “warrant further investigation,” the researchers note.
Predictive risk marker?
“This research shows that psychotropic medications can be considered a predictive risk marker for post-COVID dementia. In patients taking psychotropic medications, COVID-19 could have accelerated progression of dementia after hospitalization,” lead author Yun Freudenberg-Hua, MD, the Feinstein Institutes, said in a news release.
It is unclear why psychotropic medications may raise the risk for dementia onset after COVID, the investigators note.
“It is intuitive that psychotropic medications indicate pre-existing neuropsychiatric conditions in which COVID-19 occurs. It is possible that psychotropic medications may potentiate the neurostructural changes that have been found in the brain of those who have recovered from COVID-19,” they write.
The sensitivity analysis in patients with documented neurologic and psychiatric diagnoses supports this interpretation.
COVID-19 may also accelerate the underlying brain disorders for which psychotropic medications were prescribed, leading to the greater incidence of post-COVID dementia, the researchers write.
“It is important to note that this study is in no way recommending people should stop taking antipsychotics but simply that clinicians need to factor in a patient’s medication history while considering post-COVID aftereffects,” Dr. Freudenberg-Hua said.
“Given that the number of patients with dementia is projected to triple in the next 30 years, these findings have significant public health implications,” Dr. Sinvani added.
She noted that “care partners and health care professionals” should look for early signs of dementia, such as forgetfulness and depressive symptoms, in their patients.
“Future studies must continue to evaluate these associations, which are key for potential future interventions to prevent dementia,” Dr. Sinvani said.
The study was funded by the National Institutes of Health. Dr. Freudenberg-Hua co-owns stock and stock options from Regeneron Pharmaceuticals. Dr. Sinvani has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Results from a large study of more than 1,700 patients who had been hospitalized with COVID showed a greater than twofold increased risk for post-COVID dementia in those taking antipsychotics and mood stabilizers/anticonvulsants – medications often used to treat schizophrenia, psychosis, bipolar disorder, and seizures.
“We know that pre-existing psychiatric illness is associated with poor COVID-19 outcomes, but our study is the first to show an association with certain psychiatric medications and dementia,” co-investigator Liron Sinvani, MD, the Feinstein Institutes for Medical Research, Manhasset, New York, said in an interview.
“Our study highlights the potential interaction between baseline neuropsychiatric disease, psychotropic medications, COVID-19, and dementia,” Dr. Sinvani added.
The findings were published online March 18 in Frontiers in Medicine.
‘Striking’ dementia rate
Using electronic health records, the researchers evaluated pre-COVID psychotropic medication use and post-COVID dementia onset in 1,755 adults aged 65 and older. All were hospitalized with COVID-19 at Northwell Health between March 1 and April 20, 2020.
A “striking” 13% of the participants (n = 223) developed dementia within 1-year of follow-up, the investigators report.
Among the 438 patients (25%) exposed to at least one psychotropic medication before COVID-19, 105 (24%) developed dementia in the year following COVID versus 118 of 1,317 (9%) patients with no pre-COVID exposure to psychotropic medication (odds ratio, 3.2; 95% confidence interval, 2.37-4.32).
Both pre-COVID psychotropic medication use (OR, 2.7; 95% CI, 1.8-4.0, P < .001) and delirium (OR, 3.0; 95% CI, 1.9-4.6, P < .001) were significantly associated with post-COVID dementia at 1 year.
In a sensitivity analysis in the subset of 423 patients with at least one documented neurologic or psychiatric diagnosis at the time of COVID admission, and after adjusting for confounding factors, pre-COVID psychotropic medication use remained significantly linked to post-COVID dementia onset (OR, 3.09; 95% CI, 1.5-6.6, P = .002).
Drug classes most strongly associated with 1-year post-COVID dementia onset were antipsychotics (OR, 2.8, 95% CI, 1.7-4.4, P < .001) and mood stabilizers/anticonvulsants (OR, 2.4, 95% CI, 1.39-4.02, P = .001).
In a further exploratory analysis, the psychotropics valproic acid (multiple brands) and haloperidol (Haldol) had the largest association with post-COVID dementia.
Antidepressants as a class were not associated with post-COVID dementia, but the potential effects of two commonly prescribed antidepressants in older adults, mirtazapine (Remeron) and escitalopram (Lexapro), “warrant further investigation,” the researchers note.
Predictive risk marker?
“This research shows that psychotropic medications can be considered a predictive risk marker for post-COVID dementia. In patients taking psychotropic medications, COVID-19 could have accelerated progression of dementia after hospitalization,” lead author Yun Freudenberg-Hua, MD, the Feinstein Institutes, said in a news release.
It is unclear why psychotropic medications may raise the risk for dementia onset after COVID, the investigators note.
“It is intuitive that psychotropic medications indicate pre-existing neuropsychiatric conditions in which COVID-19 occurs. It is possible that psychotropic medications may potentiate the neurostructural changes that have been found in the brain of those who have recovered from COVID-19,” they write.
The sensitivity analysis in patients with documented neurologic and psychiatric diagnoses supports this interpretation.
COVID-19 may also accelerate the underlying brain disorders for which psychotropic medications were prescribed, leading to the greater incidence of post-COVID dementia, the researchers write.
“It is important to note that this study is in no way recommending people should stop taking antipsychotics but simply that clinicians need to factor in a patient’s medication history while considering post-COVID aftereffects,” Dr. Freudenberg-Hua said.
“Given that the number of patients with dementia is projected to triple in the next 30 years, these findings have significant public health implications,” Dr. Sinvani added.
She noted that “care partners and health care professionals” should look for early signs of dementia, such as forgetfulness and depressive symptoms, in their patients.
“Future studies must continue to evaluate these associations, which are key for potential future interventions to prevent dementia,” Dr. Sinvani said.
The study was funded by the National Institutes of Health. Dr. Freudenberg-Hua co-owns stock and stock options from Regeneron Pharmaceuticals. Dr. Sinvani has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM FRONTIERS IN MEDICINE
Common eye disorder in children tied to mental illness
Misaligned eyes in children are associated with an increased prevalence of mental illness, results of a large study suggest.
“Psychiatrists who have a patient with depression or anxiety and notice that patient also has strabismus might think about the link between those two conditions and refer that patient,” study investigator Stacy L. Pineles, MD, professor, department of ophthalmology, University of California, Los Angeles, told this news organization.
The study was published online March 10 in JAMA Ophthalmology.
A common condition
Strabismus, a condition in which the eyes don’t line up or are “crossed,” is one of the most common eye diseases in children, with some estimates suggesting it affects more than 1.5 million American youth.
Patients with strabismus have problems making eye contact and are affected socially and functionally, said Dr. Pineles. They’re often met with a negative bias, as shown by children’s responses to pictures of faces with and without strabismus, she said.
There is a signal from previous research suggesting that strabismus is linked to a higher risk of mental illness. However, most of these studies were small and had relatively homogenous populations, said Dr. Pineles.
The new study includes over 12 million children (mean age, 8.0 years) from a private health insurance claims database that represents diverse races and ethnicities as well as geographic regions across the United States.
The sample included 352,636 children with strabismus and 11,652,553 children with no diagnosed eye disease who served as controls. Most participants were White (51.6%), came from a family with an annual household income of $40,000 or more (51.0%), had point-of-service insurance (68.7%), and had at least one comorbid condition (64.5%).
The study evaluated five mental illness diagnoses. These included anxiety disorder, depressive disorder, substance use or addictive disorder, bipolar disorder, and schizophrenia.
Overall, children with strabismus had a higher prevalence of all these illnesses, with the exception of substance use disorder.
After adjusting for age, sex, race and ethnicity, census region, education level of caregiver, family net worth, and presence of at least one comorbid condition, the odds ratios among those with versus without strabismus were: 2.01 (95% confidence interval, 1.99-2.04; P < .001) for anxiety disorder, 1.83 (95% CI, 1.76-1.90; P < .001) for schizophrenia, 1.64 (95% CI, 1.59-1.70; P < .001) for bipolar disorder, and 1.61 (95% CI, 1.59-1.63; P < .001) for depressive disorder.
Substance use disorder had a negative unadjusted association with strabismus, but after adjustment for confounders, the association was not significant (OR, 0.99; 95% CI, 0.97-1.02; P = .48).
Dr. Pineles noted that the study participants, who were all under age 19, may be too young to have substance use disorders.
The results for substance use disorders provided something of an “internal control” and reaffirmed results for the other four conditions, said Dr. Pineles.
“When you do research on such a large database, you’re very likely to find significant associations; the dataset is so large that even very small differences become statistically significant. It was interesting that not everything gave us a positive association.”
Researchers divided the strabismus group into those with esotropia, where the eyes turn inward (52.2%), exotropia, where they turn outward (46.3%), and hypertropia, where one eye wanders upward (12.5%). Investigators found that all three conditions were associated with increased risk of anxiety disorder, depressive disorder, bipolar disorders, and schizophrenia.
Investigators note that rates in the current study were lower than in previous studies, which showed that children with congenital esotropia were 2.6 times more likely to receive a mental health diagnosis, and children with intermittent exotropia were 2.7 times more likely to receive a mental health diagnosis.
“It is probable that our study found a lower risk than these studies, because our study was cross-sectional and claims based, whereas these studies observed the children to early adulthood and were based on medical records,” the investigators note.
It’s impossible to determine from this study how strabismus is connected to mental illness. However, Dr. Pineles believes depression and anxiety might be tied to strabismus via teasing, which affects self-esteem, although genetics could also play a role. For conditions such as schizophrenia, a shared genetic link with strabismus might be more likely, she added.
“Schizophrenia is a pretty severe diagnosis, so just being teased or having poor self-esteem is probably not enough” to develop schizophrenia.
Based on her clinical experience, Dr. Pineles said that realigning the eyes of patients with milder forms of depression or anxiety “definitely anecdotally helps these patients a lot.”
Dr. Pineles and colleagues have another paper in press that examines mental illnesses and other serious eye disorders in children and shows similar findings, she said.
Implications for insurance coverage?
In an accompanying editorial, experts, led by S. Grace Prakalapakorn, MD, department of ophthalmology and pediatrics, Duke University Medical Center, Durham, N.C., noted the exclusion of children covered under government insurance or without insurance is an important study limitation, largely because socioeconomic status is a risk factor for poor mental health.
