Depression

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

A new study sheds light on the neurologic underpinnings of late-life depression (LLD) with apathy and its frequently poor response to treatment.

Investigators headed by Faith Gunning, PhD, of the Institute of Geriatric Psychiatry, Weill Cornell Medicine, New York, analyzed baseline and posttreatment brain MRIs and functional MRIs (fMRIs) of older adults with depression who participated in a 12-week open-label nonrandomized clinical trial of escitalopram. Participants had undergone clinical and cognitive assessments.

Disturbances were found in resting state functional connectivity (rsFC) between the salience network (SN) and other large-scale networks that support goal-directed behavior, especially in patients with depression who also had features of apathy.

Even after participants had completed escitalopram treatment, apathy-related variability in functional connectivity was associated with poor antidepressant response and persistent cognitive dysfunction.

“This study suggests that, among older adults with depression, distinct network abnormalities may be associated with apathy and poor response to first-line pharmacotherapy and may serve as promising targets for novel interventions,” the investigators write.

The study was published online in JAMA Network Open.
 

A leading cause of disability

LLD is a “leading cause of disability and medical morbidity in older adulthood,” with one-third to one-half of patients with LLD also suffering from apathy, the authors write.

Older adults with depression and comorbid apathy have poorer outcomes, including lower remission rates and poorer response to first-line antidepressants, compared with those with LLD but who do not have apathy.

Despite the high prevalence of apathy in people with depression, “little is known about its optimal treatment and, more broadly, about the brain-based mechanisms of apathy,” the authors note.

An “emerging hypothesis” points to the role of a compromised SN and its large-scale connections between apathy and poor treatment response in LLD.

The SN (which includes the insula and the dorsal anterior cingulate cortex) “attributes motivational value to a stimulus” and “dynamically coordinates the activity of other large-scale networks, including the executive control network and default mode network (DMN).”

Preliminary studies of apathy in patients with depression report reduced volume in structures of the SN and suggest disruption in functional connectivity among the SN, DMN, and the executive control network; but the mechanisms linking apathy to poor antidepressant response in LLD “are not well understood.”

“Connectometry” is a “novel approach to diffusion MRI analysis that quantifies the local connectome of white matter pathways.” It has been used along with resting-state imagery, but it had not been used in studying apathy.

The researchers investigated the functional connectivity of the SN, hypothesizing that alterations in connectivity among key nodes of the SN and other core circuits that modulate goal-directed behavior (DMN and the executive control network) were implicated in individuals with depression and apathy.

They applied connectometry to “identify pathway-level disruptions in structural connectivity,” hypothesizing that compromise of frontoparietal and frontolimbic pathways would be associated with apathy in patients with LLD.

They also wanted to know whether apathy-related network abnormalities were associated with antidepressant response after 12 weeks of pharmacotherapy with the selective serotonin reuptake inhibitor escitalopram.
 

Emerging model

The study included 40 older adults (65% women; mean [SD] age, 70.0 [6.6] years) with DSM-IV–diagnosis major depressive disorder (without psychotic features) who were from a single-group, open-label escitalopram treatment trial.

The Hamilton-Depression (HAM-D) scale was used to assess depression, while the Apathy Evaluation Scale was used to assess apathy. On the Apathy Evaluation Scale, a score of greater than 40.5 represents “clinically significant apathy.” Participants completed these tests at baseline and after 12 weeks of escitalopram treatment.

They also completed a battery of neuropsychological tests to assess cognition and underwent MRI imaging. fMRI was used to map group differences in rsFC of the SN, and diffusion connectometry was used to “evaluate pathway-level disruptions in structural connectivity.”

Of the participants, 20 had clinically significant apathy. There were no differences in age, sex, educational level, or the severity of depression at baseline between those who did and those who did not have apathy.

Compared with participants with depression but not apathy, those with depression and comorbid apathy had lower rsFC of salience network seeds (specifically, the dorsolateral prefrontal cortex [DLPFC], premotor cortex, midcingulate cortex, and paracentral lobule).

They also had greater rsFC in the lateral temporal cortex and temporal pole (z > 2.7; Bonferroni-corrected threshold of P < .0125).

Additionally, participants with apathy had lower structural connectivity in the splenium, cingulum, and fronto-occipital fasciculus, compared with those without apathy (t > 2.5; false discovery rate–corrected P = .02).

Of the 27 participants who completed escitalopram treatment; 16 (59%) achieved remission (defined as an HAM-D score <10). Participants with apathy had poorer response to escitalopram treatment.

Lower insula-DLPFC/midcingulate cortex rsFC was associated with less improvement in depressive symptoms (HAM-D percentage change, beta [df] = .588 [26]; P = .001) as well as a greater likelihood that the participant would not achieve remission after treatment (odds ratio, 1.041; 95% confidence interval, 1.003-1.081; P = .04).

In regression models, lower insula-DLPFC/midcingulate cortex rsFC was found to be a mediator of the association between baseline apathy and persistence of depression.

The SN findings were also relevant to cognition. Lower dorsal anterior cingulate-DLPFC/paracentral rsFC was found to be associated with residual cognitive difficulties on measures of attention and executive function (beta [df] = .445 [26] and beta [df] = .384 [26], respectively; for each, P = .04).

