MDedge Psychiatry

A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.

In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.

“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.

The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.

Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.

The findings were presented at the annual congress of the Schizophrenia International Research Society.
 

Time to relapse

To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.

After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.

Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.

Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.

Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.

In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.

The primary endpoint was time to impending relapse, the criteria for which included the following:

• Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
• Hospitalization because of worsening psychotic symptoms.
• Violent behavior resulting in clinically significant injury or damage.

Well tolerated?

In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.

This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).

At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).

While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.

Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.

The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”

Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”

He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.

“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.

The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
 

‘Highly desirable’ option

Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”

However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.

That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.

Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”

In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”

“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.

He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.

However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.

Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”

The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.

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

A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.

In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.

“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.

The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.

Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.

The findings were presented at the annual congress of the Schizophrenia International Research Society.
 

Time to relapse

To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.

After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.

Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.

Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.

Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.

In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.

The primary endpoint was time to impending relapse, the criteria for which included the following:

• Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
• Hospitalization because of worsening psychotic symptoms.
• Violent behavior resulting in clinically significant injury or damage.

Well tolerated?

In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.

This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).

At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).

While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.

Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.

The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”

Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”

He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.

“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.

The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
 

‘Highly desirable’ option

Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”

However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.

That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.

Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”

In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”

“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.

He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.

However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.

Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”

The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.

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

A long-acting subcutaneous antipsychotic (LASCA) suspension that combines risperidone with a novel copolymer substantially reduces risk for relapse and prolongs time to impending relapse for patients with schizophrenia, new research suggests.

In the phase 3 Risperidone Subcutaneous Extended-Release (RISE) trial, which included more than 500 patients with schizophrenia, those who received the novel combination treatment, known as TV-46000, had relapse reduced by 80% with monthly administration and by 63.5% with the bimonthly dose.

“Long-acting injectable medications are grossly underutilized,” study investigator John M. Kane, MD, Hofstra University, Hempstead, N.Y., told this news organization.

The attributes of TV-46000, which include its subcutaneous delivery rather than intramuscular injections, its being active within 24 hours of first treatment, and its being administered monthly or bimonthly, “might be advantageous for some patients,” Dr. Kane noted.

Because it is also effective in reducing risk for relapse, TV-46000 is “another alternative when people are looking at the possibility of using a long-acting injectable formulation,” he added.

The findings were presented at the annual congress of the Schizophrenia International Research Society.
 

Time to relapse

To examine the efficacy and safety of monthly and bimonthly doses of the drug, the researchers recruited patients aged 13-65 years who were diagnosed with schizophrenia more than a year previously and who had experienced at least one relapse in the previous 24 months.

After a screening period of up to 4 weeks, participants entered a 12-week pretreatment phase, during which their condition was stabilized on oral risperidone. During this period, the patients’ conditions had to remain stable for at least 4 consecutive weeks.

Patients were then randomly assigned in a 1:1:1 ratio to receive TV-46000 monthly, TV-46000 every 2 months, or matching placebo. All doses were given as subcutaneous injections.

Treatment was continued until participants experienced a relapse event, met at least one criteria for study withdrawal, or the study recorded a total of 90 or more relapse events.

Of 1,267 patients screened, 863 were enrolled in the study, and 544 underwent randomization. The median age of the patients who underwent randomization was 52 years; 61% were male; and the majority (59%) were Black.

In addition, the average length of time with the disease was 20.8 years, and the average time since the most recent relapse was 10.2 months.

The primary endpoint was time to impending relapse, the criteria for which included the following:

• Increases in Positive and Negative Syndrome Scale (PANSS) scores from randomization.
• Hospitalization because of worsening psychotic symptoms.
• Violent behavior resulting in clinically significant injury or damage.

Well tolerated?

In the intent-to-treat population, which comprised all adults who underwent randomization, monthly TV-46000 was associated with a fivefold prolongation of time to impending relapse in comparison with placebo; TV-46000 given every 2 months prolonged the time 2.7-fold.

This translated into a significant benefit vs. placebo for both TV-46000 monthly (hazard ratio for impending relapse, 0.2) and TV-46000 every 2 months (HR, 0.375; P < .0001 for both comparisons).

At the trial’s endpoint, impending relapse rates were 29% in the placebo group vs. 7% in the TV-46000 monthly group and 13% in the group that received TV-46000 every 2 months (P < .0001 for both).

While more patients in the two active-treatment groups met the strict criteria for remission, which included no relapse during the study and PANSS scores of 3 or less for at least 6 months prior to the study endpoint, the differences were not significant.

Treatment-related adverse events (AEs) were experienced by 39%-42% of the TV-46000 groups and by 26% of the placebo group. Serious AEs were experienced by 4%-6% of the TV-46000 groups and by 8% of the placebo group.

The investigators note that TV-46000 was “well tolerated” and that there were no new safety signals in comparison with what is already known about risperidone and “other long-acting risperidone formulations.”

Expanding on the reasons why long-acting antipsychotics are underprescribed, Dr. Kane said that “doctors often overestimate how adherent their patients are.”

He added that doctors may worry they are “insulting” their patient by suggesting they receive injections in order to increase adherence and that doctors are “not very good” at having these types of conversation with their patients.

“We did a study where we trained the clinical staff on how to have those conversations, and the result was the uptake [in patients switching to long-acting antipsychotics] was very high,” Dr. Kane said.

The personnel who received training included all of the medical team, therapists, who spend “much more time” with the patient than does the prescriber, and also social workers, case managers, and rehabilitation counselors, who are typically “not very familiar” with the idea of long-acting medications, he added.
 

‘Highly desirable’ option

Commenting on the study, Stephen R. Saklad, PharmD, director of the psychiatric pharmacy program, University of Texas Health Science Center at San Antonio, said that to call TV-46000 a LASCA rather than a depot injection is merely a “change in nomenclature.”

However, compared with a once-monthly subcutaneous injection of risperidone (Perseris), which was approved by the U.S. Food and Drug Administration in 2018 for the treatment of schizophrenia, the new drug has fewer injection site reactions, said Dr. Saklad, who was not involved with the current research.

That benefit plus having efficacy similar to that of oral risperidone and having the “more patient- and clinician-desirable administration location” of the upper arm as well as the abdomen means the option to switch a risperidone-stabilized patient directly to TV-46000 monthly or bimonthly is “highly desirable,” he added.

Dr. Saklad also noted the reduction in the likelihood of impending relapse with TV-46000 over placebo is a relatively large effect size “and shows the value toward improving the care of these patients.”

In addition, he agreed with Dr. Kane that the uptake of long-acting antipsychotics is “deplorably low.”

“This is due to a number of factors that include patient reluctance to get a ‘shot’ or ‘jab,’ clinician inexperience with LAIs during training, and the incorrect presentation of LAIs as a punishment paradigm for ‘bad’ patients,” Dr. Saklad said.

He added that “everyone tires of taking their medication or just forgets to take a dose,” and most patients with other disorders will resume their medication the next day.

However, patients with schizophrenia have a “specific cognitive difficulty” in making the connection between stopping their medication and a later relapse. If they miss a dose, they will “incorrectly conclude that they are now ‘well’ and don’t need the medication any longer,” he said.

Dr. Saklad stressed that for a patient with schizophrenia a relapse can mean substantial loss of function and of assets such as housing or support networks, and many “will complete suicide.”

The study was supported by Teva Branded Pharmaceutical Products R&D. Dr. Kane reported relationships with Alkermes, Allergan, Dainioppon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen, Janssen Pharmaceuticals, Johnson & Johnson, LB Pharmaceuticals, Merck, Neurocine, North Shore Therapeutics, Novartis Pharmaceutical, Otsuka, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, Otsuka, Lundbeck, Sunovion, UptoDate, and Vanguard Research Group.

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

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

The U.S. Preventive Services Task Force on Apr. 12 posted draft recommendations on screening for depression and anxiety in children and adolescents.

For the first time, the USPSTF is recommending screening children ages 8 and older for anxiety.

It also recommended screening children ages 12 and older for depression, which was consistent with the USPSTF’s prior recommendations on the topic.

These B-grade draft recommendations are for children and teens who are not showing signs or symptoms of these conditions. The task force emphasized that anyone who has concerns about or shows signs of these conditions should be connected to care.

Task force member Martha Kubik, PhD, RN, a professor with George Mason University, Fairfax, Va, said in a statement: “Fortunately, we found that screening older children for anxiety and depression is effective in identifying these conditions so children and teens can be connected to the support they need.”

The group cited in its recommendation on anxiety the 2018-2019 National Survey of Children’s Health, which found that 7.8% of children and adolescents ages 3-17 years had a current anxiety disorder. It also noted that the National Survey on LGBTQ Youth Mental Health found that 72% of LGBTQ youth and 77% of transgender and nonbinary youth described general anxiety disorder symptoms.

“Anxiety disorders in childhood and adolescence are associated with an increased likelihood of a future anxiety disorder or depression,” the task force authors wrote.

They highlighted that “the prevalence of anxiety in Black youth may be evolving.” Previously, studies had suggested that young Black people may have had lower rates of mental health disorders, compared with their White counterparts.

“However, recent cohorts of Black children or adolescents have reported a higher prevalence of anxiety disorders than in the past,” the authors wrote.

Joanna Quigley, MD, clinical associate professor and associate medical director for child & adolescent services at the University of Michigan, Ann Arbor, said in an interview she was not surprised the USPSTF recommended screening for anxiety starting at age 8.

That’s when parents and providers see anxiety disorders begin to present or become more problematic, she said.

“It’s also acknowledging the importance of prevention,” she said. “The sooner we can identify these challenges for kids, the sooner we can intervene and have better outcomes for that child across their lifespan.”

Screening gets providers and families in the habit of thinking about these concerns when a child or adolescent comes in for another kind of visit, Dr. Quigley said. Chest pains in a well-child check, for example, may trigger thoughts to consider anxiety later if the child is brought in for a cardiac check for chest pains.

“It creates a culture of awareness that is important as well,” Dr. Quigley said. “I think part of what the task force is trying to do is saying that identifying anxiety can be a precursor to what could turn out to be related to depression or related to ADHD and factors we think about when we think about suicide risk as well.

“We’re seeing an increase in suicide in the younger age group as well, which is a huge concern, “ she noted.

Dr. Quigley said, if these recommendations are adopted after the comment period, pediatricians and family practice providers will likely be doing most of the screening for anxiety, but there may also be a role for the screening in pediatric subspecialty care, such as those treating children with chronic illness and in specialized mental health care.

She added: “This builds on the national conversation going on about the mental health crisis, declared a national emergency in the fall. This deserves attention in continuing the momentum.”
 

Factors that may signal higher risk for depression

While the USPSTF recommends screening for major depressive disorder in all adolescents aged 12 years and older, the USPSTF notes that several risk factors might help identify those at higher risk.

Markers for higher risk include a combination of factors such as a family history of depression, prior episode of depression, and other mental health or behavioral problems.

“Other psychosocial risk factors include childhood abuse or neglect, exposure to traumatic events, bullying (either as perpetrators or as victims), adverse life events, early exposure to stress, maltreatment, and an insecure parental relationship,” the task force authors wrote.

There was limited evidence, however, on the benefits and harms of screening children younger than 8 for anxiety and screening kids younger than 12 for depression.
 

Not enough evidence for suicide risk screening

The authors of the recommendations acknowledged that, while suicide is a leading cause of death for older children and teens, evidence is still too sparse to make recommendations regarding screening for suicide risk in those without signs or symptoms at any age.

They also explained that evidence is lacking and inconsistent on the effectiveness of treatment (psychotherapy, pharmacotherapy, or collaborative care) for suicide risk in improving outcomes in children and adolescents.

Comments on the USPSTF recommendations may be submitted until May 9, 2022. The USPSTF topic leads review all comments, revise the draft recommendations, put them to a vote by the full task force, and then post the final versions to the website.

The task force authors and Dr. Quigley reported no financial disclosures.

AUT00206, a novel compound that targets potassium channels in brain interneurons, not only improves gamma oscillations in patients with schizophrenia, it also improves their symptoms, new randomized trial data suggest.

In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.

The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.

In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.

Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.

The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
 

‘Opportunity to intervene’

Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”

For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.

In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.

Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.

Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.

To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.

Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.

At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
 

Positive associations

Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.

There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).

Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).

While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.

They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”

However, Dr. Large noted that participants in their next study will have fragile X syndrome.

He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”

Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.

In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
 

Preliminary but worth pursuing?

Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”

Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.

He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”

The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.

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

AUT00206, a novel compound that targets potassium channels in brain interneurons, not only improves gamma oscillations in patients with schizophrenia, it also improves their symptoms, new randomized trial data suggest.

In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.

The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.

In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.

Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.

The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
 

‘Opportunity to intervene’

Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”

For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.

In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.

Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.

Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.

To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.

Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.

At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
 

Positive associations

Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.