The editorialists point to studies showing that surgical correction of ocular misalignments may be associated with reduced anxiety and depression. However, health insurance coverage for such surgical correction “may not be available owing to a misconception that these conditions are ‘cosmetic’.”
Evidence of the broader association of strabismus with physical and mental health “may play an important role in shifting policy to promote insurance coverage for timely strabismus care,” they write.
As many mental health disorders begin in childhood or adolescence, “it is paramount to identify, address, and, if possible, prevent mental health disorders at a young age, because failure to intervene in a timely fashion can have lifelong health consequences,” say Dr. Prakalapakorn and colleagues.
With mental health conditions and disorders increasing worldwide, compounded by the stressors of the COVID-19 pandemic, additional studies are needed to explore the causal relationships between ocular and psychiatric phenomena, their treatment, and outcomes, they add.
The study was supported by a grant from the National Eye Institute and an unrestricted grant from Research to Prevent Blindness. Dr. Pineles has reported no relevant conflicts of interest. Commentary author Manpreet K. Singh, MD, has reported receiving research support from Stanford’s Maternal Child Health Research Institute and Stanford’s Department of Psychiatry and Behavioral Sciences, the National Institute of Mental Health, the National Institute on Aging, the Patient-Centered Outcomes Research Institute, Johnson & Johnson, Allergan, and the Brain and Behavior Research Foundation; serving on the advisory board for Sunovion and Skyland Trail; serving as a consultant for Johnson & Johnson; previously serving as a consultant for X, the moonshot factory, Alphabet, and Limbix Health; receiving honoraria from the American Academy of Child and Adolescent Psychiatry; and receiving royalties from American Psychiatric Association Publishing and Thrive Global. Commentary author Nathan Congdon, MD, has reported receiving personal fees from Belkin Vision outside the submitted work.
A version of this article first appeared on Medscape.com.
Misaligned eyes in children are associated with an increased prevalence of mental illness, results of a large study suggest.
“Psychiatrists who have a patient with depression or anxiety and notice that patient also has strabismus might think about the link between those two conditions and refer that patient,” study investigator Stacy L. Pineles, MD, professor, department of ophthalmology, University of California, Los Angeles, told this news organization.
The study was published online March 10 in JAMA Ophthalmology.
A common condition
Strabismus, a condition in which the eyes don’t line up or are “crossed,” is one of the most common eye diseases in children, with some estimates suggesting it affects more than 1.5 million American youth.
Patients with strabismus have problems making eye contact and are affected socially and functionally, said Dr. Pineles. They’re often met with a negative bias, as shown by children’s responses to pictures of faces with and without strabismus, she said.
There is a signal from previous research suggesting that strabismus is linked to a higher risk of mental illness. However, most of these studies were small and had relatively homogenous populations, said Dr. Pineles.
The new study includes over 12 million children (mean age, 8.0 years) from a private health insurance claims database that represents diverse races and ethnicities as well as geographic regions across the United States.
The sample included 352,636 children with strabismus and 11,652,553 children with no diagnosed eye disease who served as controls. Most participants were White (51.6%), came from a family with an annual household income of $40,000 or more (51.0%), had point-of-service insurance (68.7%), and had at least one comorbid condition (64.5%).
The study evaluated five mental illness diagnoses. These included anxiety disorder, depressive disorder, substance use or addictive disorder, bipolar disorder, and schizophrenia.
Overall, children with strabismus had a higher prevalence of all these illnesses, with the exception of substance use disorder.
After adjusting for age, sex, race and ethnicity, census region, education level of caregiver, family net worth, and presence of at least one comorbid condition, the odds ratios among those with versus without strabismus were: 2.01 (95% confidence interval, 1.99-2.04; P < .001) for anxiety disorder, 1.83 (95% CI, 1.76-1.90; P < .001) for schizophrenia, 1.64 (95% CI, 1.59-1.70; P < .001) for bipolar disorder, and 1.61 (95% CI, 1.59-1.63; P < .001) for depressive disorder.
Substance use disorder had a negative unadjusted association with strabismus, but after adjustment for confounders, the association was not significant (OR, 0.99; 95% CI, 0.97-1.02; P = .48).
Dr. Pineles noted that the study participants, who were all under age 19, may be too young to have substance use disorders.
The results for substance use disorders provided something of an “internal control” and reaffirmed results for the other four conditions, said Dr. Pineles.
“When you do research on such a large database, you’re very likely to find significant associations; the dataset is so large that even very small differences become statistically significant. It was interesting that not everything gave us a positive association.”
Researchers divided the strabismus group into those with esotropia, where the eyes turn inward (52.2%), exotropia, where they turn outward (46.3%), and hypertropia, where one eye wanders upward (12.5%). Investigators found that all three conditions were associated with increased risk of anxiety disorder, depressive disorder, bipolar disorders, and schizophrenia.
Investigators note that rates in the current study were lower than in previous studies, which showed that children with congenital esotropia were 2.6 times more likely to receive a mental health diagnosis, and children with intermittent exotropia were 2.7 times more likely to receive a mental health diagnosis.
“It is probable that our study found a lower risk than these studies, because our study was cross-sectional and claims based, whereas these studies observed the children to early adulthood and were based on medical records,” the investigators note.
It’s impossible to determine from this study how strabismus is connected to mental illness. However, Dr. Pineles believes depression and anxiety might be tied to strabismus via teasing, which affects self-esteem, although genetics could also play a role. For conditions such as schizophrenia, a shared genetic link with strabismus might be more likely, she added.
“Schizophrenia is a pretty severe diagnosis, so just being teased or having poor self-esteem is probably not enough” to develop schizophrenia.
Based on her clinical experience, Dr. Pineles said that realigning the eyes of patients with milder forms of depression or anxiety “definitely anecdotally helps these patients a lot.”
Dr. Pineles and colleagues have another paper in press that examines mental illnesses and other serious eye disorders in children and shows similar findings, she said.
Implications for insurance coverage?
In an accompanying editorial, experts, led by S. Grace Prakalapakorn, MD, department of ophthalmology and pediatrics, Duke University Medical Center, Durham, N.C., noted the exclusion of children covered under government insurance or without insurance is an important study limitation, largely because socioeconomic status is a risk factor for poor mental health.
The editorialists point to studies showing that surgical correction of ocular misalignments may be associated with reduced anxiety and depression. However, health insurance coverage for such surgical correction “may not be available owing to a misconception that these conditions are ‘cosmetic’.”
Evidence of the broader association of strabismus with physical and mental health “may play an important role in shifting policy to promote insurance coverage for timely strabismus care,” they write.
As many mental health disorders begin in childhood or adolescence, “it is paramount to identify, address, and, if possible, prevent mental health disorders at a young age, because failure to intervene in a timely fashion can have lifelong health consequences,” say Dr. Prakalapakorn and colleagues.
With mental health conditions and disorders increasing worldwide, compounded by the stressors of the COVID-19 pandemic, additional studies are needed to explore the causal relationships between ocular and psychiatric phenomena, their treatment, and outcomes, they add.
The study was supported by a grant from the National Eye Institute and an unrestricted grant from Research to Prevent Blindness. Dr. Pineles has reported no relevant conflicts of interest. Commentary author Manpreet K. Singh, MD, has reported receiving research support from Stanford’s Maternal Child Health Research Institute and Stanford’s Department of Psychiatry and Behavioral Sciences, the National Institute of Mental Health, the National Institute on Aging, the Patient-Centered Outcomes Research Institute, Johnson & Johnson, Allergan, and the Brain and Behavior Research Foundation; serving on the advisory board for Sunovion and Skyland Trail; serving as a consultant for Johnson & Johnson; previously serving as a consultant for X, the moonshot factory, Alphabet, and Limbix Health; receiving honoraria from the American Academy of Child and Adolescent Psychiatry; and receiving royalties from American Psychiatric Association Publishing and Thrive Global. Commentary author Nathan Congdon, MD, has reported receiving personal fees from Belkin Vision outside the submitted work.
A version of this article first appeared on Medscape.com.
Misaligned eyes in children are associated with an increased prevalence of mental illness, results of a large study suggest.
“Psychiatrists who have a patient with depression or anxiety and notice that patient also has strabismus might think about the link between those two conditions and refer that patient,” study investigator Stacy L. Pineles, MD, professor, department of ophthalmology, University of California, Los Angeles, told this news organization.
The study was published online March 10 in JAMA Ophthalmology.
A common condition
Strabismus, a condition in which the eyes don’t line up or are “crossed,” is one of the most common eye diseases in children, with some estimates suggesting it affects more than 1.5 million American youth.
Patients with strabismus have problems making eye contact and are affected socially and functionally, said Dr. Pineles. They’re often met with a negative bias, as shown by children’s responses to pictures of faces with and without strabismus, she said.
There is a signal from previous research suggesting that strabismus is linked to a higher risk of mental illness. However, most of these studies were small and had relatively homogenous populations, said Dr. Pineles.
The new study includes over 12 million children (mean age, 8.0 years) from a private health insurance claims database that represents diverse races and ethnicities as well as geographic regions across the United States.
The sample included 352,636 children with strabismus and 11,652,553 children with no diagnosed eye disease who served as controls. Most participants were White (51.6%), came from a family with an annual household income of $40,000 or more (51.0%), had point-of-service insurance (68.7%), and had at least one comorbid condition (64.5%).
The study evaluated five mental illness diagnoses. These included anxiety disorder, depressive disorder, substance use or addictive disorder, bipolar disorder, and schizophrenia.
Overall, children with strabismus had a higher prevalence of all these illnesses, with the exception of substance use disorder.
After adjusting for age, sex, race and ethnicity, census region, education level of caregiver, family net worth, and presence of at least one comorbid condition, the odds ratios among those with versus without strabismus were: 2.01 (95% confidence interval, 1.99-2.04; P < .001) for anxiety disorder, 1.83 (95% CI, 1.76-1.90; P < .001) for schizophrenia, 1.64 (95% CI, 1.59-1.70; P < .001) for bipolar disorder, and 1.61 (95% CI, 1.59-1.63; P < .001) for depressive disorder.
Substance use disorder had a negative unadjusted association with strabismus, but after adjustment for confounders, the association was not significant (OR, 0.99; 95% CI, 0.97-1.02; P = .48).
Dr. Pineles noted that the study participants, who were all under age 19, may be too young to have substance use disorders.
The results for substance use disorders provided something of an “internal control” and reaffirmed results for the other four conditions, said Dr. Pineles.