“These findings support an emerging model of apathy, which proposes that apathy may arise from dysfunctional interactions among core networks (that is, SN, DMN, and executive control) that support motivated behavior,” the investigators write.

“This may cause a failure of network integration, leading to difficulties with salience processing, action planning, and behavioral initiation that manifests clinically as apathy,” they conclude.

One limitation they note was the lack of longitudinal follow-up after acute treatment and a “relatively limited neuropsychological battery.” Therefore, they could not “establish the persistence of treatment differences nor the specificity of cognitive associations.”

The investigators add that “novel interventions that modulate interactions among affected circuits may help to improve clinical outcomes in this distinct subgroup of older adults with depression, for whom few effective treatments exist.”

Commenting on the study, Helen Lavretsy, MD, professor of psychiatry in residence and director of the Late-Life Mood, Stress, and Wellness Research Program and the Integrative Psychiatry Clinic, Jane and Terry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, said, the findings “can be used in future studies targeting apathy and the underlying neural mechanisms of brain connectivity.” Dr. Lavretsy was not involved with the study.
The study was supported by grants from the National Institute of Mental Health. Dr. Gunning reported receiving grants from the National Institute of Mental Health during the conduct of the study and grants from Akili Interactive. The other authors’ disclosures are listed on the original article. Dr. Lavretsky reports no relevant financial relationships.

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

If you grew up in the 1970s and 1980s, chances are high you’re familiar with “Go Ask Alice.”

What was then said to be the real diary of a 15-year-old promising teen turned drug addict was released in 1971 as a cautionary tale and has since sold over 5 million copies. The diary was harrowing against the backdrop of the war on drugs and soon became both acclaimed and banned from classrooms across the country.

Schools citied “inappropriate” language that “borders on pornography” as grounds to prohibit teenagers from reading Alice’s story. But as much as the book’s vivid writing offended readers, it drew millions in with its profanity and graphic descriptions of sex, drugs, and mental health struggles.

At the time, The New York Times reviewed the book as “a strong, painfully honest, nakedly candid and true story ... a document of horrifying reality,” but the popular diary was later found to be a ploy – a fake story written by a 54-year-old Mormon youth counselor named Beatrice Sparks.

Now, Ms. Sparks, who died in 2012, has been further exposed in radio personality Rick Emerson’s new book, “Unmask Alice: LSD, Satanic Panic, and the Imposter Behind the World’s Most Notorious Diaries.” Mr. Emerson published the exposé in July, years after he had the idea to investigate Ms. Sparks’s work in 2015. The book details Ms. Sparks’s background, her journey in creating Alice, and her quest to be recognized for the teen diary she had published as “Anonymous.”

“After 30 years of trying, Beatrice Sparks had changed the world. And nobody knew it,” Mr. Emerson told the New York Post.In his work, Mr. Emerson also dives into the profound impact of the diary at a time when not as much research existed on teen mental health.

When the teenager whose diary inspired Ms. Sparks’s writing “died in March 1971, the very first true study of adolescent psychology had just barely come out,” Mr. Emerson said to Rolling Stone. “Mental health, especially for young people, was still very much on training wheels.”

According to Mr. Emerson, a lack of insight into mental health issues allowed Ms. Sparks’s description to go relatively unchallenged and for the book’s influence to spread despite its misinformation.

“It’s indisputable that large sections of ‘Go Ask Alice’ are just embellished and/or false,” he told the Post.
 

Then versus now

When “Go Ask Alice” was published, child psychiatry and psychology literature contained relatively few references to depression, confirming a 2021 analysis of academic literature on childhood and adolescent depression from 1970 to 2019.

This landscape is in stark contrast to today, where thousands of studies on the topic have been done, compared with the mere dozens in the 1970s.

Anxiety and depression in minors have increased over time, a trend worsened by the COVID-19 pandemic, according to the CDC. Studies have shown that reported drug use in teens has decreased over time, proving significant during the pandemic, according to the National Institutes of Health.

While Alice from “Go Ask Alice” has not existed in either, comparing the two periods can offer insight into teen struggles in the 1970s versus today and sheds light on how literature – fiction or even faked nonfiction – can transform a nation.

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

If you grew up in the 1970s and 1980s, chances are high you’re familiar with “Go Ask Alice.”

What was then said to be the real diary of a 15-year-old promising teen turned drug addict was released in 1971 as a cautionary tale and has since sold over 5 million copies. The diary was harrowing against the backdrop of the war on drugs and soon became both acclaimed and banned from classrooms across the country.

Schools citied “inappropriate” language that “borders on pornography” as grounds to prohibit teenagers from reading Alice’s story. But as much as the book’s vivid writing offended readers, it drew millions in with its profanity and graphic descriptions of sex, drugs, and mental health struggles.

At the time, The New York Times reviewed the book as “a strong, painfully honest, nakedly candid and true story ... a document of horrifying reality,” but the popular diary was later found to be a ploy – a fake story written by a 54-year-old Mormon youth counselor named Beatrice Sparks.