There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).

Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).

While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.

They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”

However, Dr. Large noted that participants in their next study will have fragile X syndrome.

He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”

Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.

In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
 

Preliminary but worth pursuing?

Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”

Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.

He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”

The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.

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

AUT00206, a novel compound that targets potassium channels in brain interneurons, not only improves gamma oscillations in patients with schizophrenia, it also improves their symptoms, new randomized trial data suggest.

In a randomized, double-blind study that included two dozen men with schizophrenia, AUT00206, compared with placebo, increased the power of gamma oscillations, which were in turn associated with positive symptom scores.

The investigators note that targeting a potassium channel linked to brain gamma oscillations may offer a novel way to treat schizophrenia.

In addition, lead author Charles Large, PhD, chief executive officer, Autifony Therapeutics, Stevenage, United Kingdom, told this news organization that it may be “important” to study patients relatively early in their disease course. Participants in the current study were diagnosed less than 5 years previously.

Many previous trials in this area have failed, “and some of the questions were maybe the patients were sort of beyond the point in which you can actually make a difference,” Dr. Large said.

The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
 

‘Opportunity to intervene’

Dr. Large noted that patients with chronic, long-term symptoms of schizophrenia have been treated with antipsychotics for decades, “and the pathology of that stage is then different.”

For the current study, the investigators hypothesized that the brain may be more “plastic” earlier on in the disease course, and so “maybe there’s an opportunity to intervene and make a change,” said Dr. Large.

In addition, patients with schizophrenia have abnormalities in both their resting state and induced and evolved gamma oscillations, which can include increased resting state power – and reduced power and “phase locking” to cyclical stimuli – the researchers note.

Previous studies have suggested such abnormalities are associated with dysfunction in parvalbumin-expressing interneurons (PVINs) found in cortical and subcortical circuits.

Moreover, Kv3.1 potassium channels expressed on PVINs are integral to establishing and maintaining fast-firing activity and to network synchronization across the brain. They may, therefore, offer a “potential therapeutic approach” for countering PVIN dysfunction, the investigators write.

To examine the impact of AUT00206, a novel Kv3.1/Kv3.2 positive neuromodulator, on resting state and induced gamma oscillations, they conducted a randomized, double-blind study in 24 men with schizophrenia who were aged 18-50 years.

Participants had been diagnosed less than 5 years previously and were stable on a maximum of two antipsychotic medications. They were randomly assigned 2:1 to a loading 2,000-mg dose of AUT00206 on day 1 and then 800 mg twice daily for 27 days or to placebo.

At baseline/day 1, and on a further 3 days over the treatment period, the men underwent resting-state electroencephalography, 40-Hz auditory steady-state response stimulation, and deviant and standard stimulation in an auditory oddball paradigm to assess resting state, induced, and evoked oscillations, respectively.
 

Positive associations

Results showed that early auditory gamma responses were increased at day 28 in patients who received AUT00206 but not in those who received placebo. The active drug was also associated with increases in the power of gamma oscillations from Day 5 in response to stimuli but not in phase locking.

There was also a significant positive association between frontal resting gamma power and baseline Positive and Negative Syndrome Scale (PANSS) positive symptom severity scores (r = 0.675; P < .001).

Moreover, changes in PANSS positive scores were significantly correlated with a decrease in frontal resting gamma power in patients treated with AUT00206 (r = 0.532; P = .05).

While a similar correlation was not found with placebo, the investigators note this “may be in part due to the low number” of individuals in the group.

They add that a larger study is now needed to confirm their findings and to “explore efficacy versus clinical symptoms.”

However, Dr. Large noted that participants in their next study will have fragile X syndrome.

He added the reason for this is “not because we’ve given up on schizophrenia – we feel that schizophrenia is a massive opportunity.”

Patients with schizophrenia are heterogeneous, both in terms of their clinical course and prior treatment. So it is “impossible” for a company of their size to take all of that into account in a single study, Dr. Large said.

In contrast, fragile X is “genetically homogenous,” and so it is possible to focus on the deficit and then translate the findings out into a “broader population.”
 

Preliminary but worth pursuing?

Commenting on the study, James M. McNally, PhD, assistant professor of psychiatry, Harvard Medical School, Boston, said the findings are “quite preliminary” and that the investigators provided “limited information as to how their findings were derived.”

Nevertheless, it is “nice to see that they observed a significant correlation between resting gamma and positive symptom severity at baseline [and] that the observed change in gamma correlates with change in PANSS scores,” said Dr. McNally, who was not involved with the research.

He added that the “idea of targeting Kv3.1 function to restore PV neuron/gamma activity is very interesting and worth pursuing.”

The study was funded by Autifony Therapeutics, of which Dr. Large is an employee.

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

Driving from his home in Asheville, N.C., to his new job at the tiny Cane Creek clinic, Benjamin Gilmer, MD, was eager to start his new life and pay off his medical school debts.

The rural clinic had been forced to close after his predecessor, family physician Vince Gilmer, MD, (no relation) had been convicted of first-degree murder 4 years earlier. He was serving a life sentence in a West Virginia prison without the possibility of parole. He is still behind bars and could not comment on this story.

As the months flew by, Benjamin Gilmer’s patients shared stories about the other Dr. Gilmer that surprised him. They described Vince Gilmer as a caring, generous person who went out of his way to help them. He made house calls, and if a patient couldn’t afford to pay him, he would accept a bushel of corn instead.

Yet there was no doubt about the gruesome murder. Vince Gilmer was convicted of strangling his frail 60-year-old father with a rope in his Toyota truck. He then cut off all his father’s fingers and dumped his father’s body by the side of the road.

“Four years later, his patients were still shocked about what happened and couldn’t reconcile the person they knew with the event that happened,” says Benjamin Gilmer.

Yet, Vince Gilmer had admitted to the killing, and the prosecution had presented evidence at the trial that it was premeditated and that he tried to cover up the crime. The detectives found the “murder” weapons in Vince’s truck: the ropes he strangled his father with and the garden shears that he cut off his fingers with. They also had evidence that he drove to Virginia to dump the body, returned to see patients for several days as if nothing had happened, and then ran away when a detective came to arrest him.

But something kept gnawing away at Benjamin Gilmer. Could there be a medical explanation for his sudden change in personality and behavior?

Little did he know that he would embark on a journey to solve a medical mystery, and then even fight to get the convicted killer out of prison.
 

Solving a medical mystery

Benjamin Gilmer decided to investigate what might have happened to Vince in the months leading up to the murder. He talked to his friends and found several clues about Vince’s medical history. They recalled that he suffered a concussion in a car accident 6 months before the murder, which suggested he could have had a traumatic brain injury.

Benjamin Gilmer also discovered that Vince’s father was diagnosed with schizophrenia and had been in a residential psychiatric facility in Virginia until he was released that fateful night to Vince’s custody.

Vince had written to friends that “something is wrong with my brain and help me.” He mentioned SSRI discontinuation syndrome because he abruptly stopped taking his medication the week of the murder (which can cause electric shock sensations and mood swings among other symptoms).

Vince had mentioned the SSRI discontinuation syndrome at his trial and that his father had sexually molested him for years and that he tried to molest him again during the ride in his truck. However, the court dismissed that information because Vince represented himself, dismissed his court-appointed attorneys, and lacked expert testimony about his mental state.

The prosecutor portrayed Vince as a lying sociopath who had planned his father’s murder down to the last detail. The judge agreed. Two psychiatrists and a psychologist who later evaluated him in prison concluded that he was faking his symptoms and denied his requests for an SSRI.

Meanwhile, Benjamin Gilmer became increasingly preoccupied with what happened to Vince. “It was hard to erase a memory that had so tainted that community,” he said.

When Sarah Koenig, a journalist and former producer of the radio program This American Life, called Benjamin Gilmer to interview him about the coincidence of taking over Vince Gilmer’s practice and sharing the same last name, he refused. “I was scared and didn’t want to be on his radar, I was afraid of how he might react.”

In spring 2012, he called Koenig and agreed to collaborate on an episode about Vince’s case. Benjamin Gilmer wrote to Vince Gilmer in prison, asking for a meeting. To his surprise, Vince wanted to meet them.

When Vince shuffled into the waiting area at the Wallens Ridge State Prison in West Virginia, Benjamin Gilmer was shocked by his appearance. “He looked like a caged animal, it was very hard for him to string together ideas and express himself, and he was twitching and shaking dramatically. He looked 20 years older than his actual age of 50 and like someone you would imagine in the movie One Flew Over the Cuckoo’s Nest,” said Benjamin Gilmer.

He felt that “there was something clearly wrong with him.” They agreed to a second meeting, and this time Benjamin Gilmer invited a psychiatrist, Steve Buie, MD, to observe Vince. As the visit ended and Vince turned to leave, Dr. Buie watched his shuffling gait. They suspected he may have Huntington’s disease, “which explained why he had delusions and his mind was unraveling,” says Benjamin Gilmer. But they had no way of testing him in prison.

Unexpectedly, an event happened that turned the whole case on its head. Vince was moved to a psychiatric hospital in southern Virginia because he had threatened to commit suicide. The chief psychiatrist, Colin Angliker, MD, was willing to order a genetic test, and the results confirmed the diagnosis: Vince Gilmer had a terminal degenerative brain disease.

Benjamin Gilmer worried how Vince would take the news. To his surprise, Vince was grateful and relieved. He finally knew what was wrong with him.

Vince also improved with the SSRI that Dr. Angliker prescribed — he was less anxious and more mentally alert. “He expressed joy for the first time, despite the death sentence of a diagnosis.”

Still, he was going to spend the rest of his life in prison for the crime he committed.

After the This American Life episode aired in 2013, Benjamin Gilmer felt that he couldn’t just abandon Vince to the prison system, where thousands of inmates with mental illness languish without adequate treatment.

Benjamin Gilmer decided he had a new — although controversial — mission — to get Vince out.
 

Confronting the politics of a pardon

After nearly a decade of trying, Benjamin Gilmer now admits that he was naive to think he could get him released quickly.

After the episode aired, offers of legal help started to arrive, and a team was assembled who agreed to work on the case pro bono. They wanted justice for Vince but also to prevent anyone else with mental illness from experiencing a similar tragedy.

The goal was to get Vince transferred to a secure hospital, a psychiatric facility dedicated to Huntington’s patients, or a nursing home with a dementia unit.

However, after realizing that Vince may not survive a potentially lengthy court battle, the legal team decided to ask the governor of Virginia to grant a clemency pardon.

They gathered the evidence for Vince’s case and presented their petition to Gov. Terry McAuliffe (D). He rejected it at the end of his term in 2017.

The team tried again with his successor, Gov. Ralph Northam (D), a neurologist. He dashed their hopes when he rejected their petition in late 2021.

That was a huge setback. The team had spent $1 million and had exhausted every contact they could make with the governor’s office, says Gilmer. “We were totally demoralized.”

He dreaded having to tell Vince that yet another governor had rejected their clemency petition. “I went to prison and could see the hopelessness and despair in his reaction. I lost it emotionally,” says Benjamin Gilmer.

Vince surprised him by hugging and comforting him and thanking him for all his efforts. They had developed a strong bond over a decade of visits and calls. Benjamin Gilmer had even brought his wife and children along on special occasions.

“I thought of him as a friend, as a patient, and someone who was really suffering, all those things helped our relationship evolve and kept me engaged with him all these years and continued to inspire me to fight for him. I also liked him because I knew what he was like before the murder from the stories I was hearing from his friends and patients.”

But his continuous advocacy came at a personal cost. “This battle pushed me to my limits emotionally and intellectually. I was busy building my career, trying to be a good doctor, teacher, husband, and father to two young children. I became so distracted that my wife confronted me several times about not being more emotionally present,” says Benjamin Gilmer.

But he knows that without Vince in his life, he would not have written his first book (released earlier this year) about the case and their unlikely friendship.
 

A pardon is finally granted

He had also given Gov. Northam’s staff advance copies of the book. In a highly unusual move, the governor reversed his previous rejection and granted Vince Gilmer his long-awaited pardon on January 12.

Benjamin Gilmer isn’t ready to celebrate yet. “Despite being a free man, Vince is still living behind bars because we haven’t been able to find him an available bed in a secure treatment facility. There has been a shortage of beds due to COVID.”

He says Vince is looking forward to being safe and being surrounded by people who are committed to caring for him and not punishing him. He can’t wait to be around his family and to give and receive hugs.

“After a while, it was hard not to believe that I was supposed to be in his path and this was just part of my destiny,” says Benjamin Gilmer.

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

Driving from his home in Asheville, N.C., to his new job at the tiny Cane Creek clinic, Benjamin Gilmer, MD, was eager to start his new life and pay off his medical school debts.