“When you do research on such a large database, you’re very likely to find significant associations; the dataset is so large that even very small differences become statistically significant. It was interesting that not everything gave us a positive association.”
Researchers divided the strabismus group into those with esotropia, where the eyes turn inward (52.2%), exotropia, where they turn outward (46.3%), and hypertropia, where one eye wanders upward (12.5%). Investigators found that all three conditions were associated with increased risk of anxiety disorder, depressive disorder, bipolar disorders, and schizophrenia.
Investigators note that rates in the current study were lower than in previous studies, which showed that children with congenital esotropia were 2.6 times more likely to receive a mental health diagnosis, and children with intermittent exotropia were 2.7 times more likely to receive a mental health diagnosis.
“It is probable that our study found a lower risk than these studies, because our study was cross-sectional and claims based, whereas these studies observed the children to early adulthood and were based on medical records,” the investigators note.
It’s impossible to determine from this study how strabismus is connected to mental illness. However, Dr. Pineles believes depression and anxiety might be tied to strabismus via teasing, which affects self-esteem, although genetics could also play a role. For conditions such as schizophrenia, a shared genetic link with strabismus might be more likely, she added.
“Schizophrenia is a pretty severe diagnosis, so just being teased or having poor self-esteem is probably not enough” to develop schizophrenia.
Based on her clinical experience, Dr. Pineles said that realigning the eyes of patients with milder forms of depression or anxiety “definitely anecdotally helps these patients a lot.”
Dr. Pineles and colleagues have another paper in press that examines mental illnesses and other serious eye disorders in children and shows similar findings, she said.
Implications for insurance coverage?
In an accompanying editorial, experts, led by S. Grace Prakalapakorn, MD, department of ophthalmology and pediatrics, Duke University Medical Center, Durham, N.C., noted the exclusion of children covered under government insurance or without insurance is an important study limitation, largely because socioeconomic status is a risk factor for poor mental health.
The editorialists point to studies showing that surgical correction of ocular misalignments may be associated with reduced anxiety and depression. However, health insurance coverage for such surgical correction “may not be available owing to a misconception that these conditions are ‘cosmetic’.”
Evidence of the broader association of strabismus with physical and mental health “may play an important role in shifting policy to promote insurance coverage for timely strabismus care,” they write.
As many mental health disorders begin in childhood or adolescence, “it is paramount to identify, address, and, if possible, prevent mental health disorders at a young age, because failure to intervene in a timely fashion can have lifelong health consequences,” say Dr. Prakalapakorn and colleagues.
With mental health conditions and disorders increasing worldwide, compounded by the stressors of the COVID-19 pandemic, additional studies are needed to explore the causal relationships between ocular and psychiatric phenomena, their treatment, and outcomes, they add.
The study was supported by a grant from the National Eye Institute and an unrestricted grant from Research to Prevent Blindness. Dr. Pineles has reported no relevant conflicts of interest. Commentary author Manpreet K. Singh, MD, has reported receiving research support from Stanford’s Maternal Child Health Research Institute and Stanford’s Department of Psychiatry and Behavioral Sciences, the National Institute of Mental Health, the National Institute on Aging, the Patient-Centered Outcomes Research Institute, Johnson & Johnson, Allergan, and the Brain and Behavior Research Foundation; serving on the advisory board for Sunovion and Skyland Trail; serving as a consultant for Johnson & Johnson; previously serving as a consultant for X, the moonshot factory, Alphabet, and Limbix Health; receiving honoraria from the American Academy of Child and Adolescent Psychiatry; and receiving royalties from American Psychiatric Association Publishing and Thrive Global. Commentary author Nathan Congdon, MD, has reported receiving personal fees from Belkin Vision outside the submitted work.
A version of this article first appeared on Medscape.com.
DSM-5 update: What’s new?
Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.
It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.
The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.
“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.
For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.
However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
Money maker?
Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”
Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”
The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.
Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”
Prolonged grief: Timely or overkill?
Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020.
Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.
The diagnostic criteria for PCBD include:
- The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
- Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
- The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
- The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.
Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”
DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.
The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.
However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”
“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.
The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.
“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.
Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
Changes to gender terminology
The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.
Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.
“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.
“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.
However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.
Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.
“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.
That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”
A version of this article first appeared on Medscape.com.
Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.
It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.
The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.
“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.
For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.
However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
Money maker?
Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”
Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”
The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.
Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”
Prolonged grief: Timely or overkill?
Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020.
Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.
The diagnostic criteria for PCBD include:
- The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
- Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
- The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
- The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.
Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”
DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.
The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.
However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”
“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.
The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.
“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.
Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
Changes to gender terminology
The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.
Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.
“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.
“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.
However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.
Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.
“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.
That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”
A version of this article first appeared on Medscape.com.
Ahead of its official release on March 18, the new Diagnostic and Statistical Manual of Mental Disorders, which is in the form of a textbook, is already drawing some criticism.
It also includes symptom codes for suicidal behavior and nonsuicidal self-injury, clarifying modifications to criteria sets for more than 70 disorders, including autism spectrum disorder; changes in terminology for gender dysphoria; and a comprehensive review of the impact of racism and discrimination on the diagnosis and manifestations of mental disorders.
The Text Revision is a compilation of iterative changes that have been made online on a rolling basis since the DSM-5 was first published in 2013.
“The goal of the Text Revision was to allow a thorough revision of the text, not the criteria,” Paul Appelbaum, MD, chair of the APA’s DSM steering committee, told this news organization.
For the Text Revision, some 200 experts across a variety of APA working groups recommended changes to the text based on a comprehensive literature review, said Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law, and director of the division of law, ethics and psychiatry at Columbia University, New York.
However, there’s not a lot that’s new, in part, because there have been few therapeutic advances.
Money maker?
Allen Frances, MD, chair of the DSM-4 task force and professor and chair emeritus of psychiatry at Duke University, Durham, N.C., said the APA is publishing the Text Revision “just to make money. They’re very anxious to do anything that will increase sales and having a revision forces some people, especially in institutions, to buy the book, even though it may not have anything substantive to add to the original.”
Dr. Frances told this news organization that when the APA published the first DSM in the late 1970s, “it became an instantaneous best-seller, to everyone’s surprise.”
The APA would not comment on how many of the $170 (list price) volumes it sells or how much those sales contribute to its budget.
Dr. Appelbaum acknowledged, “at any point in time, the canonical version is the online version.” However, it’s clear from DSM-5 sales “that many people still value having a hard copy of the DSM available to them.”
Prolonged grief: Timely or overkill?
Persistent complex bereavement disorder (PCBD) was listed as a “condition for further study” in DSM-5. After a 2019 workshop aimed at getting consensus for diagnosis criteria, the APA board approved the new prolonged grief disorder in October 2020, and the APA assembly approved the new disorder in November 2020.
Given the 950,000 deaths from COVID-19 over the past 2 years, inclusion of prolonged grief disorder in the DSM-5 may arrive at just the right time.
The diagnostic criteria for PCBD include:
- The development of a persistent grief response (longer than a year for adults and 6 months for children and adolescents) characterized by one or both of the following symptoms, which have been present most days to a clinically significant degree, and have occurred nearly every day for at least the last month: intense yearning/longing for the deceased person; preoccupation with thoughts or memories of the deceased person.
- Since the death, at least three symptoms present most days to a clinically significant degree, and occurring nearly every day for at least the last month, including identity disruption, marked sense of disbelief about the death, avoidance of reminders that the person is dead, intense emotional pain related to the death, difficulty reintegrating into one’s relationships and activities after the death, emotional numbness, feeling that life is meaningless as a result of the death, and intense loneliness as a result of the death.
- The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
- The duration and severity of the bereavement reaction clearly exceed expected social, cultural, or religious norms for the individual’s culture and context.
- The symptoms are not better explained by another mental disorder, such as major depressive disorder (MDD) or PTSD, and are not attributable to the physiological effects of a substance or another medical condition.
Dr. Frances said he believes creating a new diagnosis pathologizes grief. In DSM-3 and DSM-4, an exception was made under the diagnosis of MDD for individuals who had recently lost a loved one. “We wanted to have at least an opportunity for people to grieve without being stigmatized, mislabeled, and overtreated with medication.”
DSM-5 removed the bereavement exclusion. After 2 weeks, people who are grieving and have particular symptoms could receive a diagnosis of MDD, said Dr. Frances. He believes the exclusion should have been broadened to cover anyone experiencing a major loss – such as a job loss or divorce. If someone is having prolonged symptoms that interfere with functioning, they should get an MDD diagnosis.
The new disorder “doesn’t solve anything, it just adds to the confusion and stigmatization, and it’s part of a kind of creeping medical imperialization of everyday life, where everything has to have a mental disorder label,” Dr. Frances said.
However, Dr. Appelbaum countered that “the criteria for prolonged grief disorder are constructed in such a way as to make every effort to exclude people who are going through a normal grieving process.”
“Part of the purpose of the data analyses was to ensure the criteria that were adopted would, in fact, effectively distinguish between what anybody goes through, say when someone close to you dies, and this unusual prolonged grieving process without end that affects a much smaller number of people but which really can be crippling for them,” he added.
The Text Revision adds new symptom codes for suicidal behavior and nonsuicidal self-injury, which appear in the chapter, “Other Conditions That May Be a Focus of Clinical Attention,” said Dr. Appelbaum.
“Both suicidal behavior and nonsuicidal self-injury seem pretty persuasively to fall into that category – something a clinician would want to know about, pay attention to, and factor into treatment planning, although they are behaviors that cross many diagnostic categories,” he added.
Codes also provide a systematic way of ascertaining the incidence and prevalence of such behaviors, said Dr. Appelbaum.
Changes to gender terminology
The Text Revision also tweaks some terminology with respect to transgender individuals. The term “desired gender” is now “experienced gender”, the term “cross-sex medical procedure” is now “gender-affirming medical procedure”, and the terms “natal male/natal female” are now “individual assigned male/female at birth”.
Dr. Frances said that the existence of gender dysphoria as a diagnosis has been a matter of controversy ever since it was first included.
“The transgender community has had mixed feelings on whether there should be anything at all in the manual,” he said. On one hand is the argument that gender dysphoria should be removed because it’s not really a psychiatric issue.
“We seriously considered eliminating it altogether in DSM-4,” said Dr. Frances.
However, an argument in favor of keeping it was that if the diagnosis was removed, it would mean that people could not receive treatment. “There’s no right argument for this dilemma,” he said.