Now, Ms. Sparks, who died in 2012, has been further exposed in radio personality Rick Emerson’s new book, “Unmask Alice: LSD, Satanic Panic, and the Imposter Behind the World’s Most Notorious Diaries.” Mr. Emerson published the exposé in July, years after he had the idea to investigate Ms. Sparks’s work in 2015. The book details Ms. Sparks’s background, her journey in creating Alice, and her quest to be recognized for the teen diary she had published as “Anonymous.”

“After 30 years of trying, Beatrice Sparks had changed the world. And nobody knew it,” Mr. Emerson told the New York Post.In his work, Mr. Emerson also dives into the profound impact of the diary at a time when not as much research existed on teen mental health.

When the teenager whose diary inspired Ms. Sparks’s writing “died in March 1971, the very first true study of adolescent psychology had just barely come out,” Mr. Emerson said to Rolling Stone. “Mental health, especially for young people, was still very much on training wheels.”

According to Mr. Emerson, a lack of insight into mental health issues allowed Ms. Sparks’s description to go relatively unchallenged and for the book’s influence to spread despite its misinformation.

“It’s indisputable that large sections of ‘Go Ask Alice’ are just embellished and/or false,” he told the Post.
 

Then versus now

When “Go Ask Alice” was published, child psychiatry and psychology literature contained relatively few references to depression, confirming a 2021 analysis of academic literature on childhood and adolescent depression from 1970 to 2019.

This landscape is in stark contrast to today, where thousands of studies on the topic have been done, compared with the mere dozens in the 1970s.

Anxiety and depression in minors have increased over time, a trend worsened by the COVID-19 pandemic, according to the CDC. Studies have shown that reported drug use in teens has decreased over time, proving significant during the pandemic, according to the National Institutes of Health.

While Alice from “Go Ask Alice” has not existed in either, comparing the two periods can offer insight into teen struggles in the 1970s versus today and sheds light on how literature – fiction or even faked nonfiction – can transform a nation.

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

If you grew up in the 1970s and 1980s, chances are high you’re familiar with “Go Ask Alice.”

What was then said to be the real diary of a 15-year-old promising teen turned drug addict was released in 1971 as a cautionary tale and has since sold over 5 million copies. The diary was harrowing against the backdrop of the war on drugs and soon became both acclaimed and banned from classrooms across the country.

Schools citied “inappropriate” language that “borders on pornography” as grounds to prohibit teenagers from reading Alice’s story. But as much as the book’s vivid writing offended readers, it drew millions in with its profanity and graphic descriptions of sex, drugs, and mental health struggles.

At the time, The New York Times reviewed the book as “a strong, painfully honest, nakedly candid and true story ... a document of horrifying reality,” but the popular diary was later found to be a ploy – a fake story written by a 54-year-old Mormon youth counselor named Beatrice Sparks.

Now, Ms. Sparks, who died in 2012, has been further exposed in radio personality Rick Emerson’s new book, “Unmask Alice: LSD, Satanic Panic, and the Imposter Behind the World’s Most Notorious Diaries.” Mr. Emerson published the exposé in July, years after he had the idea to investigate Ms. Sparks’s work in 2015. The book details Ms. Sparks’s background, her journey in creating Alice, and her quest to be recognized for the teen diary she had published as “Anonymous.”

“After 30 years of trying, Beatrice Sparks had changed the world. And nobody knew it,” Mr. Emerson told the New York Post.In his work, Mr. Emerson also dives into the profound impact of the diary at a time when not as much research existed on teen mental health.

When the teenager whose diary inspired Ms. Sparks’s writing “died in March 1971, the very first true study of adolescent psychology had just barely come out,” Mr. Emerson said to Rolling Stone. “Mental health, especially for young people, was still very much on training wheels.”

According to Mr. Emerson, a lack of insight into mental health issues allowed Ms. Sparks’s description to go relatively unchallenged and for the book’s influence to spread despite its misinformation.

“It’s indisputable that large sections of ‘Go Ask Alice’ are just embellished and/or false,” he told the Post.
 

Then versus now

When “Go Ask Alice” was published, child psychiatry and psychology literature contained relatively few references to depression, confirming a 2021 analysis of academic literature on childhood and adolescent depression from 1970 to 2019.

This landscape is in stark contrast to today, where thousands of studies on the topic have been done, compared with the mere dozens in the 1970s.

Anxiety and depression in minors have increased over time, a trend worsened by the COVID-19 pandemic, according to the CDC. Studies have shown that reported drug use in teens has decreased over time, proving significant during the pandemic, according to the National Institutes of Health.

While Alice from “Go Ask Alice” has not existed in either, comparing the two periods can offer insight into teen struggles in the 1970s versus today and sheds light on how literature – fiction or even faked nonfiction – can transform a nation.

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

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

Many psychiatrists have had the grim experience of a newly referred patient explaining that her (and it is most often “her”) primary care doctor has been prescribing lorazepam 8 mg per day or alprazolam 6 mg per day and is sending her to you for help with ongoing anxiety. For conscientious psychiatrists, this means the beginning of a long tapering process along with a great deal of reassuring of a patient who is terrified of feeling overwhelmed with anxiety. The same problem occurs with patients taking large doses of sedatives who are still unable to sleep.