The rural clinic had been forced to close after his predecessor, family physician Vince Gilmer, MD, (no relation) had been convicted of first-degree murder 4 years earlier. He was serving a life sentence in a West Virginia prison without the possibility of parole. He is still behind bars and could not comment on this story.

As the months flew by, Benjamin Gilmer’s patients shared stories about the other Dr. Gilmer that surprised him. They described Vince Gilmer as a caring, generous person who went out of his way to help them. He made house calls, and if a patient couldn’t afford to pay him, he would accept a bushel of corn instead.

Yet there was no doubt about the gruesome murder. Vince Gilmer was convicted of strangling his frail 60-year-old father with a rope in his Toyota truck. He then cut off all his father’s fingers and dumped his father’s body by the side of the road.

“Four years later, his patients were still shocked about what happened and couldn’t reconcile the person they knew with the event that happened,” says Benjamin Gilmer.

Yet, Vince Gilmer had admitted to the killing, and the prosecution had presented evidence at the trial that it was premeditated and that he tried to cover up the crime. The detectives found the “murder” weapons in Vince’s truck: the ropes he strangled his father with and the garden shears that he cut off his fingers with. They also had evidence that he drove to Virginia to dump the body, returned to see patients for several days as if nothing had happened, and then ran away when a detective came to arrest him.

But something kept gnawing away at Benjamin Gilmer. Could there be a medical explanation for his sudden change in personality and behavior?

Little did he know that he would embark on a journey to solve a medical mystery, and then even fight to get the convicted killer out of prison.
 

Solving a medical mystery

Benjamin Gilmer decided to investigate what might have happened to Vince in the months leading up to the murder. He talked to his friends and found several clues about Vince’s medical history. They recalled that he suffered a concussion in a car accident 6 months before the murder, which suggested he could have had a traumatic brain injury.

Benjamin Gilmer also discovered that Vince’s father was diagnosed with schizophrenia and had been in a residential psychiatric facility in Virginia until he was released that fateful night to Vince’s custody.

Vince had written to friends that “something is wrong with my brain and help me.” He mentioned SSRI discontinuation syndrome because he abruptly stopped taking his medication the week of the murder (which can cause electric shock sensations and mood swings among other symptoms).

Vince had mentioned the SSRI discontinuation syndrome at his trial and that his father had sexually molested him for years and that he tried to molest him again during the ride in his truck. However, the court dismissed that information because Vince represented himself, dismissed his court-appointed attorneys, and lacked expert testimony about his mental state.

The prosecutor portrayed Vince as a lying sociopath who had planned his father’s murder down to the last detail. The judge agreed. Two psychiatrists and a psychologist who later evaluated him in prison concluded that he was faking his symptoms and denied his requests for an SSRI.

Meanwhile, Benjamin Gilmer became increasingly preoccupied with what happened to Vince. “It was hard to erase a memory that had so tainted that community,” he said.

When Sarah Koenig, a journalist and former producer of the radio program This American Life, called Benjamin Gilmer to interview him about the coincidence of taking over Vince Gilmer’s practice and sharing the same last name, he refused. “I was scared and didn’t want to be on his radar, I was afraid of how he might react.”

In spring 2012, he called Koenig and agreed to collaborate on an episode about Vince’s case. Benjamin Gilmer wrote to Vince Gilmer in prison, asking for a meeting. To his surprise, Vince wanted to meet them.

When Vince shuffled into the waiting area at the Wallens Ridge State Prison in West Virginia, Benjamin Gilmer was shocked by his appearance. “He looked like a caged animal, it was very hard for him to string together ideas and express himself, and he was twitching and shaking dramatically. He looked 20 years older than his actual age of 50 and like someone you would imagine in the movie One Flew Over the Cuckoo’s Nest,” said Benjamin Gilmer.

He felt that “there was something clearly wrong with him.” They agreed to a second meeting, and this time Benjamin Gilmer invited a psychiatrist, Steve Buie, MD, to observe Vince. As the visit ended and Vince turned to leave, Dr. Buie watched his shuffling gait. They suspected he may have Huntington’s disease, “which explained why he had delusions and his mind was unraveling,” says Benjamin Gilmer. But they had no way of testing him in prison.

Unexpectedly, an event happened that turned the whole case on its head. Vince was moved to a psychiatric hospital in southern Virginia because he had threatened to commit suicide. The chief psychiatrist, Colin Angliker, MD, was willing to order a genetic test, and the results confirmed the diagnosis: Vince Gilmer had a terminal degenerative brain disease.

Benjamin Gilmer worried how Vince would take the news. To his surprise, Vince was grateful and relieved. He finally knew what was wrong with him.

Vince also improved with the SSRI that Dr. Angliker prescribed — he was less anxious and more mentally alert. “He expressed joy for the first time, despite the death sentence of a diagnosis.”

Still, he was going to spend the rest of his life in prison for the crime he committed.

After the This American Life episode aired in 2013, Benjamin Gilmer felt that he couldn’t just abandon Vince to the prison system, where thousands of inmates with mental illness languish without adequate treatment.

Benjamin Gilmer decided he had a new — although controversial — mission — to get Vince out.
 

Confronting the politics of a pardon

After nearly a decade of trying, Benjamin Gilmer now admits that he was naive to think he could get him released quickly.

After the episode aired, offers of legal help started to arrive, and a team was assembled who agreed to work on the case pro bono. They wanted justice for Vince but also to prevent anyone else with mental illness from experiencing a similar tragedy.

The goal was to get Vince transferred to a secure hospital, a psychiatric facility dedicated to Huntington’s patients, or a nursing home with a dementia unit.

However, after realizing that Vince may not survive a potentially lengthy court battle, the legal team decided to ask the governor of Virginia to grant a clemency pardon.

They gathered the evidence for Vince’s case and presented their petition to Gov. Terry McAuliffe (D). He rejected it at the end of his term in 2017.

The team tried again with his successor, Gov. Ralph Northam (D), a neurologist. He dashed their hopes when he rejected their petition in late 2021.

That was a huge setback. The team had spent $1 million and had exhausted every contact they could make with the governor’s office, says Gilmer. “We were totally demoralized.”

He dreaded having to tell Vince that yet another governor had rejected their clemency petition. “I went to prison and could see the hopelessness and despair in his reaction. I lost it emotionally,” says Benjamin Gilmer.

Vince surprised him by hugging and comforting him and thanking him for all his efforts. They had developed a strong bond over a decade of visits and calls. Benjamin Gilmer had even brought his wife and children along on special occasions.

“I thought of him as a friend, as a patient, and someone who was really suffering, all those things helped our relationship evolve and kept me engaged with him all these years and continued to inspire me to fight for him. I also liked him because I knew what he was like before the murder from the stories I was hearing from his friends and patients.”

But his continuous advocacy came at a personal cost. “This battle pushed me to my limits emotionally and intellectually. I was busy building my career, trying to be a good doctor, teacher, husband, and father to two young children. I became so distracted that my wife confronted me several times about not being more emotionally present,” says Benjamin Gilmer.

But he knows that without Vince in his life, he would not have written his first book (released earlier this year) about the case and their unlikely friendship.
 

A pardon is finally granted

He had also given Gov. Northam’s staff advance copies of the book. In a highly unusual move, the governor reversed his previous rejection and granted Vince Gilmer his long-awaited pardon on January 12.

Benjamin Gilmer isn’t ready to celebrate yet. “Despite being a free man, Vince is still living behind bars because we haven’t been able to find him an available bed in a secure treatment facility. There has been a shortage of beds due to COVID.”

He says Vince is looking forward to being safe and being surrounded by people who are committed to caring for him and not punishing him. He can’t wait to be around his family and to give and receive hugs.

“After a while, it was hard not to believe that I was supposed to be in his path and this was just part of my destiny,” says Benjamin Gilmer.

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

Driving from his home in Asheville, N.C., to his new job at the tiny Cane Creek clinic, Benjamin Gilmer, MD, was eager to start his new life and pay off his medical school debts.

The rural clinic had been forced to close after his predecessor, family physician Vince Gilmer, MD, (no relation) had been convicted of first-degree murder 4 years earlier. He was serving a life sentence in a West Virginia prison without the possibility of parole. He is still behind bars and could not comment on this story.

As the months flew by, Benjamin Gilmer’s patients shared stories about the other Dr. Gilmer that surprised him. They described Vince Gilmer as a caring, generous person who went out of his way to help them. He made house calls, and if a patient couldn’t afford to pay him, he would accept a bushel of corn instead.

Yet there was no doubt about the gruesome murder. Vince Gilmer was convicted of strangling his frail 60-year-old father with a rope in his Toyota truck. He then cut off all his father’s fingers and dumped his father’s body by the side of the road.

“Four years later, his patients were still shocked about what happened and couldn’t reconcile the person they knew with the event that happened,” says Benjamin Gilmer.

Yet, Vince Gilmer had admitted to the killing, and the prosecution had presented evidence at the trial that it was premeditated and that he tried to cover up the crime. The detectives found the “murder” weapons in Vince’s truck: the ropes he strangled his father with and the garden shears that he cut off his fingers with. They also had evidence that he drove to Virginia to dump the body, returned to see patients for several days as if nothing had happened, and then ran away when a detective came to arrest him.

But something kept gnawing away at Benjamin Gilmer. Could there be a medical explanation for his sudden change in personality and behavior?

Little did he know that he would embark on a journey to solve a medical mystery, and then even fight to get the convicted killer out of prison.
 

Solving a medical mystery

Benjamin Gilmer decided to investigate what might have happened to Vince in the months leading up to the murder. He talked to his friends and found several clues about Vince’s medical history. They recalled that he suffered a concussion in a car accident 6 months before the murder, which suggested he could have had a traumatic brain injury.

Benjamin Gilmer also discovered that Vince’s father was diagnosed with schizophrenia and had been in a residential psychiatric facility in Virginia until he was released that fateful night to Vince’s custody.

Vince had written to friends that “something is wrong with my brain and help me.” He mentioned SSRI discontinuation syndrome because he abruptly stopped taking his medication the week of the murder (which can cause electric shock sensations and mood swings among other symptoms).

Vince had mentioned the SSRI discontinuation syndrome at his trial and that his father had sexually molested him for years and that he tried to molest him again during the ride in his truck. However, the court dismissed that information because Vince represented himself, dismissed his court-appointed attorneys, and lacked expert testimony about his mental state.

The prosecutor portrayed Vince as a lying sociopath who had planned his father’s murder down to the last detail. The judge agreed. Two psychiatrists and a psychologist who later evaluated him in prison concluded that he was faking his symptoms and denied his requests for an SSRI.

Meanwhile, Benjamin Gilmer became increasingly preoccupied with what happened to Vince. “It was hard to erase a memory that had so tainted that community,” he said.

When Sarah Koenig, a journalist and former producer of the radio program This American Life, called Benjamin Gilmer to interview him about the coincidence of taking over Vince Gilmer’s practice and sharing the same last name, he refused. “I was scared and didn’t want to be on his radar, I was afraid of how he might react.”

In spring 2012, he called Koenig and agreed to collaborate on an episode about Vince’s case. Benjamin Gilmer wrote to Vince Gilmer in prison, asking for a meeting. To his surprise, Vince wanted to meet them.

When Vince shuffled into the waiting area at the Wallens Ridge State Prison in West Virginia, Benjamin Gilmer was shocked by his appearance. “He looked like a caged animal, it was very hard for him to string together ideas and express himself, and he was twitching and shaking dramatically. He looked 20 years older than his actual age of 50 and like someone you would imagine in the movie One Flew Over the Cuckoo’s Nest,” said Benjamin Gilmer.

He felt that “there was something clearly wrong with him.” They agreed to a second meeting, and this time Benjamin Gilmer invited a psychiatrist, Steve Buie, MD, to observe Vince. As the visit ended and Vince turned to leave, Dr. Buie watched his shuffling gait. They suspected he may have Huntington’s disease, “which explained why he had delusions and his mind was unraveling,” says Benjamin Gilmer. But they had no way of testing him in prison.

Unexpectedly, an event happened that turned the whole case on its head. Vince was moved to a psychiatric hospital in southern Virginia because he had threatened to commit suicide. The chief psychiatrist, Colin Angliker, MD, was willing to order a genetic test, and the results confirmed the diagnosis: Vince Gilmer had a terminal degenerative brain disease.

Benjamin Gilmer worried how Vince would take the news. To his surprise, Vince was grateful and relieved. He finally knew what was wrong with him.

Vince also improved with the SSRI that Dr. Angliker prescribed — he was less anxious and more mentally alert. “He expressed joy for the first time, despite the death sentence of a diagnosis.”

Still, he was going to spend the rest of his life in prison for the crime he committed.

After the This American Life episode aired in 2013, Benjamin Gilmer felt that he couldn’t just abandon Vince to the prison system, where thousands of inmates with mental illness languish without adequate treatment.