Dr. Frances, who has been a frequent critic of DSM-5, said he believes the manual continues to miss opportunities to tighten criteria for many diagnoses, including ADHD and autism spectrum disorder.
“There’s a consistent pattern of taking behaviors and symptoms of behaviors that are on the border with normality and expanding the definition of mental disorder and reducing the realm of normality,” he said.
That has consequences, Dr. Frances added. “When someone gets a diagnosis that they need to get, it’s the beginning of a much better future. When someone gets a diagnosis that’s a mislabel that they don’t need, it has all harms and no benefits. It’s stigmatizing, leads to too much treatment, the wrong treatment, and it’s much more harmful than helpful.”
A version of this article first appeared on Medscape.com.
Sublingual dexmedetomidine may rapidly calm bipolar agitation
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The phase 3 SERENITY II trial included almost 400 adults with bipolar I or II disorder and acute agitation.
Results showed relief from acute agitation kicked in beginning at 20 minutes after administration of the treatment and continued to 120 minutes, principal investigator Sheldon H. Preskorn, MD, professor, department of psychiatry and behavioral sciences, University of Kansas, Wichita, and colleagues reported.
“Patients who are mild to moderately agitated in whom there is the potential for escalation to more severe agitation,” are good candidates for sublingual dexmedetomidine, Dr. Preskorn told this news organization.
He noted that, while “comparative claims require comparative studies,” a key advantage is that it “can be self-administered by patients reliably because of the adherence of the film to the mucosa.”
The findings were published online Feb. 22, 2022 in JAMA.
Tough-to-manage symptom
Preliminary results were presented at the 2021 annual meeting of the American Psychiatric Association and reported by this news organization at that time.
Agitation is a common and tough-to-manage symptom associated with multiple neuropsychiatric conditions, including bipolar disorder.
The phase 3 SERENITY II trial enrolled 380 adults (mean age, 45 years; 55% women) with bipolar I or II disorder and acute agitation in the emergency department.
All participants had a total score of 14 or greater on the five items of the Positive and Negative Syndrome Scale–Excited Component (PEC) scale at baseline and a score of 4 or greater on at least one PEC item.
Patients were randomly allocated to a single dose of sublingual dexmedetomidine (120 mcg or 180 mcg) or placebo. All but two patients completed the study.
Baseline agitation was mild to moderate, with an overall mean PEC total score of 18.
Rapid relief
Mean change from baseline in the PEC total score at 2 hours (primary endpoint) was –9 and –10.4 with the 120-mcg and 180-mcg doses of sublingual dexmedetomidine, respectively, versus –4.9 for placebo.
Least-square mean differences from placebo in the sublingual dexmedetomidine groups at 2 hours were statistically significant for both doses (both, P < .001 vs. placebo).
Statistically significant treatment effects were first evident 20 minutes after dosing for both of the dexmedetomidine doses versus placebo.
Patients in both active-treatment groups showed greater improvement in PEC total score than patients in the placebo group at all subsequent time points through 2 hours post dosing.
Sublingual dexmedetomidine was also associated with significant improvement on the secondary outcomes of Clinical Global Impressions–Improvement and Agitation-Calmness Evaluation Scale.
Adverse events occurred in 35.7% and 34.9% of patients taking 180 mcg and 120 mcg sublingual dexmedetomidine, respectively, compared with 17.5% of patients taking placebo. The most commonly reported adverse events were somnolence, dry mouth, hypotension, and dizziness. No treatment-related serious or severe adverse events were reported.
FDA action date: April 5
In an accompanying editorial, John K. Hsiao, MD, National Institutes of Health, Bethesda, Md., noted that an “out-of-control, agitated, possibly aggressive patient in a medical setting is a crisis demanding swift and safe resolution.
“Today, emergency departments now rival and perhaps surpass psychiatric units as settings where out-of-control, agitated patients must be managed,” Dr. Hsiao said.
The current study “provides evidence to support a novel, potentially important addition to the armamentarium for managing behavioral agitation,” he wrote.
BioXcel Therapeutics has submitted a new drug application to the Food and Drug Administration. The Prescription Drug User Fee Act target action date is April 5.
In a statement, Frank D. Yocca, PhD, chief scientific officer of BioXcel Therapeutics, said the company is looking forward to potential FDA approval of the treatment for agitation associated with bipolar disorders and schizophrenia.
“Building on the strength of these compelling data, we are also confidently progressing BXCL501 as a potential acute treatment for agitation associated with Alzheimer’s disease,” Dr. Yocca added.
The study was funded by BioXcel Therapeutics. Dr. Preskorn reported receiving consulting fees from BioXcel and receiving research grants from, serving as a consultant for, on advisory boards of, and on the speakers bureau of Alkermes, BioXcel Therapeutics, Eisai, Janssen, Novartis, Otsuka, Sunovion, and Usona Institute. Dr. Hsiao has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JAMA
Lumateperone for major depressive episodes in bipolar I or bipolar II disorder
Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.1 Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 12and Figure 23). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.6 Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.7,8
Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetiapine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.9 Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,12 only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.
Continue to: Table 1...
Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).13 Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).15 At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.19 This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.13 There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.13
In addition to the low risk of adverse events of all types, lumateperone has several pharmacologic features that distinguish it from other agents in its class. One unique aspect of lumateperone’s pharmacology is differential actions at presynaptic and postsynaptic dopamine D2 receptors noted in preclinical assays, a property that may explain its ability to act as an antipsychotic despite low D2 receptor occupancy.16 Preclinical assays also predicted that lumateperone was likely to have antidepressant effects.15,19,20 Unlike every SGA except ziprasidone, lumateperone also possesses moderate binding affinity for serotonin transporters (SERT) (Ki 33 nM), with SERT occupancy of approximately 30% at 42 mg.21 Lumateperone facilitates dopamine D1-mediated neurotransmission, and this is associated with increased glutamate signaling in the prefrontal cortex and antidepressant actions.14,22 While the extent of SERT occupancy is significantly below the ≥80% SERT occupancy seen with selective serotonin reuptake inhibitors, it is hypothesized that near saturation of the 5HT2A receptor might act synergistically with modest 5HT reuptake inhibition and D1-mediated effects to promote the downstream glutamatergic effects that correlate with antidepressant activity (eg, changes in markers such as phosphorylation of glutamate N-methyl-D-aspartate receptor subunits, potentiation of AMPA receptor-mediated transmission).15,22
Continue to: Clinical implications...
Clinical implications
The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.23
Efficacy in adults with BD I or II depression.
The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,17 and 1 study when used adjunctively to lithium or VPA.18 The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.17 Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.17
The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).
The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.18 Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.18 Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).
The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.18 As of this writing, a secondary analysis by BD subtype has not yet been presented.
A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.
Continue on to: Adverse reactions...
Adverse reactions
In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.17 The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).13 Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.13 Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.17 Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.
Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).13 Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.13 Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.18 Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.18
Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.13
Continue on to: Pharmacologic profile...
Pharmacologic profile
Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).
Clinical considerations
Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.
The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.
Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.13
Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:
- data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
- favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
- no need for titration.
Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.
Contraindications. The only contraindication is known hypersensitivity to lumateperone.
Bottom Line
Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.
1. Malhi GS, Bell E, Boyce P, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary. Bipolar Disord. 2020;22(8):805-821.
2. Judd LL, Akishal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530-537.
3. Judd LL, Akishal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261-269.
4. Post RM. Treatment of bipolar depression: evolving recommendations. Psychiatr Clin North Am. 2016;39(1):11-33.
5. Pacchiarotti I, Verdolini N. Antidepressants in bipolar II depression: yes and no. Eur Neuropsychopharmacol 2021;47:48-50.
6. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
7. Allain N, Leven C, Falissard B, et al. Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies. Acta Psychiatr Scand. 2017;135(2):106-116.
8. Gitlin MJ. Antidepressants in bipolar depression: an enduring controversy. Int J Bipolar Disord. 2018;6(1):25.
9. Verdolini N, Hidalgo-Mazzei D, Del Matto L, et al. Long-term treatment of bipolar disorder type I: a systematic and critical review of clinical guidelines with derived practice algorithms. Bipolar Disord. 2021;23(4):324-340.
10. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195.
11. Vraylar [package insert]. Madison, NJ: Allergan USA, Inc.; 2019.
12. Chakrabarty T, Hadijpavlou G, Bond DJ, et al. Bipolar II disorder in context: a review of its epidemiology, disability and economic burden. In: Parker G. Bipolar II Disorder: Modelling, Measuring and Managing. 3rd ed. Cambridge University Press; 2019:49-59.
13. Caplyta [package insert]. New York, NY: Intra-Cellular Therapies, Inc.; 2021.
14. Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016;16(6):601-614.
15. Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015;232:605-621.
16. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.
17. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry 2021;178(12):1098-1106.
18. Yatham LN, et al. Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: results from a randomized clinical trial. Poster presented at: American Psychiatric Association Annual Meeting. May 1-3, 2021; virtual conference.
19. Vanover K, Glass S, Kozauer S, et al. 30 Lumateperone (ITI-007) for the treatment of schizophrenia: overview of placebo-controlled clinical trials and an open-label safety switching study. CNS Spectrums. 2019;24(1):190-191.
20. Kumar B, Kuhad A, Kuhad A. Lumateperone: a new treatment approach for neuropsychiatric disorders. Drugs Today (Barc). 2018;54(12):713-719.
21. Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology (Berl). 2015;232(15):2863-72.
22. Björkholm C, Marcus MM, Konradsson-Geuken Å, et al. The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism. Eur Neuropsychopharmacol. 2017;27(4):411-417.
23. Bai Y, Yang H, Chen G, et al. Acceptability of acute and maintenance pharmacotherapy of bipolar disorder: a systematic review of randomized, double-blind, placebo-controlled clinical trials. J Clin Psychopharmacol. 2020;40(2):167-179.
24. Vyas P, Hwang BJ, Braši´c JR. An evaluation of lumateperone tosylate for the treatment of schizophrenia. Expert Opin Pharmacother. 2020;21(2):139-145.
25. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
26. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):169-77.
Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.1 Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 12and Figure 23). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.6 Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.7,8
Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetiapine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.9 Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,12 only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.
Continue to: Table 1...
Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).13 Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).15 At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.19 This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.13 There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.13
In addition to the low risk of adverse events of all types, lumateperone has several pharmacologic features that distinguish it from other agents in its class. One unique aspect of lumateperone’s pharmacology is differential actions at presynaptic and postsynaptic dopamine D2 receptors noted in preclinical assays, a property that may explain its ability to act as an antipsychotic despite low D2 receptor occupancy.16 Preclinical assays also predicted that lumateperone was likely to have antidepressant effects.15,19,20 Unlike every SGA except ziprasidone, lumateperone also possesses moderate binding affinity for serotonin transporters (SERT) (Ki 33 nM), with SERT occupancy of approximately 30% at 42 mg.21 Lumateperone facilitates dopamine D1-mediated neurotransmission, and this is associated with increased glutamate signaling in the prefrontal cortex and antidepressant actions.14,22 While the extent of SERT occupancy is significantly below the ≥80% SERT occupancy seen with selective serotonin reuptake inhibitors, it is hypothesized that near saturation of the 5HT2A receptor might act synergistically with modest 5HT reuptake inhibition and D1-mediated effects to promote the downstream glutamatergic effects that correlate with antidepressant activity (eg, changes in markers such as phosphorylation of glutamate N-methyl-D-aspartate receptor subunits, potentiation of AMPA receptor-mediated transmission).15,22
Continue to: Clinical implications...
Clinical implications
The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.23
Efficacy in adults with BD I or II depression.
The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,17 and 1 study when used adjunctively to lithium or VPA.18 The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.17 Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.17
The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).
The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.18 Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.18 Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).
The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.18 As of this writing, a secondary analysis by BD subtype has not yet been presented.
A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.
Continue on to: Adverse reactions...
Adverse reactions
In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.17 The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).13 Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.13 Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.17 Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.
Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).13 Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.13 Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.18 Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.18
Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.13
Continue on to: Pharmacologic profile...
Pharmacologic profile
Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).
Clinical considerations
Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.
The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.
Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.13
Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:
- data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
- favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
- no need for titration.
Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.
Contraindications. The only contraindication is known hypersensitivity to lumateperone.
Bottom Line
Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.
Among patients with bipolar I or II disorder (BD I or II), major depressive episodes represent the predominant mood state when not euthymic, and are disproportionately associated with the functional disability of BD and its suicide risk.1 Long-term naturalistic studies of weekly mood states in patients with BD I or II found that the proportion of time spent depressed greatly exceeded that spent in a mixed, hypomanic, or manic state during >12 years of follow-up (Figure 12and Figure 23). In the 20th century, traditional antidepressants represented the sole option for management of bipolar depression despite concerns of manic switching or lack of efficacy.4,5 Efficacy concerns were subsequently confirmed by placebo-controlled studies, such as the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial, which found limited effectiveness of adjunctive antidepressants for bipolar depression.6 Comprehensive reviews of randomized controlled trials and observational studies documented the risk of mood cycling and manic switching, especially in patients with BD I, even if antidepressants were used in the presence of mood-stabilizing medications.7,8
Several newer antipsychotics have been FDA-approved for treating depressive episodes associated with BD (Table 1). Approval of olanzapine/fluoxetine combination (OFC) in December 2003 for depressive episodes associated with BD I established that mechanisms exist which can effectively treat acute depressive episodes in patients with BD without an inordinate risk of mood instability. Subsequent approval of quetiapine in October 2006 for depression associated with BD I or II, lurasidone in June 2013, and cariprazine in May 2019 for major depression in BD I greatly expanded the options for management of acute bipolar depression. However, despite the array of molecules available, for certain patients these agents presented tolerability issues such as sedation, weight gain, akathisia, or parkinsonism that could hamper effective treatment.9 Safety and efficacy data in bipolar depression for adjunctive use with lithium or divalproex/valproate (VPA) also are lacking for quetiapine, OFC, and cariprazine.10,11 Moreover, despite the fact that BD II is as prevalent as BD I, and that patients with BD II have comparable rates of comorbidity, chronicity, disability, and suicidality,12 only quetiapine was approved for acute treatment of depression in patients with BD II. This omission is particularly problematic because the depressive episodes of BD II predominate over the time spent in hypomanic and cycling/mixed states (50.3% for depression vs 3.6% for hypomania/cycling/mixed combined), much more than is seen with BD I (31.9% for depression vs 14.8% for hypomania/cycling/mixed combined).2,3 The paucity of data for the use of newer antipsychotics in BD II depression presents a problem when patients cannot tolerate or refuse to consider quetiapine. This prevents clinicians from engaging in evidence-based efficacy discussions of other options, even if it is assumed that the tolerability profile for BD II depression patients may be similar to that seen when these agents are used for BD I depression.
Continue to: Table 1...
Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).13 Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).15 At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.19 This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.13 There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.13
In addition to the low risk of adverse events of all types, lumateperone has several pharmacologic features that distinguish it from other agents in its class. One unique aspect of lumateperone’s pharmacology is differential actions at presynaptic and postsynaptic dopamine D2 receptors noted in preclinical assays, a property that may explain its ability to act as an antipsychotic despite low D2 receptor occupancy.16 Preclinical assays also predicted that lumateperone was likely to have antidepressant effects.15,19,20 Unlike every SGA except ziprasidone, lumateperone also possesses moderate binding affinity for serotonin transporters (SERT) (Ki 33 nM), with SERT occupancy of approximately 30% at 42 mg.21 Lumateperone facilitates dopamine D1-mediated neurotransmission, and this is associated with increased glutamate signaling in the prefrontal cortex and antidepressant actions.14,22 While the extent of SERT occupancy is significantly below the ≥80% SERT occupancy seen with selective serotonin reuptake inhibitors, it is hypothesized that near saturation of the 5HT2A receptor might act synergistically with modest 5HT reuptake inhibition and D1-mediated effects to promote the downstream glutamatergic effects that correlate with antidepressant activity (eg, changes in markers such as phosphorylation of glutamate N-methyl-D-aspartate receptor subunits, potentiation of AMPA receptor-mediated transmission).15,22
Continue to: Clinical implications...
Clinical implications
The approval of lumateperone for both BD I and BD II depression, and for its use as monotherapy and for adjunctive use with lithium or VPA, satisfies several unmet needs for the management of acute major depressive episodes in patients with BD. Clinicians now have both safety and tolerability data to present to their bipolar spectrum patients regardless of subtype, and regardless of whether the patient requires mood stabilizer therapy. The tolerability advantages for lumateperone seen in schizophrenia trials were replicated in a diagnostic group that is very sensitive to D2-related adverse effects, and for whom any signal of clinically significant weight gain or sedation often represents an insuperable barrier to patient acceptance.23
Efficacy in adults with BD I or II depression.
The efficacy of lumateperone for major depressive episodes has been established in 2 pivotal, double-blind, placebo-controlled trials in BD I or II patients: 1 monotherapy study,17 and 1 study when used adjunctively to lithium or VPA.18 The first study was a 6-week, double-blind, placebo-controlled monotherapy trial (study 404) in which 377 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode were randomized in a 1:1 manner to lumateperone 42 mg/d or placebo given once daily in the evening. Symptom entry criteria included a Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥20, and scores ≥4 on the depression and overall BD illness subscales of the Clinical Global Impressions Scale–Bipolar Version Severity scale (CGI-BP-S) at screening and at baseline.17 Study entry also required a score ≤12 on the Young Mania Rating Scale (YMRS) at screening and at baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS. Several secondary efficacy measures were examined, including the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS), or remission (MADRS score ≤12), and differential changes in MADRS scores from baseline for BD I and BD II subgroups.17
The patient population was 58% female and 91% White, with 79.9% diagnosed as BD I and 20.1% as BD II. The least squares mean changes on the MADRS total score from baseline to Day 43 were lumateperone 42 mg/d: -16.7 points; placebo: -12.1 points (P < .0001), and the effect size for this difference was moderate: 0.56. Secondary analyses indicated that 51.1% of those taking lumateperone 42 mg/d and 36.7% taking placebo met response criteria (P < .001), while 39.9% of those taking lumateperone 42 mg/d and 33.5% taking placebo met remission criteria (P = .018). Importantly, depression improvement was observed both in patients with BD I (effect size 0.49, P < .0001) and in those with BD II (effect size 0.81, P < .001).
The second pivotal trial (study 402) was a 6-week, double-blind, placebo-controlled adjunctive trial in which 528 patients age 18 to 75 with BD I or BD II experiencing a major depressive episode despite treatment with lithium or VPA were randomized in a 1:1:1 manner to lumateperone 28 mg/d, lumateperone 42 mg/d, or placebo given once daily in the evening.18 Like the monotherapy trial, symptom entry criteria included a MADRS total score ≥20, and scores ≥4 on the depression and overall illness CGI-BP-S subscales at screening and baseline.18 Study entry also required a score ≤12 on the YMRS at screening and baseline. The duration of the major depressive episode must have been ≥2 weeks but <6 months before screening, with symptoms causing clinically significant distress or functional impairment. The primary outcome measure was change from baseline in MADRS for lumateperone 42 mg/d compared to placebo. Secondary efficacy measures included MADRS changes for lumateperone 28 mg/d and the proportion of patients meeting criteria for treatment response (≥50% decrease in MADRS) or remission (MADRS score ≤12).
The patient population was 58% female and 88% White, with 83.3% diagnosed as BD I, 16.7% diagnosed as BD II, and 28.6% treated with lithium vs 71.4% on VPA. The effect size for the difference in MADRS total score from baseline to Day 43 for lumateperone 42 mg/d was 0.27 (P < .05), while that for the lumateperone 28 mg/d dose did not reach statistical significance. Secondary analyses indicated that response rates for lumateperone 28 mg/d and lumateperone 42 mg/d were significantly higher than for placebo (both P < .05). Response rates were placebo: 39%; lumateperone 28 mg/d: 50%; and lumateperone 42 mg/d: 45%. Remission rates were similar at Day 43 in both lumateperone groups compared with placebo: placebo: 31%, lumateperone 28 mg/d: 31%, and lumateperone 42 mg/d: 28%.18 As of this writing, a secondary analysis by BD subtype has not yet been presented.
A third study examining lumateperone monotherapy failed to establish superiority of lumateperone over placebo (NCT02600494). The data regarding tolerability from that study were incorporated in product labeling describing adverse reactions.
Continue on to: Adverse reactions...