Mark Olfson and coauthors quantified benzodiazepine use in the United States in 2008 using a large prescription database, and found that 5.2% of adults between 18 and 80 years old were taking these drugs.¹ The percentage increased with age, to 8.7% of those 65-80 years, in whom 31% received long-term prescriptions from a psychiatrist. Benzodiazepine use was twice as prevalent in women, compared with men. This occurs despite peer-reviewed publications and articles in the popular press regarding the risks of long-term benzodiazepine use in the elderly. Fang-Yu Lin and coauthors documented a 2.23-fold higher risk of hip fracture in zolpidem users that increased with age; elderly users had a 21-fold higher incidence of fracture, compared with younger users, and were twice as likely to sustain a fracture than elderly nonusers.²

Rashona Thomas and Edid Ramos-Rivas reviewed the risks of benzodiazepines in older patients with insomnia and document the increase in serious adverse events such as falls, fractures, and cognitive and behavioral changes.³ Many patients have ongoing prescriptions that make discontinuation difficult, given the potential for withdrawal agitation, seizures, insomnia, nightmares and even psychosis.

Greta Bushnell and coauthors pointed to the problem of simultaneous prescribing of a new antidepressant with a benzodiazepine by 10% of doctors initiating antidepressants.⁴ Over 12% of this group of patients continued benzodiazepines long term, even though there was no difference in the response to antidepressant treatment at 6 months. Those with long-term benzodiazepine use were also more likely to have recent prescriptions for opiates.

A Finnish research team found that 34% of middle-aged and 55% of elderly people developed long-term use of benzodiazepines after an initial prescription.⁵ Those who became long-term users were more often older male receivers of social benefits, with psychiatric comorbidities and substance abuse histories.

Kevin Xu and coauthors reviewed a National Health and Nutrition Examination Survey dataset from 1999 to 2015 with follow-up on over 5,000 individuals in that period.⁶ They found doubling of all-cause mortality in users of benzodiazepines with or without accompanying use of opiates, a statistically significant increase.

Perhaps most alarming is the increased risk for Alzheimer’s dementia diagnosis in users of benzodiazepines. Two separate studies (Billoti de Gage and colleagues and Ettcheto and colleagues^7,8) provided reviews of evidence for the relationship between use of benzodiazepines and development of dementia, and repeated warnings about close monitoring of patients and the need for alternative treatments for anxiety and insomnia in the elderly.
 

Be alert to underlying issues

Overburdened primary practitioners faced with complaints about sleep and anxiety understandably turn to medication rather than taking time to discuss the reasons for these problems or to describe nonmedication approaches to relief of symptoms. Even insured patients may have very limited options for “covered” psychiatric consultation, as many competent psychiatrists have moved to a cash-only system. It is easier to renew prescriptions than to counsel patients or refer them, and many primary care practitioners have limited experience with diagnosing causes of anxiety and insomnia, much less alternative medication approaches.

Psychiatrists should be aware of the frequency of underlying mood disorders that include sleep and anxiety as prominent symptoms; in fact, these symptoms are often what motivates patients to pursue treatment. It is critical to obtain not only a personal history of symptoms beginning in childhood up to the present, but also a family history of mood and anxiety problems. Mood dysregulation disorders are highly hereditary and a family history of mania or psychosis should raise concern about the cause of symptoms in one’s patient. A strong personal and/or family history of alcohol abuse and dependence may cover underlying undiagnosed mood dysregulation. Primary care physicians may not recognize mood dysregulation unless a patient is clearly manic or psychotic.

There is a cohort of patients who do well on antidepressant medication, but anorgasmia, fatigue, and emotional blunting are common side effects that affect compliance. When patients have unexpected responses to SSRI medications such as euphoria, agitation, anxiety, insomnia, and more prominent mood swings, primary care physicians may add a benzodiazepine, expecting the problem to abate with time. Unfortunately, this often leads to ongoing use of benzodiazepines, since attempts to stop them causes withdrawal effects that are indistinguishable from the original anxiety symptoms.

Most psychiatrists are aware that some patients need mood stabilization rather than mood elevation to maintain an adequate baseline mood. Lithium, anticonvulsants, and second-generation antipsychotics may be effective without adding antidepressant medication. Managing dosing and side effects requires time for follow-up visits with patients after initiating treatment but leads to more stability and better outcomes.

Benzodiazepines are appropriate and helpful in situations that cause transient anxiety and with patients who have done poorly with other options. Intermittent use is key to avoiding tolerance and inevitable dose increases. Some individuals can take low daily doses that are harmless, though these likely only prevent withdrawal rather than preventing anxiety. The placebo effect of taking a pill is powerful. And some patients take more doses than they admit to. Most practitioners have heard stories about the alprazolam that was accidentally spilled into the sink or the prescription bottle of diazepam that was lost or the lorazepam supply that was stolen by the babysitter.

These concepts are illustrated in case examples below.
 