Benjamin Gilmer decided he had a new — although controversial — mission — to get Vince out.
 

Confronting the politics of a pardon

After nearly a decade of trying, Benjamin Gilmer now admits that he was naive to think he could get him released quickly.

After the episode aired, offers of legal help started to arrive, and a team was assembled who agreed to work on the case pro bono. They wanted justice for Vince but also to prevent anyone else with mental illness from experiencing a similar tragedy.

The goal was to get Vince transferred to a secure hospital, a psychiatric facility dedicated to Huntington’s patients, or a nursing home with a dementia unit.

However, after realizing that Vince may not survive a potentially lengthy court battle, the legal team decided to ask the governor of Virginia to grant a clemency pardon.

They gathered the evidence for Vince’s case and presented their petition to Gov. Terry McAuliffe (D). He rejected it at the end of his term in 2017.

The team tried again with his successor, Gov. Ralph Northam (D), a neurologist. He dashed their hopes when he rejected their petition in late 2021.

That was a huge setback. The team had spent $1 million and had exhausted every contact they could make with the governor’s office, says Gilmer. “We were totally demoralized.”

He dreaded having to tell Vince that yet another governor had rejected their clemency petition. “I went to prison and could see the hopelessness and despair in his reaction. I lost it emotionally,” says Benjamin Gilmer.

Vince surprised him by hugging and comforting him and thanking him for all his efforts. They had developed a strong bond over a decade of visits and calls. Benjamin Gilmer had even brought his wife and children along on special occasions.

“I thought of him as a friend, as a patient, and someone who was really suffering, all those things helped our relationship evolve and kept me engaged with him all these years and continued to inspire me to fight for him. I also liked him because I knew what he was like before the murder from the stories I was hearing from his friends and patients.”

But his continuous advocacy came at a personal cost. “This battle pushed me to my limits emotionally and intellectually. I was busy building my career, trying to be a good doctor, teacher, husband, and father to two young children. I became so distracted that my wife confronted me several times about not being more emotionally present,” says Benjamin Gilmer.

But he knows that without Vince in his life, he would not have written his first book (released earlier this year) about the case and their unlikely friendship.
 

A pardon is finally granted

He had also given Gov. Northam’s staff advance copies of the book. In a highly unusual move, the governor reversed his previous rejection and granted Vince Gilmer his long-awaited pardon on January 12.

Benjamin Gilmer isn’t ready to celebrate yet. “Despite being a free man, Vince is still living behind bars because we haven’t been able to find him an available bed in a secure treatment facility. There has been a shortage of beds due to COVID.”

He says Vince is looking forward to being safe and being surrounded by people who are committed to caring for him and not punishing him. He can’t wait to be around his family and to give and receive hugs.

“After a while, it was hard not to believe that I was supposed to be in his path and this was just part of my destiny,” says Benjamin Gilmer.

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

New research points to a general mechanism that may explain how psychedelics act on the brain to alleviate depression and potentially other psychiatric conditions marked by fixed patterns of thinking, including rumination and excessive self-focus.

Led by investigators from the University of California, San Francisco, and Imperial College London’s Centre for Psychedelic Research, the findings come from a new analysis of brain scans of almost 60 patients with resistant depression treated with psilocybin.

Thomas Angus/Imperial College London

“Not much is known about the changes in brain function after psychedelic experience. There has been much more research done on the acute brain action of psychedelics, but there is very little on the postacute or subacute changes in brain function,” study investigator Robin Carhart-Harris, PhD, former head of the Imperial Centre for Psychedelic Research and now director of the Neuroscape psychedelics division at UCSF, and senior author of the study, told this news organization.

“This research is a major advance because it is showing replication across two datasets with different designs. One in which the scanning is done 1 day after intervention and the other one when the posttreatment scanning is done 3 weeks after the second of two psilocybin therapy sessions,” Dr. Carhart-Harris added.

The study was published online in Nature Medicine.
 

A disruptor?

Psilocybin is one of a number of psychedelics under investigation as a potential therapy for psychiatric disorders. In the last 15 years, at least six separate clinical trials have reported impressive improvements in depressive symptoms with psilocybin therapy. Several studies have tested a synthesized a form of the drug to treat patients with depression and anxiety – with promising results.

However, the therapeutic action of psilocybin and other serotonergic psychedelics is still not completely understood, although it is known that they affect 5-HT_2A receptors and are hypothesized to briefly disrupt these connections, allowing them to reform in new ways in the days and weeks following treatment.

This research assessed the subacute impact of psilocybin on brain function in two clinical trials of depression:

The first trial was an open-label trial of oral psilocybin in patients with treatment-resistant depression.

Patients had baseline clinical assessment and resting-state functional MRI, followed by fixed-order “low” (10 mg) and “high” (25 mg) psilocybin therapy dosing days separated by 1 week. Of the 19 patients recruited, 3 were excluded as a result of excessive fMRI head motion. The team confirmed an antidepressant effect of psilocybin in 16 patients via reduced questionnaire scores from baseline.

Brain network modularity was significantly reduced 1 day after psilocybin therapy in 10 of 16 participants (mean difference, –0.29; t₁₅, 2.87; 95% confidence interval, 0.07-0.50; P = .012; d = 0.72). This result implies an increase in functional connectivity between the brain’s main intrinsic networks. 

Pre- vs posttreatment change in modularity significantly correlated with change in Beck Depression Inventory (BDI) score at 6 months, relative to baseline (r₁₄ = 0.54, 95% CI, 0.14-0.78, P = .033). Results imply that decreased brain modularity 1 day after psilocybin therapy relates to long-term improvements in symptom severity.
 

Effective antidepressant alternative?

The second trial was a double-blind, phase 2, randomized, controlled trial comparing psilocybin with escitalopram (Lexapro). Twenty-one patients were included in the escitalopram imaging sample and 22 patients were included in the psilocybin imaging sample. 

Patients received either 2 x 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (psilocybin arm) or 2 x 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (escitalopram arm). Functional MRI was recorded at baseline and 3 weeks after the second psilocybin dose.

On average, BDI-measured reductions in depressive symptom severity were significantly greater under psilocybin than escitalopram, indicating superior efficacy of psilocybin therapy versus escitalopram.

Evidence indicated that the reduction in network modularity and its relationship to depression severity was specific to the psilocybin group. In the escitalopram group, network modularity did not change from baseline and there was no significant correlation between changes in modularity and changes in BDI scores. 

Post–psilocybin therapy changes in network flexibility were correlated with changes in BDI score. After false discovery rate correction, increased executive network dynamic flexibility strongly correlated with greater symptom improvement at the 6-week primary endpoint for the psilocybin arm (r20, –0.76, 95% CI, −0.90 to –0.50, P = .001).

There were no significant correlations between changes in BDI scores and changes in dynamic flexibility in the escitalopram arm.

Imperial Centre for Psychedelic Research

“These findings are important because for the first time we find that psilocybin works differently from conventional antidepressants, making the brain more flexible and fluid and less entrenched in the negative thinking patterns associated with depression. This supports our initial predictions and confirms psilocybin could be a real alternative approach to depression treatments,” study investigator David Nutt, DM, head of the Imperial Centre for Psychedelic Research, London, said in a release.

“In previous studies we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here we’re seeing it weeks after treatment for depression, which suggests a carryover of the acute drug action,” said Dr. Carhart-Harris.
 

Durable effect?

“We don’t yet know how long the changes in brain activity seen with psilocybin therapy last, and we need to do more research to understand this,” said Dr. Carhart-Harris, who is a member of the UCSF Weill Institute for Neurosciences. “If the changes don’t last, then is it related to relapse into a depressive episode? We need to do follow-up scans to see where people’s brains are at 3 months or even 6 months after treatment.

“We do know that some people relapse, and it may be that after a while their brains revert to the rigid patterns of activity we see in depression.

“One exciting implication of our findings is that we have discovered a fundamental mechanism via which psychedelic therapy works not just for depression but other mental illnesses, such as anorexia or addiction. We now need to test if this is the case, and if it is, then we have found something important,” added Dr. Carhart-Harris.

Successful phase 3, double-blind randomized, controlled trials will be required to achieve licensing for psilocybin therapy, but pragmatic trials may better address questions regarding treatment practicability, specificity, and optimization. Given the emerging research into psychedelic therapy, it is important for large-scale trials to establish the generalizability, reliability, and specificity of the drug’s antidepressant response.

So how close are we to full federal approval for psilocybin in the treatment of depression? Dr. Carhart-Harris estimated that within 4-5 years is realistic at the federal level. At the state level, in Oregon psilocybin therapy is on track for approval in 2023, including for patients currently undergoing treatment for depressive disorders. In addition, things are opening up in Canada, with some special-access opportunities.

The researchers cautioned that, while these findings are encouraging, trials assessing psilocybin for depression have taken place under controlled, clinical conditions, using a regulated dose formulated in a laboratory, and involved extensive psychological support by a mental health professional – before, during, and after dosing. Taking psychedelics in the absence of these combined safeguards may not have a positive outcome.

The research was supported by funding from the Alex Mosley Charitable Trust and founding donors of the Imperial Centre for Psychedelic Research. One coauthor was supported by the Imperial College London EPSRC Centre London for doctoral training in neurotechnology.

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

New research points to a general mechanism that may explain how psychedelics act on the brain to alleviate depression and potentially other psychiatric conditions marked by fixed patterns of thinking, including rumination and excessive self-focus.

Led by investigators from the University of California, San Francisco, and Imperial College London’s Centre for Psychedelic Research, the findings come from a new analysis of brain scans of almost 60 patients with resistant depression treated with psilocybin.

Thomas Angus/Imperial College London

“Not much is known about the changes in brain function after psychedelic experience. There has been much more research done on the acute brain action of psychedelics, but there is very little on the postacute or subacute changes in brain function,” study investigator Robin Carhart-Harris, PhD, former head of the Imperial Centre for Psychedelic Research and now director of the Neuroscape psychedelics division at UCSF, and senior author of the study, told this news organization.

“This research is a major advance because it is showing replication across two datasets with different designs. One in which the scanning is done 1 day after intervention and the other one when the posttreatment scanning is done 3 weeks after the second of two psilocybin therapy sessions,” Dr. Carhart-Harris added.

The study was published online in Nature Medicine.
 

A disruptor?

Psilocybin is one of a number of psychedelics under investigation as a potential therapy for psychiatric disorders. In the last 15 years, at least six separate clinical trials have reported impressive improvements in depressive symptoms with psilocybin therapy. Several studies have tested a synthesized a form of the drug to treat patients with depression and anxiety – with promising results.

However, the therapeutic action of psilocybin and other serotonergic psychedelics is still not completely understood, although it is known that they affect 5-HT_2A receptors and are hypothesized to briefly disrupt these connections, allowing them to reform in new ways in the days and weeks following treatment.

This research assessed the subacute impact of psilocybin on brain function in two clinical trials of depression:

The first trial was an open-label trial of oral psilocybin in patients with treatment-resistant depression.

Patients had baseline clinical assessment and resting-state functional MRI, followed by fixed-order “low” (10 mg) and “high” (25 mg) psilocybin therapy dosing days separated by 1 week. Of the 19 patients recruited, 3 were excluded as a result of excessive fMRI head motion. The team confirmed an antidepressant effect of psilocybin in 16 patients via reduced questionnaire scores from baseline.

Brain network modularity was significantly reduced 1 day after psilocybin therapy in 10 of 16 participants (mean difference, –0.29; t₁₅, 2.87; 95% confidence interval, 0.07-0.50; P = .012; d = 0.72). This result implies an increase in functional connectivity between the brain’s main intrinsic networks. 

Pre- vs posttreatment change in modularity significantly correlated with change in Beck Depression Inventory (BDI) score at 6 months, relative to baseline (r₁₄ = 0.54, 95% CI, 0.14-0.78, P = .033). Results imply that decreased brain modularity 1 day after psilocybin therapy relates to long-term improvements in symptom severity.
 

Effective antidepressant alternative?

The second trial was a double-blind, phase 2, randomized, controlled trial comparing psilocybin with escitalopram (Lexapro). Twenty-one patients were included in the escitalopram imaging sample and 22 patients were included in the psilocybin imaging sample. 

Patients received either 2 x 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (psilocybin arm) or 2 x 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (escitalopram arm). Functional MRI was recorded at baseline and 3 weeks after the second psilocybin dose.

On average, BDI-measured reductions in depressive symptom severity were significantly greater under psilocybin than escitalopram, indicating superior efficacy of psilocybin therapy versus escitalopram.

Evidence indicated that the reduction in network modularity and its relationship to depression severity was specific to the psilocybin group. In the escitalopram group, network modularity did not change from baseline and there was no significant correlation between changes in modularity and changes in BDI scores. 