Adverse reactions
In the positive monotherapy trial, there were 376 patients in the modified intent-to-treat efficacy population to receive lumateperone (N = 188) or placebo (N = 188) with nearly identical completion rates in the active treatment and placebo cohorts: lumateperone, 88.8%; placebo, 88.3%.17 The proportion experiencing mania was low in both cohorts (lumateperone, 1.1%; placebo, 2.1%), and there was 1 case of hypomania in each group. One participant in the lumateperone group and 1 in the placebo group discontinued the study due to a serious adverse event of mania. There was no worsening of mania in either group as measured by mean change in the YMRS score. There was also no suicidal behavior in either cohort during the study. Pooling the 2 monotherapy trials, the adverse events that occurred at ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone 42 mg/d: 13%, placebo: 3%), dizziness (lumateperone 42 mg/d: 8%, placebo: 4%), and nausea (lumateperone 42 mg/d: 8%, placebo: 3%).13 Rates of EPS were low for both groups: lumateperone 42 mg/d: 1.3%, placebo: 1.1%.13 Mean weight change at Day 43 was +0.11 kg for lumateperone and +0.03 kg for placebo in the positive monotherapy trial.17 Moreover, compared to placebo, lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant. No patient exhibited a corrected QT interval >500 ms at any time, and increases ≥60 ms from baseline were similar between the lumateperone (n = 1, 0.6%) and placebo (n = 3, 1.8%) cohorts.
Complete safety and tolerability data for the adjunctive trial has not yet been published, but discontinuation rates due to treatment-emergent adverse effects for the 3 arms were: lumateperone 42 mg/d: 5.6%; lumateperone 28 mg/d: 1.7%; and placebo: 1.7%. Overall, 81.4% of patients completed the trial, with only 1 serious adverse event (lithium toxicity) occurring in a patient taking lumateperone 42 mg/d. While this led to study discontinuation, it was not considered related to lumateperone exposure by the investigator. There was no worsening of mania in either lumateperone dosage group or the placebo cohort as measured by mean change in YMRS score: -1.2 for placebo, -1.4 for lumateperone 28 mg/d, and -1.6 for lumateperone 42 mg/d. Suicidal behavior was not observed in any group during treatment. The adverse events that occurred at rates ≥5% in lumateperone-treated patients and at more than twice the rate of the placebo group were somnolence/sedation (lumateperone, 13%; placebo, 3%), dizziness (lumateperone, 11%; placebo, 2%), and nausea (lumateperone, 9%; placebo, 4%).13 Rates of EPS were low for both groups: lumateperone, 4.0%, placebo, 2.3%.13 Mean weight changes at Day 43 were +0.23 kg for placebo, +0.02 kg for lumateperone 28 mg/d, and 0.00 kg for lumateperone 42 mg/d.18 Compared to placebo, both doses of lumateperone exhibited comparable effects on serum prolactin and all metabolic parameters, including fasting insulin, fasting glucose, and fasting lipids, none of which were clinically significant.18
Lastly, the package insert notes that in an uncontrolled, open-label trial of lumateperone for up to 6 months in patients with BD depression, the mean weight change was -0.01 ± 3.1 kg at Day 175.13
Continue on to: Pharmacologic profile...
Pharmacologic profile
Lumateperone’s preclinical discovery program found an impact on markers associated with increased glutamatergic neurotransmission, properties that were predicted to yield antidepressant benefit.14,15,24 This is hypothesized to be based on the complex pharmacology of lumateperone, including dopamine D1 agonism, modest SERT occupancy, and near saturation of the 5HT2A receptor.15,22 Dopamine D2 affinity is modest (32 nM), and the D2 receptor occupancy at the 42 mg dose is low. These properties translate to rates of EPS in clinical studies of schizophrenia and BD that are close to that of placebo. Lumateperone has very high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), which also helps mitigate D2-related adverse effects and may be part of the therapeutic antidepressant mechanism. Underlying the tolerability profile is the low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).
Clinical considerations
Data from the lumateperone BD depression trials led to it being only the second agent approved for acute major depression in BD II patients, and the only agent which has approvals as monotherapy and adjunctive therapy for both BD subtypes. The monotherapy trial results substantiate that lumateperone was robustly effective regardless of BD subtype, with significant improvement in depressive symptoms experienced by patients with BD I (effect size 0.49, P < .0001) and those with BD II (effect size 0.81, P < .001). Effect sizes in acute BD depression studies are much larger in monotherapy trials than in adjunctive trials, as the latter group represents patients who have already failed pretreatment with a mood stabilizer.25,26 In the lurasidone BD I depression trials, the effect size based on mean change in MADRS score over the course of 6 weeks was 0.51 in the monotherapy study compared to 0.34 when used adjunctively with lithium or VPA.25,26 In the lumateperone adjunctive study, the effect size for the difference in mean MADRS total score from baseline for lumateperone 42 mg/d, was 0.27 (P < .05). Subgroup analyses by BD subtype are not yet available for adjunctive use, but the data presented to FDA were sufficient to permit an indication for adjunctive use across both diagnostic groups.
The absence of clinically significant EPS, the minimal impact on metabolic or endocrine parameters, and the lack of a need for titration are all appealing properties. At the present there is only 1 marketed dose (42 mg capsules), so the package insert includes cautionary language regarding situations when a patient might encounter less drug exposure (concurrent use of cytochrome P450 [CYP] 3A4 inducers), or greater drug exposure due to concurrent use of moderate or strong CYP3A4 inhibitors, as well as in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria (Child-Pugh B or C). These are not contraindications.
Unique properties of lumateperone include efficacy established as monotherapy for BD I and BD II patients, and efficacy for adjunctive use with lithium or VPA. Additionally, the extremely low rates of significant EPS and lack of clinically significant metabolic or endocrine adverse effects are unique properties of lumateperone.13
Why Rx? Reasons to prescribe lumateperone for adult BD depression patients include:
- data support efficacy for BD I and BD II patients, and for monotherapy or adjunctive use with lithium/VPA
- favorable tolerability profile, including no significant signal for EPS, endocrine or metabolic adverse effects, or QT prolongation
- no need for titration.
Dosing. There is only 1 dose available for lumateperone: 42 mg capsules (Table 3). As the dose cannot be modified, the package insert contains cautionary language regarding situations with less drug exposure (use of CYP3A4 inducers), or greater drug exposure (use with moderate or strong CYP3A4 inhibitors or in patients with moderate or severe hepatic impairment as defined by Child-Pugh Criteria [Child-Pugh B or C]). These are not contraindications. Based on newer pharmacokinetic studies, lumateperone does not need to be dosed with food, and there is no clinically significant interaction with UGT1A4 inhibitors such as VPA.
Contraindications. The only contraindication is known hypersensitivity to lumateperone.
Bottom Line
Data support the efficacy of lumateperone for treating depressive episodes in adults with bipolar I or bipolar II disorder, either as monotherapy or adjunctive to lithium or divalproex/valproate. Potential advantages of lumateperone for this indication include a favorable tolerability profile and no need for titration.
1. Malhi GS, Bell E, Boyce P, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary. Bipolar Disord. 2020;22(8):805-821.
2. Judd LL, Akishal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530-537.
3. Judd LL, Akishal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261-269.
4. Post RM. Treatment of bipolar depression: evolving recommendations. Psychiatr Clin North Am. 2016;39(1):11-33.
5. Pacchiarotti I, Verdolini N. Antidepressants in bipolar II depression: yes and no. Eur Neuropsychopharmacol 2021;47:48-50.
6. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
7. Allain N, Leven C, Falissard B, et al. Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies. Acta Psychiatr Scand. 2017;135(2):106-116.
8. Gitlin MJ. Antidepressants in bipolar depression: an enduring controversy. Int J Bipolar Disord. 2018;6(1):25.
9. Verdolini N, Hidalgo-Mazzei D, Del Matto L, et al. Long-term treatment of bipolar disorder type I: a systematic and critical review of clinical guidelines with derived practice algorithms. Bipolar Disord. 2021;23(4):324-340.
10. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195.
11. Vraylar [package insert]. Madison, NJ: Allergan USA, Inc.; 2019.
12. Chakrabarty T, Hadijpavlou G, Bond DJ, et al. Bipolar II disorder in context: a review of its epidemiology, disability and economic burden. In: Parker G. Bipolar II Disorder: Modelling, Measuring and Managing. 3rd ed. Cambridge University Press; 2019:49-59.
13. Caplyta [package insert]. New York, NY: Intra-Cellular Therapies, Inc.; 2021.
14. Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016;16(6):601-614.
15. Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015;232:605-621.
16. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.
17. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry 2021;178(12):1098-1106.
18. Yatham LN, et al. Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: results from a randomized clinical trial. Poster presented at: American Psychiatric Association Annual Meeting. May 1-3, 2021; virtual conference.
19. Vanover K, Glass S, Kozauer S, et al. 30 Lumateperone (ITI-007) for the treatment of schizophrenia: overview of placebo-controlled clinical trials and an open-label safety switching study. CNS Spectrums. 2019;24(1):190-191.
20. Kumar B, Kuhad A, Kuhad A. Lumateperone: a new treatment approach for neuropsychiatric disorders. Drugs Today (Barc). 2018;54(12):713-719.
21. Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology (Berl). 2015;232(15):2863-72.
22. Björkholm C, Marcus MM, Konradsson-Geuken Å, et al. The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism. Eur Neuropsychopharmacol. 2017;27(4):411-417.
23. Bai Y, Yang H, Chen G, et al. Acceptability of acute and maintenance pharmacotherapy of bipolar disorder: a systematic review of randomized, double-blind, placebo-controlled clinical trials. J Clin Psychopharmacol. 2020;40(2):167-179.
24. Vyas P, Hwang BJ, Braši´c JR. An evaluation of lumateperone tosylate for the treatment of schizophrenia. Expert Opin Pharmacother. 2020;21(2):139-145.
25. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
26. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):169-77.
1. Malhi GS, Bell E, Boyce P, et al. The 2020 Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders: bipolar disorder summary. Bipolar Disord. 2020;22(8):805-821.
2. Judd LL, Akishal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530-537.
3. Judd LL, Akishal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261-269.
4. Post RM. Treatment of bipolar depression: evolving recommendations. Psychiatr Clin North Am. 2016;39(1):11-33.
5. Pacchiarotti I, Verdolini N. Antidepressants in bipolar II depression: yes and no. Eur Neuropsychopharmacol 2021;47:48-50.
6. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711-1722.
7. Allain N, Leven C, Falissard B, et al. Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies. Acta Psychiatr Scand. 2017;135(2):106-116.