Case one

Ms. A, a 55-year-old married female business administrator, admitted to using zolpidem at 40 mg per night for the past several months. She began with the typical dose of 10 mg at bedtime prescribed by her internist, but after several weeks, needed an additional 10 mg at 2 a.m. to stay asleep. As weeks passed, she found that she needed an additional 20 mg when she awoke at 2 a.m. Within months, she needed 20 mg to initiate sleep and 20 mg to maintain sleep. She obtained extra zolpidem from her gynecologist and came for consultation when refill requests were refused.

Ms. A had a family history of high anxiety in her mother and depressed mood in multiple paternal relatives, including her father. She had trouble sleeping beginning in adolescence, significant premenstrual dysphoria, and postpartum depression that led to a prescription for sertraline. Instead of feeling better, Ms. A remembers being agitated and unable to sleep, so she stopped it. Ms. A was now perimenopausal, and insomnia was worse. She had gradually increased wine consumption to a bottle of wine each night after work to “settle down.” This allowed her to fall asleep, but she inevitably awoke within 4 hours. Her internist noted an elevation in ALT and asked Ms. A about alcohol consumption. She was alarmed and cut back to one glass of wine per night but again couldn’t sleep. Her internist started zolpidem at that point.

The psychiatrist explained the concepts of tolerance and addiction and a plan to slowly taper off zolpidem while using quetiapine for sleep. She decreased to 20 mg of zolpidem at bedtime with quetiapine 50 mg and was able to stay asleep. After 3 weeks, Ms. A took zolpidem 10 mg at bedtime with quetiapine 75 mg and again, was able to fall asleep and stay asleep. After another 3 weeks, she increased quetiapine to 100 mg and stopped zolpidem without difficulty. This dose of quetiapine has continued to work well without significant side effects.
 

Case two

Ms. B, a 70-year-old married housewife, was referred for help with longstanding anxiety when her primary care doctor recognized that lorazepam, initially helpful at 1 mg twice daily, had required titration to 2 mg three times daily. Ms. B was preoccupied with having lorazepam on hand and never missed a dose. She had little interest in activities beyond her home, rarely socialized, and had fallen twice. She napped for 2 hours each afternoon, and sometimes had trouble staying asleep through the night.

Ms. B was reluctant to talk about her childhood history of hostility and undermining by her mother, who clearly preferred her older brother and was competitive with Ms. B. Her father traveled for work during the week and had little time for her. Ms. B had always seen herself as stupid and unlovable, which interfered with making friends. She attended college for 1 year but dropped out to marry her husband. He was also anxious and had difficulty socializing, but they found reassurance in each other. Their only child, a son in his 40s, was estranged from them, having married a woman who disliked Ms. B. Ms. B felt hopeless about developing a relationship with her grandchildren who were rarely allowed to visit. Despite her initial shame in talking about these painful problems, Ms. B realized that she felt better and scheduled monthly visits to check in.

Ms. B understood the risks of using lorazepam and wanted to stop it but was terrified of becoming anxious again. We set up a very slow tapering schedule that lowered her total dose by 0.5 mg every 2 weeks. At the same time, she began escitalopram which was effective at 20 mg. Ms. B noted that she no longer felt anxious upon awakening but was still afraid to miss a dose of lorazepam. As she felt more confident and alert, Ms. B joined a painting class at a local community center and was gratified to find that she was good at working with watercolors. She invited her neighbors to come for dinner and was surprised at how friendly and open they were. Once she had tapered to 1 mg twice daily, Ms. B began walking for exercise as she now had enough energy that it felt good to move around. After 6 months, she was completely off lorazepam, and very grateful to have discovered her capacity to improve her pleasure in life.
 

Case three

Ms. C, a 48-year-old attorney was referred for help with anxiety and distress in the face of separation from her husband who had admitted to an affair after she heard him talking to his girlfriend from their basement. She was unsure whether she wanted to save the marriage or end it and was horrified at the thought of dating. She had never felt especially anxious or depressed and had a supportive circle of close friends. She was uncharacteristically unable to concentrate long enough to consider her options because of anxiety.

A dose of clonazepam 0.5 mg allowed her to stay alert but calm enough to reflect on her feelings. She used it intermittently over several months and maintained regular individual psychotherapy sessions that allowed her to review the situation thoroughly. On her psychiatrist’s recommendation, she contacted a colleague to represent her if she decided to initiate divorce proceedings. She attempted to engage her husband in marital therapy, and his reluctance made it clear to her that she could no longer trust him. Ms. C offered him the option of a dissolution if he was willing to cooperate, or to sue for divorce if not. Once Ms. C regained her confidence and recognized that she would survive this emotionally fraught situation, she no longer needed clonazepam.
 

Summary

Benzodiazepines are particularly ill-suited to scheduled use since the risk of tolerance, escalating doses, and psychological addiction along with pharmacologic tolerance is high. The risks, which include cognitive slowing, falls and fractures, and withdrawal phenomena when abruptly stopped, make this class dangerous for all patients but particularly the elderly. Benzodiazepines are nonetheless useful medications for patients able to use them intermittently, whether on an alternating basis with other medications (for example, quetiapine alternating with clonazepam for chronic insomnia) or because symptoms of anxiety are intermittent. Psychiatrists treating tolerant patients should be familiar with the approach of tapering slowly while introducing more appropriate medications at adequate doses to manage symptoms.