Post–psilocybin therapy changes in network flexibility were correlated with changes in BDI score. After false discovery rate correction, increased executive network dynamic flexibility strongly correlated with greater symptom improvement at the 6-week primary endpoint for the psilocybin arm (r20, –0.76, 95% CI, −0.90 to –0.50, P = .001).

There were no significant correlations between changes in BDI scores and changes in dynamic flexibility in the escitalopram arm.

Imperial Centre for Psychedelic Research

“These findings are important because for the first time we find that psilocybin works differently from conventional antidepressants, making the brain more flexible and fluid and less entrenched in the negative thinking patterns associated with depression. This supports our initial predictions and confirms psilocybin could be a real alternative approach to depression treatments,” study investigator David Nutt, DM, head of the Imperial Centre for Psychedelic Research, London, said in a release.

“In previous studies we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here we’re seeing it weeks after treatment for depression, which suggests a carryover of the acute drug action,” said Dr. Carhart-Harris.
 

Durable effect?

“We don’t yet know how long the changes in brain activity seen with psilocybin therapy last, and we need to do more research to understand this,” said Dr. Carhart-Harris, who is a member of the UCSF Weill Institute for Neurosciences. “If the changes don’t last, then is it related to relapse into a depressive episode? We need to do follow-up scans to see where people’s brains are at 3 months or even 6 months after treatment.

“We do know that some people relapse, and it may be that after a while their brains revert to the rigid patterns of activity we see in depression.

“One exciting implication of our findings is that we have discovered a fundamental mechanism via which psychedelic therapy works not just for depression but other mental illnesses, such as anorexia or addiction. We now need to test if this is the case, and if it is, then we have found something important,” added Dr. Carhart-Harris.

Successful phase 3, double-blind randomized, controlled trials will be required to achieve licensing for psilocybin therapy, but pragmatic trials may better address questions regarding treatment practicability, specificity, and optimization. Given the emerging research into psychedelic therapy, it is important for large-scale trials to establish the generalizability, reliability, and specificity of the drug’s antidepressant response.

So how close are we to full federal approval for psilocybin in the treatment of depression? Dr. Carhart-Harris estimated that within 4-5 years is realistic at the federal level. At the state level, in Oregon psilocybin therapy is on track for approval in 2023, including for patients currently undergoing treatment for depressive disorders. In addition, things are opening up in Canada, with some special-access opportunities.

The researchers cautioned that, while these findings are encouraging, trials assessing psilocybin for depression have taken place under controlled, clinical conditions, using a regulated dose formulated in a laboratory, and involved extensive psychological support by a mental health professional – before, during, and after dosing. Taking psychedelics in the absence of these combined safeguards may not have a positive outcome.

The research was supported by funding from the Alex Mosley Charitable Trust and founding donors of the Imperial Centre for Psychedelic Research. One coauthor was supported by the Imperial College London EPSRC Centre London for doctoral training in neurotechnology.

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

New research points to a general mechanism that may explain how psychedelics act on the brain to alleviate depression and potentially other psychiatric conditions marked by fixed patterns of thinking, including rumination and excessive self-focus.

Led by investigators from the University of California, San Francisco, and Imperial College London’s Centre for Psychedelic Research, the findings come from a new analysis of brain scans of almost 60 patients with resistant depression treated with psilocybin.

Thomas Angus/Imperial College London

“Not much is known about the changes in brain function after psychedelic experience. There has been much more research done on the acute brain action of psychedelics, but there is very little on the postacute or subacute changes in brain function,” study investigator Robin Carhart-Harris, PhD, former head of the Imperial Centre for Psychedelic Research and now director of the Neuroscape psychedelics division at UCSF, and senior author of the study, told this news organization.

“This research is a major advance because it is showing replication across two datasets with different designs. One in which the scanning is done 1 day after intervention and the other one when the posttreatment scanning is done 3 weeks after the second of two psilocybin therapy sessions,” Dr. Carhart-Harris added.

The study was published online in Nature Medicine.
 

A disruptor?

Psilocybin is one of a number of psychedelics under investigation as a potential therapy for psychiatric disorders. In the last 15 years, at least six separate clinical trials have reported impressive improvements in depressive symptoms with psilocybin therapy. Several studies have tested a synthesized a form of the drug to treat patients with depression and anxiety – with promising results.

However, the therapeutic action of psilocybin and other serotonergic psychedelics is still not completely understood, although it is known that they affect 5-HT_2A receptors and are hypothesized to briefly disrupt these connections, allowing them to reform in new ways in the days and weeks following treatment.

This research assessed the subacute impact of psilocybin on brain function in two clinical trials of depression:

The first trial was an open-label trial of oral psilocybin in patients with treatment-resistant depression.

Patients had baseline clinical assessment and resting-state functional MRI, followed by fixed-order “low” (10 mg) and “high” (25 mg) psilocybin therapy dosing days separated by 1 week. Of the 19 patients recruited, 3 were excluded as a result of excessive fMRI head motion. The team confirmed an antidepressant effect of psilocybin in 16 patients via reduced questionnaire scores from baseline.

Brain network modularity was significantly reduced 1 day after psilocybin therapy in 10 of 16 participants (mean difference, –0.29; t₁₅, 2.87; 95% confidence interval, 0.07-0.50; P = .012; d = 0.72). This result implies an increase in functional connectivity between the brain’s main intrinsic networks. 

Pre- vs posttreatment change in modularity significantly correlated with change in Beck Depression Inventory (BDI) score at 6 months, relative to baseline (r₁₄ = 0.54, 95% CI, 0.14-0.78, P = .033). Results imply that decreased brain modularity 1 day after psilocybin therapy relates to long-term improvements in symptom severity.
 

Effective antidepressant alternative?

The second trial was a double-blind, phase 2, randomized, controlled trial comparing psilocybin with escitalopram (Lexapro). Twenty-one patients were included in the escitalopram imaging sample and 22 patients were included in the psilocybin imaging sample. 

Patients received either 2 x 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (psilocybin arm) or 2 x 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (escitalopram arm). Functional MRI was recorded at baseline and 3 weeks after the second psilocybin dose.

On average, BDI-measured reductions in depressive symptom severity were significantly greater under psilocybin than escitalopram, indicating superior efficacy of psilocybin therapy versus escitalopram.

Evidence indicated that the reduction in network modularity and its relationship to depression severity was specific to the psilocybin group. In the escitalopram group, network modularity did not change from baseline and there was no significant correlation between changes in modularity and changes in BDI scores. 

Post–psilocybin therapy changes in network flexibility were correlated with changes in BDI score. After false discovery rate correction, increased executive network dynamic flexibility strongly correlated with greater symptom improvement at the 6-week primary endpoint for the psilocybin arm (r20, –0.76, 95% CI, −0.90 to –0.50, P = .001).

There were no significant correlations between changes in BDI scores and changes in dynamic flexibility in the escitalopram arm.

Imperial Centre for Psychedelic Research

“These findings are important because for the first time we find that psilocybin works differently from conventional antidepressants, making the brain more flexible and fluid and less entrenched in the negative thinking patterns associated with depression. This supports our initial predictions and confirms psilocybin could be a real alternative approach to depression treatments,” study investigator David Nutt, DM, head of the Imperial Centre for Psychedelic Research, London, said in a release.

“In previous studies we had seen a similar effect in the brain when people were scanned whilst on a psychedelic, but here we’re seeing it weeks after treatment for depression, which suggests a carryover of the acute drug action,” said Dr. Carhart-Harris.
 

Durable effect?

“We don’t yet know how long the changes in brain activity seen with psilocybin therapy last, and we need to do more research to understand this,” said Dr. Carhart-Harris, who is a member of the UCSF Weill Institute for Neurosciences. “If the changes don’t last, then is it related to relapse into a depressive episode? We need to do follow-up scans to see where people’s brains are at 3 months or even 6 months after treatment.

“We do know that some people relapse, and it may be that after a while their brains revert to the rigid patterns of activity we see in depression.

“One exciting implication of our findings is that we have discovered a fundamental mechanism via which psychedelic therapy works not just for depression but other mental illnesses, such as anorexia or addiction. We now need to test if this is the case, and if it is, then we have found something important,” added Dr. Carhart-Harris.

Successful phase 3, double-blind randomized, controlled trials will be required to achieve licensing for psilocybin therapy, but pragmatic trials may better address questions regarding treatment practicability, specificity, and optimization. Given the emerging research into psychedelic therapy, it is important for large-scale trials to establish the generalizability, reliability, and specificity of the drug’s antidepressant response.

So how close are we to full federal approval for psilocybin in the treatment of depression? Dr. Carhart-Harris estimated that within 4-5 years is realistic at the federal level. At the state level, in Oregon psilocybin therapy is on track for approval in 2023, including for patients currently undergoing treatment for depressive disorders. In addition, things are opening up in Canada, with some special-access opportunities.

The researchers cautioned that, while these findings are encouraging, trials assessing psilocybin for depression have taken place under controlled, clinical conditions, using a regulated dose formulated in a laboratory, and involved extensive psychological support by a mental health professional – before, during, and after dosing. Taking psychedelics in the absence of these combined safeguards may not have a positive outcome.

The research was supported by funding from the Alex Mosley Charitable Trust and founding donors of the Imperial Centre for Psychedelic Research. One coauthor was supported by the Imperial College London EPSRC Centre London for doctoral training in neurotechnology.

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

When benzodiazepines were first introduced, they were greeted with enthusiasm. Librium came first, in 1960, followed by Valium in 1962, and they were seen as an improvement over barbiturates for the treatment of anxiety, insomnia, and seizures. From 1968 to 1982, Valium (diazepam) was the No. 1–selling U.S. pharmaceutical: 2.3 billion tablets of Valium were sold in 1978 alone. Valium was even the subject of a 1966 Rolling Stones hit, “Mother’s Little Helper.”

By the 1980s, it became apparent that there was a downside to these medications: patients became tolerant, dependent, and some became addicted to the medications. In older patients an association was noted with falls and cognitive impairment. And while safe in overdoses when they are the only agent, combined with alcohol or opioids, benzodiazepines can be lethal and have played a significant role in the current overdose crisis.

Because of the problems that are associated with their use, benzodiazepines and their relatives, the Z-drugs used for sleep, have become stigmatized, as have the patients who use them and perhaps even the doctors who prescribe them. Still, there are circumstances where patients find these medications to be helpful, where other medications don’t work, or don’t work quickly enough. They provide fast relief in conditions where there are not always good alternatives.

In the Facebook group, “Psychiatry for All Physicians,” it’s not uncommon for physicians to ask what to do with older patients who are transferred to them on therapeutic doses of benzodiazepines or zolpidem. These are outpatients coming for routine care, and they find the medications helpful and don’t want to discontinue them. They have tried other medications that were not helpful. I’ve been surprised at how often the respondents insist the patient should be told he must taper off the medication. “Just say no,” is often the advice, and perhaps it’s more about the doctor’s discomfort than it is about the individual patient. For sleep issues, cognitive-behavioral therapy is given as the gold-standard treatment, while in my practice I have found it difficult to motivate patients to engage in it, and of those who do, it is sometimes helpful, but not a panacea. Severe anxiety and sleepless nights, however, are not benign conditions.

This “just say no, hold the line” sentiment has me wondering if our pendulum has swung too far with respect to prescribing benzodiazepines. Is this just one more issue that has become strongly polarized? Certainly the literature would support that idea, with some physicians writing about how benzodiazepines are underused, and others urging avoidance.

I posted a poll on Twitter: Has the anti-benzo movement gone too far? In addition, I started a Twitter thread of my own thoughts about prescribing and deprescribing these medications and will give a synopsis of those ideas here.

Clearly, benzodiazepines are harmful to some patients, they have side effects, can be difficult to stop because of withdrawal symptoms, and they carry the risk of addiction. That’s not in question. Many medications, however, have the potential to do more harm than good, for example ibuprofen can cause bleeding or renal problems, and Fosamax, used to treat osteoporosis, can cause osteonecrosis of the jaw and femur, to name just two.

It would be so much easier if we could know in advance who benzodiazepines will harm, just as it would be good if we could know in advance who will get tardive dyskinesia or dyslipidemia from antipsychotic medications, or who will have life-threatening adverse reactions from cancer chemotherapy with no tumor response. There are risks to both starting and stopping sedatives, and if we insist a patient stop a medication because of potential risk, then we are cutting them off from being a partner in their own care. It also creates an adversarial relationship that can be draining for the doctor and upsetting for the patient.

By definition, if someone needs hospitalization for a psychiatric condition, their outpatient benzodiazepine is not keeping them stable and stopping it may be a good idea. If someone is seen in an ED for a fall, it’s common to blame the benzodiazepine, but older people who are not on these medications also fall and have memory problems. In his book, “Being Mortal: Illness, Medicine, and What Matters Most in the End” (New York: Picador, 2014), Atul Gawande, MD, makes the point that taking more than four prescriptions medications increases the risk for falls in the elderly. Still, no one is suggesting patients be taken off their antidepressants, antihypertensives, or blood thinners.