8. Gitlin MJ. Antidepressants in bipolar depression: an enduring controversy. Int J Bipolar Disord. 2018;6(1):25.
9. Verdolini N, Hidalgo-Mazzei D, Del Matto L, et al. Long-term treatment of bipolar disorder type I: a systematic and critical review of clinical guidelines with derived practice algorithms. Bipolar Disord. 2021;23(4):324-340.
10. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 3: the clinical guidelines. Int J Neuropsychopharmacol. 2017;20(2):180-195.
11. Vraylar [package insert]. Madison, NJ: Allergan USA, Inc.; 2019.
12. Chakrabarty T, Hadijpavlou G, Bond DJ, et al. Bipolar II disorder in context: a review of its epidemiology, disability and economic burden. In: Parker G. Bipolar II Disorder: Modelling, Measuring and Managing. 3rd ed. Cambridge University Press; 2019:49-59.
13. Caplyta [package insert]. New York, NY: Intra-Cellular Therapies, Inc.; 2021.
14. Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016;16(6):601-614.
15. Snyder GL, Vanover KE, Zhu H, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology (Berl). 2015;232:605-621.
16. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.
17. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry 2021;178(12):1098-1106.
18. Yatham LN, et al. Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: results from a randomized clinical trial. Poster presented at: American Psychiatric Association Annual Meeting. May 1-3, 2021; virtual conference.
19. Vanover K, Glass S, Kozauer S, et al. 30 Lumateperone (ITI-007) for the treatment of schizophrenia: overview of placebo-controlled clinical trials and an open-label safety switching study. CNS Spectrums. 2019;24(1):190-191.
20. Kumar B, Kuhad A, Kuhad A. Lumateperone: a new treatment approach for neuropsychiatric disorders. Drugs Today (Barc). 2018;54(12):713-719.
21. Davis RE, Vanover KE, Zhou Y, et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology (Berl). 2015;232(15):2863-72.
22. Björkholm C, Marcus MM, Konradsson-Geuken Å, et al. The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism. Eur Neuropsychopharmacol. 2017;27(4):411-417.
23. Bai Y, Yang H, Chen G, et al. Acceptability of acute and maintenance pharmacotherapy of bipolar disorder: a systematic review of randomized, double-blind, placebo-controlled clinical trials. J Clin Psychopharmacol. 2020;40(2):167-179.
24. Vyas P, Hwang BJ, Braši´c JR. An evaluation of lumateperone tosylate for the treatment of schizophrenia. Expert Opin Pharmacother. 2020;21(2):139-145.
25. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):160-168.
26. Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):169-77.
When is your patient a candidate for ECT?
LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?
In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.
“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”
It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”
In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”
An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”
A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”
However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”
According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.
Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.
LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?
In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.
“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”
It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”
In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”
An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”
A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”
However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”
According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.
Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.
LAS VEGAS – How do you know when a patient is a candidate for electroconvulsive therapy (ECT)?
In the opinion of Mark S. George, MD, it depends on the level of treatment resistance, other treatments the person may be receiving for severe depression or bipolar disorder, and the level of acuity.
“Acute ECT is also useful for catatonia that does not resolve with benzodiazepines, and it also works well for acute suicidality,” Dr. George, distinguished professor of psychiatry, radiology, and neurology at the Medical University of South Carolina, Charleston, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “The other reason you would go straight to ECT would be if someone has had good prior ECT response.”
It is lifesaving. Some studies suggests that ECT is effective in Parkinson’s disease and schizophrenia. Antidepressant effects generally take 2-3 weeks, but quicker responses are sometimes seen, especially in patients with bipolar depression.”
In the past 20 years of research studies involving ECT, investigators have discovered that a generalized seizure of adequate duration is necessary for adequate antidepressant effects; reduced therapeutic effects are seen with parietal placement, meaning that proper scalp placement matters; a dose titration over the 12 treatments improves efficacy, and smaller pulse widths are more effective and may result in fewer toxic side effects. “ECT is still relatively spatially crude compared with the other brain stimulation treatments,” said Dr. George, editor-in-chief of Brain Stimulation. “It’s also invasive, requiring repeated anesthesia, and sometimes has possible side effects including impacts on short-term memory.”
An emerging adjunct to ECT is cervical invasive vagus nerve stimulation (VNS) therapy, in which mild electrical pulses applied to the left vagus nerve in the neck send signals to the brain. “Surgeons wrap a wire around the vagus nerve and connect the wire to a generator which is embedded in the chest wall,” Dr. George explained. “The generator sends out a signal through the vagus nerve intermittently. You can program how it does that.”
A device from LivaNova known as the VNS Pulse Model 102 Generator was granted clearance for depression based on a comparative study, but in the absence of class I evidence. The generator is about the size of a quarter, is embedded under the skin, and its battery lasts for 8-10 years. “Patients are given a static magnet to use to turn the device off if they’re having side effects, as a safety precaution,” said Dr. George, a staff physician at the Ralph H. Johnson VA Medical Center in Charleston. “The side effects are mainly stimulation-based and typically decrease over time. There is a low rate of treatment discontinuation and no signal for treatment-related emergence of suicidal ideation/behavior. Sometimes you can get emergent mania or hypermania, but it’s rare. It’s pretty safe, but the insurance companies have been very slow to pay. You only get about 30% remission, this takes several months to years to achieve, and there’s no way to tell who’s going to respond before you place the device.”
However, results from a 5-year observational study of patients with treatment-resistant depression who were treated at 61 sites with VNS or treatment as usual found that the antidepressant effects built over time compared with treatment as usual (Am J Psychiatry 2017;174[7]:640-8). “There is remarkable durability but it’s not very fast,” he said. “It’s three months before you start seeing any differences.”
According to Dr. George, data from an informal registry of Medicare patients who received VNS treatment “did so much better” than untreated patients. “They didn’t need as much ECT and didn’t require as many hospitalizations,” he said. “They weren’t changing medications nearly as much. They found that VNS was saving money and saving people’s lives.” As a result, in September of 2019 LivaNova launched a prospective, multicenter, randomized, controlled, blinded trial of subjects implanted with VNS therapy, called RECOVER. Active treatment and no stimulation control are randomized at least 2 weeks after implantation and observed for 12 months. The study is ongoing with results expected in 2022 or 2023.
Dr. George disclosed that he is a paid consultant for Neurolief, Microtransponder, and Sooma and that he has been a paid consultant for GSK, Cyberonics, NeuroPace, and Jazz. He is an unpaid consultant to Brainsway, Neuronetics, Neostim, Neosync, and Magnus Medical.
FROM NPA 2022
Ketamine fast, effective for suicidal crises
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In addition, a strong effect of ketamine was observed in patients with bipolar disorder, “whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was nonsignificant in those with major depressive disorders,” the researchers wrote.
“We assessed for the first time in the same study the effect of ketamine on three a priori–defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses,” study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, said in an interview.
“This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder,” Dr. Jollant added.
The study was published online Feb. 2, 2022, in the BMJ.
Swift, full remission
The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.
They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.
The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0-2 (maximum score, 38).
“We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear,” said Dr. Jollant.
They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs. 32%; odds ratio, 3.7; 95% confidence interval, 1.9-7.3; P < .001).
This antisuicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors reported.
The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0-92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3-5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9-17.3; P = .07).
At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly versus placebo (69.5% vs. 56.3%; OR, 0.8; 95% CI, 0.3-2.5; P = .7).
The researchers noted the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.
“Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain,” they wrote.
Ketamine’s side effects were “limited” with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.
The investigators acknowledged that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is “challenging to interpret.”
They pointed out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.
A new perspective on ketamine
In an accompanying editorial, Riccardo De Giorgi, MD, Wellcome Trust doctoral training fellow, department of psychiatry, University of Oxford (England), said the study challenges current thinking about ketamine.
The “unexpected” outcome (no benefit) in the depressive group “perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine,” Dr. De Giorgi wrote.
“In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder,” Dr. De Giorgi pointed out.
“While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine,” Dr. De Giorgi wrote.
“Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts,” he concluded.
Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Dr. Jollant and Dr. De Giorgi disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE BMJ
Things reproductive psychiatrists might ‘always’ or ‘never’ do in 2022
The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.
The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.
To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
Things we ‘always’ do
1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.
Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.
2. I almost always treat with consistency of medication across the peripartum period.
Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).
3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.
We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.
4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.
Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.
We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.
5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.
We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.
The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.
The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
Things we ‘never’ do
1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).
Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.
We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.
We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.
2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.
Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.
3. We never switch antidepressants once a woman has become pregnant.
Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.
If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
Final thoughts
Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.
The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.
To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
Things we ‘always’ do
1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.
Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.
2. I almost always treat with consistency of medication across the peripartum period.
Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).
3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.
We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.
4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.
Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.
We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.
5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.
We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.
The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.
The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
Things we ‘never’ do
1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).
Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.
We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.
We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.
2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.
Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.
3. We never switch antidepressants once a woman has become pregnant.
Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.
If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
Final thoughts
Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.
The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.
To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
Things we ‘always’ do
1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.
Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.
2. I almost always treat with consistency of medication across the peripartum period.
Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).
3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.
We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.
4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.
Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.
We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.
5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.
We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.
The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.
The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
Things we ‘never’ do
1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).
Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.
We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.
We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.
2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.
Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.
3. We never switch antidepressants once a woman has become pregnant.
Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.
If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
Final thoughts
Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Siblings of people with bipolar disorder have higher cancer risk
, according to new research from Taiwan.
“To our knowledge, our study is the first to report an increased overall cancer risk as well as increased risks of breast and ectodermal cancer among the unaffected siblings aged < 50 years of patients with bipolar disorder,” Ya-Mei Bai, MD, PhD, of National Yang-Ming University, Taipei, Taiwan, and colleagues write in an article published online in the International Journal of Cancer.
Most, but not all, previous studies have shown a link between bipolar disorder and cancer. Whether the elevated risk of malignancy extends to family members without the mental health condition has not been elucidated.
To investigate, the researchers turned to the National Health Insurance Research Database of Taiwan. They identified 25,356 individuals diagnosed with bipolar disorder by a psychiatrist between 1996 and 2010 and the same number of unaffected siblings, as well as more than 100,000 age-, sex-, income-, and residence-matched controls without severe mental illness.