Dr. Kaplan is training and supervising psychoanalyst at the Cincinnati Psychoanalytic Institute and volunteer professor of clinical psychiatry at the University of Cincinnati. The author reported no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

References

1. Olfson M et al. JAMA Psychiatry. 2015 Feb;72(2):136-42. doi: 10.1001/jamapsychiatry.2014.1763.

2. Lin FY et al. Sleep. 2014 Apr 1;37(4):673-9. doi: 10.5665/sleep.3566.

3. Thomas R and Ramos-Rivas E. Psychiatr Ann. 2018;48(6):266-70. doi: 10.3928/00485713-20180513-01.

4. Bushnell GA et al. JAMA Psychiatry. 2017 Jul 1;74(7):747-55. doi: 10.1001/jamapsychiatry.2017.1273.

5. Taipale H et al. JAMA Netw Open. 2020;3(10):e2019029. doi: 10.1001/jamanetworkopen.2020.19029.

6. Xu KY et al. JAMA Netw Open. 2020;3(12):e2028557. doi: 10.1001/jamanetworkopen.2020.28557.

7. Billioti de Gage S et al. BMJ. 2014;349:g5205. doi: 10.1136/bmj.g5205.

8. Ettcheto M et al. Front Aging Neurosci. 2020 Jan 8;11:344. doi: 10.3389/fnagi.2019.00344.

As I prepared to write my monthly column, I came across the statistic that 23% of physicians and 40% of nurses plan to leave their practices in the next 2 years.¹

Interestingly, the group that seems to be least impacted by this was health care administrators (with 12% of them planning on leaving their jobs).

I couldn’t stop thinking about these percentages.

I am reminded every day of the commitment and excellence of my colleagues in the health care field, and I do not want to lose them. I am hoping the following information and my thoughts on this topic will be helpful for those thinking about leaving health care.
 

Surgeon general’s burnout report

The surgeon general recently released a report on addressing health care worker burnout.² It includes several very interesting and appropriate observations. I will summarize the most important ones here:

1. Our health depends on the well-being of our health workforce.

2. Direct harm to health care workers can lead to anxiety, depression, insomnia, and interpersonal and relationship struggles.

3. Health care workers experience exhaustion from providing overwhelming care and empathy.

4. Health care workers spend less time with patients and too much time with EHRs.

5. There are health workforce shortages.

The report is comprehensive, and everything in it is correct. The real issue is how does it go from being a report to true actionable items that we as health care professionals benefit from? I think in regards to exhaustion from overwhelming care responsibilities, and empathy fatigue, we need better boundaries.

Those who go into medicine, and especially those who go into primary care, always put the patients’ needs first. When operating in a broken system, it stays broken when individuals cover for the deficiencies in the system. Adding four extra patients every day because there is no one to refer them to with availability is injurious to the health care provider, and those providers who accept these additional patients will eventually be part of the 23% who want to leave their jobs. It feels awful to say no, but until the system stops accommodating there will not be substantial change.
 

The empathy drain

One of the unreported stresses of open access for patients through EHR communications is the empathy drain on physicians. When I see a patient in clinic with chronic symptoms or issues, I spend important time making sure we have a plan and an agreed upon time frame.

With the EHR, patients frequently send multiple messages for the same symptoms between visits. It is okay to redirect the patient and share that these issues will be discussed at length at appointments. My reasoning on this is that I think it is better for me to better care for myself and stay as the doctor for my patients, than always say yes to limitless needs and soon be looking for the off ramp.

The following statistic in the surgeon general’s report really hit home. For every hour of direct patient care, physicians currently spend 2 hours on the EHR system. Most practices allow 10%-20% of time for catch up, where with statistics like this it should be 50%. This concept is fully lost on administrators, or ignored.

It is only when we refuse to continue to accept and follow a broken system that it will change. A minority of internal medicine and family doctors (4.5% in 2018) practice in direct primary care models, where these issues are addressed. Unfortunately, this model as it is currently available is not an option for lower income patients.

A major theme in the surgeon general’s report was that administrative burdens need to be reduced by 75% by 2025. When I look at the report, I see the suggestions, I just don’t see how it will be achieved. Despite almost all clinics moving to the EHR, paperwork in the form of faxes and forms has increased.

A sweeping reform would be needed to eliminate daily faxes from PT offices, visiting nurse services, prior authorization, patients reminders from insurance companies, and disability forms from patients. I am glad that there is acknowledgment of the problem, but this change will take more than 3 years.
 

Takeaways

So what do we do?

Be good to yourself, and your colleagues. The pandemic has isolated us, which accelerates burnout.

Reach out to people you care about.

We are all feeling this. Set boundaries that allow you to care for yourself, and accept that you are doing your best, even if you can’t meet the needs of all your patients all the time.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Sinsky CA et al. Covid-related stress and work intentions in a sample of US health care workers. Mayo Clin Proc Innov Qual Outcomes. 2021 Dec;5(6):1165-73.