Finally, the question is not should we be giving benzodiazepines out without careful consideration – the answer is clearly no. Physicians don’t pass out benzodiazepines “like candy” for all the above reasons. They are initiated because the patient is suffering and sometimes desperate. Anxiety, panic, intractable insomnia, and severe agitation are all miserable, and alternative treatments may take weeks to work, or not work at all. Yet these subjective symptoms may be dismissed by physicians.

So what do I do in my own practice? I don’t encourage patients to take potentially addictive medications, but I do sometimes use them. I give ‘as needed’ benzodiazepines to people in distress who don’t have a history of misusing them. I never plan to start them as a permanent standing medication, though once in a while that ends up happening. As with other medications, it is best to use the minimally effective dose.

There is some controversy as to whether it is best to use anxiety medications on an “as-needed” basis or as a standing dosage. Psychiatrists who prescribe benzodiazepines more liberally often feel it’s better to give standing doses and prevent breakthrough anxiety. Patients may appear to be ‘medication seeking’ not because they are addicted, but because the doses used are too low to adequately treat their anxiety.

My hope is that there is less risk of tolerance, dependence, or addiction with less-frequent dosing, and I prescribe as-needed benzodiazepines for panic attacks, agitated major depression while we wait for the antidepressant to “kick in,” insomnia during manic episodes, and to people who get very anxious in specific situations such as flying or for medical procedures. I sometimes prescribe them for people with insomnia that does not respond to other treatments, or for disabling generalized anxiety.

For patients who have taken benzodiazepines for many years, I continue to discuss the risks, but often they are not looking to fix something that isn’t broken, or to live a risk-free life. A few of the patients who have come to me on low standing doses of sedatives are now in their 80’s, yet they remain active, live independently, drive, travel, and have busy social lives. One could argue either that the medications are working, or that the patient has become dependent on them and needs them to prevent withdrawal.

These medications present a quandary: by denying patients treatment with benzodiazepines, we are sparing some people addictions (this is good, we should be careful), but we are leaving some people to suffer. There is no perfect answer.

What I do know is that doctors should think carefully and consider the patient in front of them. “No Benzos Ever For Anyone” or “you must come off because there is risk and people will think I am a bad doctor for prescribing them to you” can be done by a robot.

So, yes, I think the pendulum has swung a bit too far; there is a place for these medications in acute treatment for those at low risk of addiction, and there are people who benefit from them over the long run. At times, they provide immense relief to someone who is really struggling.

So what was the result of my Twitter poll? Of the 219 voters, 34.2% voted: “No, the pendulum has not swung too far, and these medications are harmful”; 65.8% voted: “Yes, these medications are helpful.” There were many comments expressing a wide variety of sentiments. Of those who had taken prescription benzodiazepines, some felt they had been harmed and wished they had never been started on them, and others continue to find them helpful. Psychiatrists, it seems, see them from the vantage point of the populations they treat.

People who are uncomfortable search for answers, and those answers may come in the form of meditation or exercise, medicines, or illicit drugs. It’s interesting that these same patients can now easily obtain “medical” marijuana, and the Rolling Stones’ “Mother’s Little Helper” is often replaced by a gin and tonic.

Dr. Dinah 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.

When benzodiazepines were first introduced, they were greeted with enthusiasm. Librium came first, in 1960, followed by Valium in 1962, and they were seen as an improvement over barbiturates for the treatment of anxiety, insomnia, and seizures. From 1968 to 1982, Valium (diazepam) was the No. 1–selling U.S. pharmaceutical: 2.3 billion tablets of Valium were sold in 1978 alone. Valium was even the subject of a 1966 Rolling Stones hit, “Mother’s Little Helper.”

By the 1980s, it became apparent that there was a downside to these medications: patients became tolerant, dependent, and some became addicted to the medications. In older patients an association was noted with falls and cognitive impairment. And while safe in overdoses when they are the only agent, combined with alcohol or opioids, benzodiazepines can be lethal and have played a significant role in the current overdose crisis.

Because of the problems that are associated with their use, benzodiazepines and their relatives, the Z-drugs used for sleep, have become stigmatized, as have the patients who use them and perhaps even the doctors who prescribe them. Still, there are circumstances where patients find these medications to be helpful, where other medications don’t work, or don’t work quickly enough. They provide fast relief in conditions where there are not always good alternatives.

In the Facebook group, “Psychiatry for All Physicians,” it’s not uncommon for physicians to ask what to do with older patients who are transferred to them on therapeutic doses of benzodiazepines or zolpidem. These are outpatients coming for routine care, and they find the medications helpful and don’t want to discontinue them. They have tried other medications that were not helpful. I’ve been surprised at how often the respondents insist the patient should be told he must taper off the medication. “Just say no,” is often the advice, and perhaps it’s more about the doctor’s discomfort than it is about the individual patient. For sleep issues, cognitive-behavioral therapy is given as the gold-standard treatment, while in my practice I have found it difficult to motivate patients to engage in it, and of those who do, it is sometimes helpful, but not a panacea. Severe anxiety and sleepless nights, however, are not benign conditions.

This “just say no, hold the line” sentiment has me wondering if our pendulum has swung too far with respect to prescribing benzodiazepines. Is this just one more issue that has become strongly polarized? Certainly the literature would support that idea, with some physicians writing about how benzodiazepines are underused, and others urging avoidance.

I posted a poll on Twitter: Has the anti-benzo movement gone too far? In addition, I started a Twitter thread of my own thoughts about prescribing and deprescribing these medications and will give a synopsis of those ideas here.

Clearly, benzodiazepines are harmful to some patients, they have side effects, can be difficult to stop because of withdrawal symptoms, and they carry the risk of addiction. That’s not in question. Many medications, however, have the potential to do more harm than good, for example ibuprofen can cause bleeding or renal problems, and Fosamax, used to treat osteoporosis, can cause osteonecrosis of the jaw and femur, to name just two.

It would be so much easier if we could know in advance who benzodiazepines will harm, just as it would be good if we could know in advance who will get tardive dyskinesia or dyslipidemia from antipsychotic medications, or who will have life-threatening adverse reactions from cancer chemotherapy with no tumor response. There are risks to both starting and stopping sedatives, and if we insist a patient stop a medication because of potential risk, then we are cutting them off from being a partner in their own care. It also creates an adversarial relationship that can be draining for the doctor and upsetting for the patient.

By definition, if someone needs hospitalization for a psychiatric condition, their outpatient benzodiazepine is not keeping them stable and stopping it may be a good idea. If someone is seen in an ED for a fall, it’s common to blame the benzodiazepine, but older people who are not on these medications also fall and have memory problems. In his book, “Being Mortal: Illness, Medicine, and What Matters Most in the End” (New York: Picador, 2014), Atul Gawande, MD, makes the point that taking more than four prescriptions medications increases the risk for falls in the elderly. Still, no one is suggesting patients be taken off their antidepressants, antihypertensives, or blood thinners.

Finally, the question is not should we be giving benzodiazepines out without careful consideration – the answer is clearly no. Physicians don’t pass out benzodiazepines “like candy” for all the above reasons. They are initiated because the patient is suffering and sometimes desperate. Anxiety, panic, intractable insomnia, and severe agitation are all miserable, and alternative treatments may take weeks to work, or not work at all. Yet these subjective symptoms may be dismissed by physicians.

So what do I do in my own practice? I don’t encourage patients to take potentially addictive medications, but I do sometimes use them. I give ‘as needed’ benzodiazepines to people in distress who don’t have a history of misusing them. I never plan to start them as a permanent standing medication, though once in a while that ends up happening. As with other medications, it is best to use the minimally effective dose.

There is some controversy as to whether it is best to use anxiety medications on an “as-needed” basis or as a standing dosage. Psychiatrists who prescribe benzodiazepines more liberally often feel it’s better to give standing doses and prevent breakthrough anxiety. Patients may appear to be ‘medication seeking’ not because they are addicted, but because the doses used are too low to adequately treat their anxiety.

My hope is that there is less risk of tolerance, dependence, or addiction with less-frequent dosing, and I prescribe as-needed benzodiazepines for panic attacks, agitated major depression while we wait for the antidepressant to “kick in,” insomnia during manic episodes, and to people who get very anxious in specific situations such as flying or for medical procedures. I sometimes prescribe them for people with insomnia that does not respond to other treatments, or for disabling generalized anxiety.

For patients who have taken benzodiazepines for many years, I continue to discuss the risks, but often they are not looking to fix something that isn’t broken, or to live a risk-free life. A few of the patients who have come to me on low standing doses of sedatives are now in their 80’s, yet they remain active, live independently, drive, travel, and have busy social lives. One could argue either that the medications are working, or that the patient has become dependent on them and needs them to prevent withdrawal.

These medications present a quandary: by denying patients treatment with benzodiazepines, we are sparing some people addictions (this is good, we should be careful), but we are leaving some people to suffer. There is no perfect answer.

What I do know is that doctors should think carefully and consider the patient in front of them. “No Benzos Ever For Anyone” or “you must come off because there is risk and people will think I am a bad doctor for prescribing them to you” can be done by a robot.

So, yes, I think the pendulum has swung a bit too far; there is a place for these medications in acute treatment for those at low risk of addiction, and there are people who benefit from them over the long run. At times, they provide immense relief to someone who is really struggling.

So what was the result of my Twitter poll? Of the 219 voters, 34.2% voted: “No, the pendulum has not swung too far, and these medications are harmful”; 65.8% voted: “Yes, these medications are helpful.” There were many comments expressing a wide variety of sentiments. Of those who had taken prescription benzodiazepines, some felt they had been harmed and wished they had never been started on them, and others continue to find them helpful. Psychiatrists, it seems, see them from the vantage point of the populations they treat.

People who are uncomfortable search for answers, and those answers may come in the form of meditation or exercise, medicines, or illicit drugs. It’s interesting that these same patients can now easily obtain “medical” marijuana, and the Rolling Stones’ “Mother’s Little Helper” is often replaced by a gin and tonic.

Dr. Dinah 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.

When benzodiazepines were first introduced, they were greeted with enthusiasm. Librium came first, in 1960, followed by Valium in 1962, and they were seen as an improvement over barbiturates for the treatment of anxiety, insomnia, and seizures. From 1968 to 1982, Valium (diazepam) was the No. 1–selling U.S. pharmaceutical: 2.3 billion tablets of Valium were sold in 1978 alone. Valium was even the subject of a 1966 Rolling Stones hit, “Mother’s Little Helper.”

By the 1980s, it became apparent that there was a downside to these medications: patients became tolerant, dependent, and some became addicted to the medications. In older patients an association was noted with falls and cognitive impairment. And while safe in overdoses when they are the only agent, combined with alcohol or opioids, benzodiazepines can be lethal and have played a significant role in the current overdose crisis.

Because of the problems that are associated with their use, benzodiazepines and their relatives, the Z-drugs used for sleep, have become stigmatized, as have the patients who use them and perhaps even the doctors who prescribe them. Still, there are circumstances where patients find these medications to be helpful, where other medications don’t work, or don’t work quickly enough. They provide fast relief in conditions where there are not always good alternatives.

In the Facebook group, “Psychiatry for All Physicians,” it’s not uncommon for physicians to ask what to do with older patients who are transferred to them on therapeutic doses of benzodiazepines or zolpidem. These are outpatients coming for routine care, and they find the medications helpful and don’t want to discontinue them. They have tried other medications that were not helpful. I’ve been surprised at how often the respondents insist the patient should be told he must taper off the medication. “Just say no,” is often the advice, and perhaps it’s more about the doctor’s discomfort than it is about the individual patient. For sleep issues, cognitive-behavioral therapy is given as the gold-standard treatment, while in my practice I have found it difficult to motivate patients to engage in it, and of those who do, it is sometimes helpful, but not a panacea. Severe anxiety and sleepless nights, however, are not benign conditions.

This “just say no, hold the line” sentiment has me wondering if our pendulum has swung too far with respect to prescribing benzodiazepines. Is this just one more issue that has become strongly polarized? Certainly the literature would support that idea, with some physicians writing about how benzodiazepines are underused, and others urging avoidance.

I posted a poll on Twitter: Has the anti-benzo movement gone too far? In addition, I started a Twitter thread of my own thoughts about prescribing and deprescribing these medications and will give a synopsis of those ideas here.

Clearly, benzodiazepines are harmful to some patients, they have side effects, can be difficult to stop because of withdrawal symptoms, and they carry the risk of addiction. That’s not in question. Many medications, however, have the potential to do more harm than good, for example ibuprofen can cause bleeding or renal problems, and Fosamax, used to treat osteoporosis, can cause osteonecrosis of the jaw and femur, to name just two.