Compared with the control group, people with bipolar disorder (odds ratio, 1.22) and their unaffected siblings (OR, 1.17) both had a higher risk of developing malignant cancer of any kind. The researchers also found that both groups were at higher risk for breast cancer, with odds ratios of 1.98 in individuals with bipolar disorder and 1.73 in their unaffected siblings.
However, the risk of skin cancer was only high in people with bipolar disorder (OR, 2.70) and not in their siblings (OR, 0.62). And conversely, the risk of kidney cancer was significantly increased in unaffected siblings (OR, 2.45) but not in people with bipolar disorder (OR, 0.47).
When stratified by the embryonic developmental layer from which tumors had originated – ectodermal, mesodermal, or endodermal – the authors observed a significantly increased risk for only ectodermal cancers. In addition, only people under age 50 in both groups (OR, 1.90 for those with bipolar disorder; OR, 1.65 for siblings) were more likely to develop an ectodermal cancer, especially of the breast, compared with the control group. The risks remained elevated after excluding breast cancer but were no longer significant.
When stratified by age, the risk of developing any cancer in both groups also only appeared to be greater for those under age 50 (OR, 1.34 in people with bipolar disorder; OR, 1.32 in siblings) compared with those aged 50 and over (OR, 0.97 and 0.99, respectively). The authors highlighted these figures in the supplemental data set but did not discuss it further in the study beyond a brief mention that “younger patients with bipolar disorder and younger unaffected siblings (< 50 years), but not older ones (≥ 50 years), were more likely to develop any malignancy during the follow-up than matched controls.”
“This paper essentially finds what we have found in our previous work – that people with bipolar disorder have a greater risk of cancer,” said Michael Berk, MBBCh, PhD, a professor of psychiatry at the Deakin University School of Medicine in Geelong, Australia, who published a systematic review and meta-analysis last spring on cancer risk and the role of lithium treatment in bipolar disorder.
“The interesting finding in our work,” Dr. Berk told this news organization, “is that this risk is attenuated by use of lithium but not other agents.”
The Taiwanese researchers propose a “biopsychosocial explanation” for their results, noting that both the nervous system and the breast and skin develop from the ectoderm, and that cancer risk factors such as smoking and obesity are more common in people with bipolar disorder and their unaffected siblings.
“The findings,” they write, “imply a genetic overlap in neurodevelopment and malignancy pathogenesis and may encourage clinicians to closely monitor patients with bipolar disorder and their unaffected siblings for cancer warning signs.”
The authors, however, caution that their study needs validation and had several limitations, including lack of adjustment for drug treatment and lifestyle and environmental factors.
“Our findings may persuade clinicians and researchers to reevaluate the cancer risk among the unaffected siblings of patients with schizophrenia and bipolar disorder because these two severe mental disorders may have a common biopsychosocial pathophysiology,” the team writes.
The study was supported by a grant from Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and the Ministry of Science and Technology, Taiwan.
A version of this article first appeared on Medscape.com.
, according to new research from Taiwan.
“To our knowledge, our study is the first to report an increased overall cancer risk as well as increased risks of breast and ectodermal cancer among the unaffected siblings aged < 50 years of patients with bipolar disorder,” Ya-Mei Bai, MD, PhD, of National Yang-Ming University, Taipei, Taiwan, and colleagues write in an article published online in the International Journal of Cancer.
Most, but not all, previous studies have shown a link between bipolar disorder and cancer. Whether the elevated risk of malignancy extends to family members without the mental health condition has not been elucidated.
To investigate, the researchers turned to the National Health Insurance Research Database of Taiwan. They identified 25,356 individuals diagnosed with bipolar disorder by a psychiatrist between 1996 and 2010 and the same number of unaffected siblings, as well as more than 100,000 age-, sex-, income-, and residence-matched controls without severe mental illness.
Compared with the control group, people with bipolar disorder (odds ratio, 1.22) and their unaffected siblings (OR, 1.17) both had a higher risk of developing malignant cancer of any kind. The researchers also found that both groups were at higher risk for breast cancer, with odds ratios of 1.98 in individuals with bipolar disorder and 1.73 in their unaffected siblings.
However, the risk of skin cancer was only high in people with bipolar disorder (OR, 2.70) and not in their siblings (OR, 0.62). And conversely, the risk of kidney cancer was significantly increased in unaffected siblings (OR, 2.45) but not in people with bipolar disorder (OR, 0.47).
When stratified by the embryonic developmental layer from which tumors had originated – ectodermal, mesodermal, or endodermal – the authors observed a significantly increased risk for only ectodermal cancers. In addition, only people under age 50 in both groups (OR, 1.90 for those with bipolar disorder; OR, 1.65 for siblings) were more likely to develop an ectodermal cancer, especially of the breast, compared with the control group. The risks remained elevated after excluding breast cancer but were no longer significant.
When stratified by age, the risk of developing any cancer in both groups also only appeared to be greater for those under age 50 (OR, 1.34 in people with bipolar disorder; OR, 1.32 in siblings) compared with those aged 50 and over (OR, 0.97 and 0.99, respectively). The authors highlighted these figures in the supplemental data set but did not discuss it further in the study beyond a brief mention that “younger patients with bipolar disorder and younger unaffected siblings (< 50 years), but not older ones (≥ 50 years), were more likely to develop any malignancy during the follow-up than matched controls.”
“This paper essentially finds what we have found in our previous work – that people with bipolar disorder have a greater risk of cancer,” said Michael Berk, MBBCh, PhD, a professor of psychiatry at the Deakin University School of Medicine in Geelong, Australia, who published a systematic review and meta-analysis last spring on cancer risk and the role of lithium treatment in bipolar disorder.
“The interesting finding in our work,” Dr. Berk told this news organization, “is that this risk is attenuated by use of lithium but not other agents.”
The Taiwanese researchers propose a “biopsychosocial explanation” for their results, noting that both the nervous system and the breast and skin develop from the ectoderm, and that cancer risk factors such as smoking and obesity are more common in people with bipolar disorder and their unaffected siblings.
“The findings,” they write, “imply a genetic overlap in neurodevelopment and malignancy pathogenesis and may encourage clinicians to closely monitor patients with bipolar disorder and their unaffected siblings for cancer warning signs.”
The authors, however, caution that their study needs validation and had several limitations, including lack of adjustment for drug treatment and lifestyle and environmental factors.
“Our findings may persuade clinicians and researchers to reevaluate the cancer risk among the unaffected siblings of patients with schizophrenia and bipolar disorder because these two severe mental disorders may have a common biopsychosocial pathophysiology,” the team writes.
The study was supported by a grant from Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and the Ministry of Science and Technology, Taiwan.
A version of this article first appeared on Medscape.com.
, according to new research from Taiwan.
“To our knowledge, our study is the first to report an increased overall cancer risk as well as increased risks of breast and ectodermal cancer among the unaffected siblings aged < 50 years of patients with bipolar disorder,” Ya-Mei Bai, MD, PhD, of National Yang-Ming University, Taipei, Taiwan, and colleagues write in an article published online in the International Journal of Cancer.
Most, but not all, previous studies have shown a link between bipolar disorder and cancer. Whether the elevated risk of malignancy extends to family members without the mental health condition has not been elucidated.
To investigate, the researchers turned to the National Health Insurance Research Database of Taiwan. They identified 25,356 individuals diagnosed with bipolar disorder by a psychiatrist between 1996 and 2010 and the same number of unaffected siblings, as well as more than 100,000 age-, sex-, income-, and residence-matched controls without severe mental illness.
Compared with the control group, people with bipolar disorder (odds ratio, 1.22) and their unaffected siblings (OR, 1.17) both had a higher risk of developing malignant cancer of any kind. The researchers also found that both groups were at higher risk for breast cancer, with odds ratios of 1.98 in individuals with bipolar disorder and 1.73 in their unaffected siblings.
However, the risk of skin cancer was only high in people with bipolar disorder (OR, 2.70) and not in their siblings (OR, 0.62). And conversely, the risk of kidney cancer was significantly increased in unaffected siblings (OR, 2.45) but not in people with bipolar disorder (OR, 0.47).
When stratified by the embryonic developmental layer from which tumors had originated – ectodermal, mesodermal, or endodermal – the authors observed a significantly increased risk for only ectodermal cancers. In addition, only people under age 50 in both groups (OR, 1.90 for those with bipolar disorder; OR, 1.65 for siblings) were more likely to develop an ectodermal cancer, especially of the breast, compared with the control group. The risks remained elevated after excluding breast cancer but were no longer significant.
When stratified by age, the risk of developing any cancer in both groups also only appeared to be greater for those under age 50 (OR, 1.34 in people with bipolar disorder; OR, 1.32 in siblings) compared with those aged 50 and over (OR, 0.97 and 0.99, respectively). The authors highlighted these figures in the supplemental data set but did not discuss it further in the study beyond a brief mention that “younger patients with bipolar disorder and younger unaffected siblings (< 50 years), but not older ones (≥ 50 years), were more likely to develop any malignancy during the follow-up than matched controls.”
“This paper essentially finds what we have found in our previous work – that people with bipolar disorder have a greater risk of cancer,” said Michael Berk, MBBCh, PhD, a professor of psychiatry at the Deakin University School of Medicine in Geelong, Australia, who published a systematic review and meta-analysis last spring on cancer risk and the role of lithium treatment in bipolar disorder.
“The interesting finding in our work,” Dr. Berk told this news organization, “is that this risk is attenuated by use of lithium but not other agents.”
The Taiwanese researchers propose a “biopsychosocial explanation” for their results, noting that both the nervous system and the breast and skin develop from the ectoderm, and that cancer risk factors such as smoking and obesity are more common in people with bipolar disorder and their unaffected siblings.
“The findings,” they write, “imply a genetic overlap in neurodevelopment and malignancy pathogenesis and may encourage clinicians to closely monitor patients with bipolar disorder and their unaffected siblings for cancer warning signs.”
The authors, however, caution that their study needs validation and had several limitations, including lack of adjustment for drug treatment and lifestyle and environmental factors.
“Our findings may persuade clinicians and researchers to reevaluate the cancer risk among the unaffected siblings of patients with schizophrenia and bipolar disorder because these two severe mental disorders may have a common biopsychosocial pathophysiology,” the team writes.
The study was supported by a grant from Taipei Veterans General Hospital, Yen Tjing Ling Medical Foundation, and the Ministry of Science and Technology, Taiwan.
A version of this article first appeared on Medscape.com.
FROM INTERNATIONAL JOURNAL OF CANCER