2. Addressing health worker burnout. The U.S. Surgeon General’s advisory on building a thriving health workforce.

As I prepared to write my monthly column, I came across the statistic that 23% of physicians and 40% of nurses plan to leave their practices in the next 2 years.¹

Interestingly, the group that seems to be least impacted by this was health care administrators (with 12% of them planning on leaving their jobs).

I couldn’t stop thinking about these percentages.

I am reminded every day of the commitment and excellence of my colleagues in the health care field, and I do not want to lose them. I am hoping the following information and my thoughts on this topic will be helpful for those thinking about leaving health care.
 

Surgeon general’s burnout report

The surgeon general recently released a report on addressing health care worker burnout.² It includes several very interesting and appropriate observations. I will summarize the most important ones here:

1. Our health depends on the well-being of our health workforce.

2. Direct harm to health care workers can lead to anxiety, depression, insomnia, and interpersonal and relationship struggles.

3. Health care workers experience exhaustion from providing overwhelming care and empathy.

4. Health care workers spend less time with patients and too much time with EHRs.

5. There are health workforce shortages.

The report is comprehensive, and everything in it is correct. The real issue is how does it go from being a report to true actionable items that we as health care professionals benefit from? I think in regards to exhaustion from overwhelming care responsibilities, and empathy fatigue, we need better boundaries.

Those who go into medicine, and especially those who go into primary care, always put the patients’ needs first. When operating in a broken system, it stays broken when individuals cover for the deficiencies in the system. Adding four extra patients every day because there is no one to refer them to with availability is injurious to the health care provider, and those providers who accept these additional patients will eventually be part of the 23% who want to leave their jobs. It feels awful to say no, but until the system stops accommodating there will not be substantial change.
 

The empathy drain

One of the unreported stresses of open access for patients through EHR communications is the empathy drain on physicians. When I see a patient in clinic with chronic symptoms or issues, I spend important time making sure we have a plan and an agreed upon time frame.

With the EHR, patients frequently send multiple messages for the same symptoms between visits. It is okay to redirect the patient and share that these issues will be discussed at length at appointments. My reasoning on this is that I think it is better for me to better care for myself and stay as the doctor for my patients, than always say yes to limitless needs and soon be looking for the off ramp.

The following statistic in the surgeon general’s report really hit home. For every hour of direct patient care, physicians currently spend 2 hours on the EHR system. Most practices allow 10%-20% of time for catch up, where with statistics like this it should be 50%. This concept is fully lost on administrators, or ignored.

It is only when we refuse to continue to accept and follow a broken system that it will change. A minority of internal medicine and family doctors (4.5% in 2018) practice in direct primary care models, where these issues are addressed. Unfortunately, this model as it is currently available is not an option for lower income patients.

A major theme in the surgeon general’s report was that administrative burdens need to be reduced by 75% by 2025. When I look at the report, I see the suggestions, I just don’t see how it will be achieved. Despite almost all clinics moving to the EHR, paperwork in the form of faxes and forms has increased.

A sweeping reform would be needed to eliminate daily faxes from PT offices, visiting nurse services, prior authorization, patients reminders from insurance companies, and disability forms from patients. I am glad that there is acknowledgment of the problem, but this change will take more than 3 years.
 

Takeaways

So what do we do?

Be good to yourself, and your colleagues. The pandemic has isolated us, which accelerates burnout.

Reach out to people you care about.

We are all feeling this. Set boundaries that allow you to care for yourself, and accept that you are doing your best, even if you can’t meet the needs of all your patients all the time.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Sinsky CA et al. Covid-related stress and work intentions in a sample of US health care workers. Mayo Clin Proc Innov Qual Outcomes. 2021 Dec;5(6):1165-73.

2. Addressing health worker burnout. The U.S. Surgeon General’s advisory on building a thriving health workforce.

As I prepared to write my monthly column, I came across the statistic that 23% of physicians and 40% of nurses plan to leave their practices in the next 2 years.¹

Interestingly, the group that seems to be least impacted by this was health care administrators (with 12% of them planning on leaving their jobs).

I couldn’t stop thinking about these percentages.

I am reminded every day of the commitment and excellence of my colleagues in the health care field, and I do not want to lose them. I am hoping the following information and my thoughts on this topic will be helpful for those thinking about leaving health care.
 

Surgeon general’s burnout report

The surgeon general recently released a report on addressing health care worker burnout.² It includes several very interesting and appropriate observations. I will summarize the most important ones here:

1. Our health depends on the well-being of our health workforce.

2. Direct harm to health care workers can lead to anxiety, depression, insomnia, and interpersonal and relationship struggles.

3. Health care workers experience exhaustion from providing overwhelming care and empathy.

4. Health care workers spend less time with patients and too much time with EHRs.

5. There are health workforce shortages.

The report is comprehensive, and everything in it is correct. The real issue is how does it go from being a report to true actionable items that we as health care professionals benefit from? I think in regards to exhaustion from overwhelming care responsibilities, and empathy fatigue, we need better boundaries.