It would be so much easier if we could know in advance who benzodiazepines will harm, just as it would be good if we could know in advance who will get tardive dyskinesia or dyslipidemia from antipsychotic medications, or who will have life-threatening adverse reactions from cancer chemotherapy with no tumor response. There are risks to both starting and stopping sedatives, and if we insist a patient stop a medication because of potential risk, then we are cutting them off from being a partner in their own care. It also creates an adversarial relationship that can be draining for the doctor and upsetting for the patient.

By definition, if someone needs hospitalization for a psychiatric condition, their outpatient benzodiazepine is not keeping them stable and stopping it may be a good idea. If someone is seen in an ED for a fall, it’s common to blame the benzodiazepine, but older people who are not on these medications also fall and have memory problems. In his book, “Being Mortal: Illness, Medicine, and What Matters Most in the End” (New York: Picador, 2014), Atul Gawande, MD, makes the point that taking more than four prescriptions medications increases the risk for falls in the elderly. Still, no one is suggesting patients be taken off their antidepressants, antihypertensives, or blood thinners.

Finally, the question is not should we be giving benzodiazepines out without careful consideration – the answer is clearly no. Physicians don’t pass out benzodiazepines “like candy” for all the above reasons. They are initiated because the patient is suffering and sometimes desperate. Anxiety, panic, intractable insomnia, and severe agitation are all miserable, and alternative treatments may take weeks to work, or not work at all. Yet these subjective symptoms may be dismissed by physicians.

So what do I do in my own practice? I don’t encourage patients to take potentially addictive medications, but I do sometimes use them. I give ‘as needed’ benzodiazepines to people in distress who don’t have a history of misusing them. I never plan to start them as a permanent standing medication, though once in a while that ends up happening. As with other medications, it is best to use the minimally effective dose.

There is some controversy as to whether it is best to use anxiety medications on an “as-needed” basis or as a standing dosage. Psychiatrists who prescribe benzodiazepines more liberally often feel it’s better to give standing doses and prevent breakthrough anxiety. Patients may appear to be ‘medication seeking’ not because they are addicted, but because the doses used are too low to adequately treat their anxiety.

My hope is that there is less risk of tolerance, dependence, or addiction with less-frequent dosing, and I prescribe as-needed benzodiazepines for panic attacks, agitated major depression while we wait for the antidepressant to “kick in,” insomnia during manic episodes, and to people who get very anxious in specific situations such as flying or for medical procedures. I sometimes prescribe them for people with insomnia that does not respond to other treatments, or for disabling generalized anxiety.

For patients who have taken benzodiazepines for many years, I continue to discuss the risks, but often they are not looking to fix something that isn’t broken, or to live a risk-free life. A few of the patients who have come to me on low standing doses of sedatives are now in their 80’s, yet they remain active, live independently, drive, travel, and have busy social lives. One could argue either that the medications are working, or that the patient has become dependent on them and needs them to prevent withdrawal.

These medications present a quandary: by denying patients treatment with benzodiazepines, we are sparing some people addictions (this is good, we should be careful), but we are leaving some people to suffer. There is no perfect answer.

What I do know is that doctors should think carefully and consider the patient in front of them. “No Benzos Ever For Anyone” or “you must come off because there is risk and people will think I am a bad doctor for prescribing them to you” can be done by a robot.

So, yes, I think the pendulum has swung a bit too far; there is a place for these medications in acute treatment for those at low risk of addiction, and there are people who benefit from them over the long run. At times, they provide immense relief to someone who is really struggling.

So what was the result of my Twitter poll? Of the 219 voters, 34.2% voted: “No, the pendulum has not swung too far, and these medications are harmful”; 65.8% voted: “Yes, these medications are helpful.” There were many comments expressing a wide variety of sentiments. Of those who had taken prescription benzodiazepines, some felt they had been harmed and wished they had never been started on them, and others continue to find them helpful. Psychiatrists, it seems, see them from the vantage point of the populations they treat.

People who are uncomfortable search for answers, and those answers may come in the form of meditation or exercise, medicines, or illicit drugs. It’s interesting that these same patients can now easily obtain “medical” marijuana, and the Rolling Stones’ “Mother’s Little Helper” is often replaced by a gin and tonic.

Dr. Dinah 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.

What causes the dramatic alterations in subjective awareness experienced during a psychedelic “trip?” A new study maps anatomical changes in specific neurotransmitter systems and brain regions that may be responsible for these effects.

Investigators gathered more than 6,800 accounts from individuals who had taken one of 27 different psychedelic compounds. Using a machine learning strategy, they extracted commonly used words from these testimonials, linking them with 40 different neurotransmitter subtypes that had likely induced these experiences.

The investigators then linked these subjective experiences with specific brain regions where the receptor combinations are most commonly found and, using gene transcription probes, created a 3D whole-brain map of the brain receptors and the subjective experiences linked to them.

“Hallucinogenic drugs may very well turn out to be the next big thing to improve clinical care of major mental health conditions,” senior author Danilo Bzdok, MD, PhD, associate professor, McGill University, Montreal, said in a press release.

“Our study provides a first step, a proof of principle, that we may be able to build machine-learning systems in the future that can accurately predict which neurotransmitter receptor combinations need to be stimulated to induce a specific state of conscious experience in a given person,” said Dr. Bzdok, who is also the Canada CIFAR AI Chair at Mila-Quebec Artificial Intelligence Institute.

The study was published online  in Science Advances.
 

‘Unique window’

Psychedelic drugs “show promise” as treatments for various psychiatric disorders, but subjective alterations of reality are “highly variable across individuals” and this “poses a key challenge as we venture to bring hallucinogenic substances into medical practice,” the investigators note.

Although the 5-HT2A receptor has been regarded as a “putative essential mechanism” of hallucinogenic experiences, it is unclear whether the experiential differences are explained by functional selectivity at the 5-HT2A receptor itself or “orchestrated by the vast array of neurotransmitter receptor subclasses on which these drugs act,” they add.

Lead author Galen Ballentine, MD, psychiatry resident, SUNY Downstate Medical Center, Brooklyn, told this news organization that he was “personally eager to find novel ways to identify the neurobiological underpinnings of different states of conscious awareness.”

Psychedelics, he said, offer a “unique window into a vast array of unusual states of consciousness and are particularly useful because they can point toward underlying mechanistic processes that are initiated in specific areas of receptor expression.”

The investigators wanted to understand “how these drugs work in order to help guide their use in clinical practice,” Dr. Ballentine said.

To explore the issue, they undertook the “largest investigation to date into the neuroscience of psychedelic drug experiences,” Dr. Ballentine said. “While most studies are limited to a single drug on a handful of subjects, this project integrates thousands of experiences induced by dozens of different hallucinogenic compounds, viewing them through the prism of 40 receptor subtypes.”
 

Unique neurotransmitter fingerprint

The researchers analyzed 6,850 experience reports of people who had taken 1 of 27 psychedelic compounds. The reports were drawn from a database hosted by the Erowid Center, an organization that collects first-hand accounts of experiences elicited by psychoactive drugs.

The researchers constructed a “bag-of-words” encoding of the text descriptions in each testimonial. Using linguistic calculation methods, they derived a final vocabulary of 14,410 words that they analyzed for descriptive experiential terms.

To shed light on the spatial distribution of these compounds that modulate neuronal activity during subjective “trips,” they compared normalized measurements of their relative binding strengths in 40 sites.

• 5-HT (5-HT2A, 5-HT2C, 5-HT2B, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT5A, 5-HT6, 5-HT7)
• Dopamine (D1, D2, D3, D4, D5)
• Adrenergic (a-1A, a-1B, a-2A, a-2B, a-2C, b-1, b-2)
• Serotonin transporter (SERT)
• Dopamine transporter (DAT)
• Norepinephrine transporter (NET)
• Imidazoline-1 receptor (I1)
• Sigma receptors (s-1, s-2)
• d-opioid receptor (DOR)
• k-opioid receptor (KOR)
• m-opioid receptor (MOR)
• Muscarinic receptors (M1, M2, M3, M4, M5)
• Histamine receptors (H1, H2)
• Calcium ion channel (CA+)
• NMDA glutamate receptor

To map receptor-experience factors to regional levels of receptor gene transcription, they utilized human gene expression data drawn from the Allen Human Brain Atlas, as well as the Shafer-Yeo brain atlas.

Via a machine-learning algorithm, they dissected the “phenomenologically rich anecdotes” into a ranking of constituent brain-behavior factors, each of which was characterized by a “unique neurotransmitter fingerprint of action and a unique experiential context” and ultimately created a dimensional map of these neurotransmitter systems.
 

Data-driven framework

Cortex-wide distribution of receptor-experience factors was found in both deep and shallow anatomical brain regions. Regions involved in genetic factor expressions were also wide-ranging, spanning from higher association cortices to unimodal sensory cortices.

The dominant factor “elucidated mystical experience in general and the dissolution of self-world boundaries (ego dissolution) in particular,” the authors report, while the second- and third-most explanatory factors “evoked auditory, visual, and emotional themes of mental expansion.”

Ego dissolution was found to be most associated with the 5-HT2A receptor, as well as other serotonin receptors (5-HT2C, 5-HT1A, 5-HT2B), adrenergic receptors a-2A and b-2, and the D2 receptor.

Alterations in sensory perception were associated with expression of the 5-HT2A receptor in the visual cortex, while modulation of the salience network by dopamine and opioid receptors were implicated in the experience transcendence of space, time, and the structure of self. Auditory hallucinations were linked to a weighted blend of receptors expressed throughout the auditory cortex.

“This data-driven framework identifies patterns that undergird diverse psychedelic experiences such as mystical bliss, existential terror, and complex hallucinations,” Dr. Ballentine commented.

“Simultaneously subjective and neurobiological, these patterns align with the leading hypothesis that psychedelics temporarily diminish top-down control of the most evolutionarily advanced regions of the brain, while at the same time amplifying bottom-up sensory processing from primary sensory cortices,” he added.
 

Forging a new path

Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics and director of the Centre of Excellence at Sheppard Pratt, Towson, Md., said, “As we try to get our arms around understanding the implications of a psychedelic exposure, forward-thinking researchers like Dr. Bzdok et al. are offering interesting ways to capture and understand the experience.”

Dr. Aaronson, an adjunct professor at the University of Maryland School of Medicine who was not involved with the study, continued: “Using the rapidly developing field of natural language processing (NLP), which looks at how language is used for a deeper understanding of human experiences, and combining it with effects of psychedelic compounds on neuronal pathways and neurochemical receptor sites, the authors are forging a new path for further inquiry.” 

In an accompanying editorial, Daniel Barron, MD, PhD, medical director, Interventional Pain Psychiatry Program, Brigham and Women’s Hospital, Boston, and Richard Friedman, MD, professor of clinical psychiatry, Weill Cornell Medical College, New York, call the work “impressive” and “clever.”

“Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets,” they write.

The research was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, a grant from the NIH grant, and the Canadian Institutes of Health Research. Dr. Bzdok was also supported by the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund) and the CIFAR Artificial Intelligence Chairs program (Canada Institute for Advanced Research), as well as Research Award and Teaching Award by Google. The other authors’ disclosures are listed on the original paper. No disclosures were listed for Dr. Barron and Dr. Friedman. Dr. Aaronson’s research is supported by Compass Pathways.

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

What causes the dramatic alterations in subjective awareness experienced during a psychedelic “trip?” A new study maps anatomical changes in specific neurotransmitter systems and brain regions that may be responsible for these effects.

Investigators gathered more than 6,800 accounts from individuals who had taken one of 27 different psychedelic compounds. Using a machine learning strategy, they extracted commonly used words from these testimonials, linking them with 40 different neurotransmitter subtypes that had likely induced these experiences.

The investigators then linked these subjective experiences with specific brain regions where the receptor combinations are most commonly found and, using gene transcription probes, created a 3D whole-brain map of the brain receptors and the subjective experiences linked to them.

“Hallucinogenic drugs may very well turn out to be the next big thing to improve clinical care of major mental health conditions,” senior author Danilo Bzdok, MD, PhD, associate professor, McGill University, Montreal, said in a press release.

“Our study provides a first step, a proof of principle, that we may be able to build machine-learning systems in the future that can accurately predict which neurotransmitter receptor combinations need to be stimulated to induce a specific state of conscious experience in a given person,” said Dr. Bzdok, who is also the Canada CIFAR AI Chair at Mila-Quebec Artificial Intelligence Institute.

The study was published online  in Science Advances.
 

‘Unique window’

Psychedelic drugs “show promise” as treatments for various psychiatric disorders, but subjective alterations of reality are “highly variable across individuals” and this “poses a key challenge as we venture to bring hallucinogenic substances into medical practice,” the investigators note.

Although the 5-HT2A receptor has been regarded as a “putative essential mechanism” of hallucinogenic experiences, it is unclear whether the experiential differences are explained by functional selectivity at the 5-HT2A receptor itself or “orchestrated by the vast array of neurotransmitter receptor subclasses on which these drugs act,” they add.

Lead author Galen Ballentine, MD, psychiatry resident, SUNY Downstate Medical Center, Brooklyn, told this news organization that he was “personally eager to find novel ways to identify the neurobiological underpinnings of different states of conscious awareness.”

Psychedelics, he said, offer a “unique window into a vast array of unusual states of consciousness and are particularly useful because they can point toward underlying mechanistic processes that are initiated in specific areas of receptor expression.”

The investigators wanted to understand “how these drugs work in order to help guide their use in clinical practice,” Dr. Ballentine said.

To explore the issue, they undertook the “largest investigation to date into the neuroscience of psychedelic drug experiences,” Dr. Ballentine said. “While most studies are limited to a single drug on a handful of subjects, this project integrates thousands of experiences induced by dozens of different hallucinogenic compounds, viewing them through the prism of 40 receptor subtypes.”
 

Unique neurotransmitter fingerprint

The researchers analyzed 6,850 experience reports of people who had taken 1 of 27 psychedelic compounds. The reports were drawn from a database hosted by the Erowid Center, an organization that collects first-hand accounts of experiences elicited by psychoactive drugs.

The researchers constructed a “bag-of-words” encoding of the text descriptions in each testimonial. Using linguistic calculation methods, they derived a final vocabulary of 14,410 words that they analyzed for descriptive experiential terms.

To shed light on the spatial distribution of these compounds that modulate neuronal activity during subjective “trips,” they compared normalized measurements of their relative binding strengths in 40 sites.

• 5-HT (5-HT2A, 5-HT2C, 5-HT2B, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT5A, 5-HT6, 5-HT7)
• Dopamine (D1, D2, D3, D4, D5)
• Adrenergic (a-1A, a-1B, a-2A, a-2B, a-2C, b-1, b-2)
• Serotonin transporter (SERT)
• Dopamine transporter (DAT)
• Norepinephrine transporter (NET)
• Imidazoline-1 receptor (I1)
• Sigma receptors (s-1, s-2)
• d-opioid receptor (DOR)
• k-opioid receptor (KOR)
• m-opioid receptor (MOR)
• Muscarinic receptors (M1, M2, M3, M4, M5)
• Histamine receptors (H1, H2)
• Calcium ion channel (CA+)
• NMDA glutamate receptor

To map receptor-experience factors to regional levels of receptor gene transcription, they utilized human gene expression data drawn from the Allen Human Brain Atlas, as well as the Shafer-Yeo brain atlas.

Via a machine-learning algorithm, they dissected the “phenomenologically rich anecdotes” into a ranking of constituent brain-behavior factors, each of which was characterized by a “unique neurotransmitter fingerprint of action and a unique experiential context” and ultimately created a dimensional map of these neurotransmitter systems.
 

Data-driven framework

Cortex-wide distribution of receptor-experience factors was found in both deep and shallow anatomical brain regions. Regions involved in genetic factor expressions were also wide-ranging, spanning from higher association cortices to unimodal sensory cortices.

The dominant factor “elucidated mystical experience in general and the dissolution of self-world boundaries (ego dissolution) in particular,” the authors report, while the second- and third-most explanatory factors “evoked auditory, visual, and emotional themes of mental expansion.”

Ego dissolution was found to be most associated with the 5-HT2A receptor, as well as other serotonin receptors (5-HT2C, 5-HT1A, 5-HT2B), adrenergic receptors a-2A and b-2, and the D2 receptor.

Alterations in sensory perception were associated with expression of the 5-HT2A receptor in the visual cortex, while modulation of the salience network by dopamine and opioid receptors were implicated in the experience transcendence of space, time, and the structure of self. Auditory hallucinations were linked to a weighted blend of receptors expressed throughout the auditory cortex.

“This data-driven framework identifies patterns that undergird diverse psychedelic experiences such as mystical bliss, existential terror, and complex hallucinations,” Dr. Ballentine commented.

“Simultaneously subjective and neurobiological, these patterns align with the leading hypothesis that psychedelics temporarily diminish top-down control of the most evolutionarily advanced regions of the brain, while at the same time amplifying bottom-up sensory processing from primary sensory cortices,” he added.
 

Forging a new path

Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics and director of the Centre of Excellence at Sheppard Pratt, Towson, Md., said, “As we try to get our arms around understanding the implications of a psychedelic exposure, forward-thinking researchers like Dr. Bzdok et al. are offering interesting ways to capture and understand the experience.”

Dr. Aaronson, an adjunct professor at the University of Maryland School of Medicine who was not involved with the study, continued: “Using the rapidly developing field of natural language processing (NLP), which looks at how language is used for a deeper understanding of human experiences, and combining it with effects of psychedelic compounds on neuronal pathways and neurochemical receptor sites, the authors are forging a new path for further inquiry.” 

In an accompanying editorial, Daniel Barron, MD, PhD, medical director, Interventional Pain Psychiatry Program, Brigham and Women’s Hospital, Boston, and Richard Friedman, MD, professor of clinical psychiatry, Weill Cornell Medical College, New York, call the work “impressive” and “clever.”

“Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets,” they write.

The research was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, a grant from the NIH grant, and the Canadian Institutes of Health Research. Dr. Bzdok was also supported by the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund) and the CIFAR Artificial Intelligence Chairs program (Canada Institute for Advanced Research), as well as Research Award and Teaching Award by Google. The other authors’ disclosures are listed on the original paper. No disclosures were listed for Dr. Barron and Dr. Friedman. Dr. Aaronson’s research is supported by Compass Pathways.

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

What causes the dramatic alterations in subjective awareness experienced during a psychedelic “trip?” A new study maps anatomical changes in specific neurotransmitter systems and brain regions that may be responsible for these effects.

Investigators gathered more than 6,800 accounts from individuals who had taken one of 27 different psychedelic compounds. Using a machine learning strategy, they extracted commonly used words from these testimonials, linking them with 40 different neurotransmitter subtypes that had likely induced these experiences.

The investigators then linked these subjective experiences with specific brain regions where the receptor combinations are most commonly found and, using gene transcription probes, created a 3D whole-brain map of the brain receptors and the subjective experiences linked to them.

“Hallucinogenic drugs may very well turn out to be the next big thing to improve clinical care of major mental health conditions,” senior author Danilo Bzdok, MD, PhD, associate professor, McGill University, Montreal, said in a press release.

“Our study provides a first step, a proof of principle, that we may be able to build machine-learning systems in the future that can accurately predict which neurotransmitter receptor combinations need to be stimulated to induce a specific state of conscious experience in a given person,” said Dr. Bzdok, who is also the Canada CIFAR AI Chair at Mila-Quebec Artificial Intelligence Institute.

The study was published online  in Science Advances.
 

‘Unique window’

Psychedelic drugs “show promise” as treatments for various psychiatric disorders, but subjective alterations of reality are “highly variable across individuals” and this “poses a key challenge as we venture to bring hallucinogenic substances into medical practice,” the investigators note.

Although the 5-HT2A receptor has been regarded as a “putative essential mechanism” of hallucinogenic experiences, it is unclear whether the experiential differences are explained by functional selectivity at the 5-HT2A receptor itself or “orchestrated by the vast array of neurotransmitter receptor subclasses on which these drugs act,” they add.

Lead author Galen Ballentine, MD, psychiatry resident, SUNY Downstate Medical Center, Brooklyn, told this news organization that he was “personally eager to find novel ways to identify the neurobiological underpinnings of different states of conscious awareness.”

Psychedelics, he said, offer a “unique window into a vast array of unusual states of consciousness and are particularly useful because they can point toward underlying mechanistic processes that are initiated in specific areas of receptor expression.”

The investigators wanted to understand “how these drugs work in order to help guide their use in clinical practice,” Dr. Ballentine said.

To explore the issue, they undertook the “largest investigation to date into the neuroscience of psychedelic drug experiences,” Dr. Ballentine said. “While most studies are limited to a single drug on a handful of subjects, this project integrates thousands of experiences induced by dozens of different hallucinogenic compounds, viewing them through the prism of 40 receptor subtypes.”
 

Unique neurotransmitter fingerprint

The researchers analyzed 6,850 experience reports of people who had taken 1 of 27 psychedelic compounds. The reports were drawn from a database hosted by the Erowid Center, an organization that collects first-hand accounts of experiences elicited by psychoactive drugs.

The researchers constructed a “bag-of-words” encoding of the text descriptions in each testimonial. Using linguistic calculation methods, they derived a final vocabulary of 14,410 words that they analyzed for descriptive experiential terms.

To shed light on the spatial distribution of these compounds that modulate neuronal activity during subjective “trips,” they compared normalized measurements of their relative binding strengths in 40 sites.

• 5-HT (5-HT2A, 5-HT2C, 5-HT2B, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT5A, 5-HT6, 5-HT7)
• Dopamine (D1, D2, D3, D4, D5)
• Adrenergic (a-1A, a-1B, a-2A, a-2B, a-2C, b-1, b-2)
• Serotonin transporter (SERT)
• Dopamine transporter (DAT)
• Norepinephrine transporter (NET)
• Imidazoline-1 receptor (I1)
• Sigma receptors (s-1, s-2)
• d-opioid receptor (DOR)
• k-opioid receptor (KOR)
• m-opioid receptor (MOR)
• Muscarinic receptors (M1, M2, M3, M4, M5)
• Histamine receptors (H1, H2)
• Calcium ion channel (CA+)
• NMDA glutamate receptor

To map receptor-experience factors to regional levels of receptor gene transcription, they utilized human gene expression data drawn from the Allen Human Brain Atlas, as well as the Shafer-Yeo brain atlas.

Via a machine-learning algorithm, they dissected the “phenomenologically rich anecdotes” into a ranking of constituent brain-behavior factors, each of which was characterized by a “unique neurotransmitter fingerprint of action and a unique experiential context” and ultimately created a dimensional map of these neurotransmitter systems.
 

Data-driven framework

Cortex-wide distribution of receptor-experience factors was found in both deep and shallow anatomical brain regions. Regions involved in genetic factor expressions were also wide-ranging, spanning from higher association cortices to unimodal sensory cortices.

The dominant factor “elucidated mystical experience in general and the dissolution of self-world boundaries (ego dissolution) in particular,” the authors report, while the second- and third-most explanatory factors “evoked auditory, visual, and emotional themes of mental expansion.”

Ego dissolution was found to be most associated with the 5-HT2A receptor, as well as other serotonin receptors (5-HT2C, 5-HT1A, 5-HT2B), adrenergic receptors a-2A and b-2, and the D2 receptor.

Alterations in sensory perception were associated with expression of the 5-HT2A receptor in the visual cortex, while modulation of the salience network by dopamine and opioid receptors were implicated in the experience transcendence of space, time, and the structure of self. Auditory hallucinations were linked to a weighted blend of receptors expressed throughout the auditory cortex.

“This data-driven framework identifies patterns that undergird diverse psychedelic experiences such as mystical bliss, existential terror, and complex hallucinations,” Dr. Ballentine commented.

“Simultaneously subjective and neurobiological, these patterns align with the leading hypothesis that psychedelics temporarily diminish top-down control of the most evolutionarily advanced regions of the brain, while at the same time amplifying bottom-up sensory processing from primary sensory cortices,” he added.
 

Forging a new path

Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics and director of the Centre of Excellence at Sheppard Pratt, Towson, Md., said, “As we try to get our arms around understanding the implications of a psychedelic exposure, forward-thinking researchers like Dr. Bzdok et al. are offering interesting ways to capture and understand the experience.”

Dr. Aaronson, an adjunct professor at the University of Maryland School of Medicine who was not involved with the study, continued: “Using the rapidly developing field of natural language processing (NLP), which looks at how language is used for a deeper understanding of human experiences, and combining it with effects of psychedelic compounds on neuronal pathways and neurochemical receptor sites, the authors are forging a new path for further inquiry.” 

In an accompanying editorial, Daniel Barron, MD, PhD, medical director, Interventional Pain Psychiatry Program, Brigham and Women’s Hospital, Boston, and Richard Friedman, MD, professor of clinical psychiatry, Weill Cornell Medical College, New York, call the work “impressive” and “clever.”

“Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets,” they write.

The research was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, a grant from the NIH grant, and the Canadian Institutes of Health Research. Dr. Bzdok was also supported by the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund) and the CIFAR Artificial Intelligence Chairs program (Canada Institute for Advanced Research), as well as Research Award and Teaching Award by Google. The other authors’ disclosures are listed on the original paper. No disclosures were listed for Dr. Barron and Dr. Friedman. Dr. Aaronson’s research is supported by Compass Pathways.

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

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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