Those who go into medicine, and especially those who go into primary care, always put the patients’ needs first. When operating in a broken system, it stays broken when individuals cover for the deficiencies in the system. Adding four extra patients every day because there is no one to refer them to with availability is injurious to the health care provider, and those providers who accept these additional patients will eventually be part of the 23% who want to leave their jobs. It feels awful to say no, but until the system stops accommodating there will not be substantial change.
 

The empathy drain

One of the unreported stresses of open access for patients through EHR communications is the empathy drain on physicians. When I see a patient in clinic with chronic symptoms or issues, I spend important time making sure we have a plan and an agreed upon time frame.

With the EHR, patients frequently send multiple messages for the same symptoms between visits. It is okay to redirect the patient and share that these issues will be discussed at length at appointments. My reasoning on this is that I think it is better for me to better care for myself and stay as the doctor for my patients, than always say yes to limitless needs and soon be looking for the off ramp.

The following statistic in the surgeon general’s report really hit home. For every hour of direct patient care, physicians currently spend 2 hours on the EHR system. Most practices allow 10%-20% of time for catch up, where with statistics like this it should be 50%. This concept is fully lost on administrators, or ignored.

It is only when we refuse to continue to accept and follow a broken system that it will change. A minority of internal medicine and family doctors (4.5% in 2018) practice in direct primary care models, where these issues are addressed. Unfortunately, this model as it is currently available is not an option for lower income patients.

A major theme in the surgeon general’s report was that administrative burdens need to be reduced by 75% by 2025. When I look at the report, I see the suggestions, I just don’t see how it will be achieved. Despite almost all clinics moving to the EHR, paperwork in the form of faxes and forms has increased.

A sweeping reform would be needed to eliminate daily faxes from PT offices, visiting nurse services, prior authorization, patients reminders from insurance companies, and disability forms from patients. I am glad that there is acknowledgment of the problem, but this change will take more than 3 years.
 

Takeaways

So what do we do?

Be good to yourself, and your colleagues. The pandemic has isolated us, which accelerates burnout.

Reach out to people you care about.

We are all feeling this. Set boundaries that allow you to care for yourself, and accept that you are doing your best, even if you can’t meet the needs of all your patients all the time.
 

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at [email protected].

References

1. Sinsky CA et al. Covid-related stress and work intentions in a sample of US health care workers. Mayo Clin Proc Innov Qual Outcomes. 2021 Dec;5(6):1165-73.

2. Addressing health worker burnout. The U.S. Surgeon General’s advisory on building a thriving health workforce.

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

Intensive home treatment may offer an alternative to inpatient care for patients in acute psychiatric crisis – but the intervention is no outright substitute, new research suggests.

In a randomized controlled trial of more than 200 participants, intensive home treatment was associated with a 34% decrease in the number of inpatient hospital days in the year following therapy, compared with usual care.

However, there was no difference between treatment groups in improvement in quality of life or patient satisfaction; and a reduction in symptom severity noted after 6 weeks of home treatment faded within 6 months.

“We found no differences in admission rates either, which suggests that intensive home treatment is not a substitute for inpatient care but a different treatment opportunity for psychiatric patients in crisis,” Jurgen Cornelis, MD, Arkin Institute for Mental Health, Amsterdam, and colleagues write.

The findings were published online in The Lancet Psychiatry.
 

Increasingly popular

“Intensive home treatment is increasingly popular as an alternative to hospitalization. It was developed to prevent or reduce levels of inpatient care and facilitate the transition between inpatient care and low-intensity outpatient care,” the investigators write.

However, there have previously been only two randomized controlled trials published that assessed this type of care, resulting in “somewhat conflicting findings,” they add.

For the current study, participants presented to psychiatric emergency wards at two medical centers in the Netherlands. They were included only if they were able to offer informed consent within 14 days.

The intensive home treatment group (n = 183) worked with a multidisciplinary team that designed a care plan tailored to their specific crisis. Treatment components included pharmacotherapy, up to three home visits each day, psychoeducation, brief supportive and cognitive behavioral therapy, social care, and support and empowerment of the patient’s informal care system.

The usual care group (n = 63) commonly received a combination of highly intensive inpatient treatment in the first phase and outpatient treatment up to two times a week in the second phase. Treatment included similar components as those in intensive home treatment.

The most common primary clinical diagnosis in both groups was mood disorder, followed by psychotic disorders, personality disorders, or anxiety disorders.

The home treatment group had a significantly higher total mean item score on the Brief Psychiatric Rating Scale (BPRS) at baseline (2.23 vs. 2.04, P = .04).
 

Mixed results

Results at 6 weeks showed the number of hospital days was 25.3% lower in the home treatment group, compared with those who received usual care.

That trend continued at 1 year, with the intensive home treatment group recording 36.6% fewer hospital days than the usual care group (mean, 42.5 days vs. 67 days, respectively; P = .03).

However, the number of patients who were admitted in the first 6 weeks and at 1 year stayed the same, as did the mean number of admissions per patient over 12 months.

The home treatment group reported significantly fewer symptoms on the BPRS depression and anxiety scale at 6 weeks, compared with the usual treatment group (P = .025), but that difference was not maintained after 6 months.

The number of adverse events, including suicide attempts, was similar between the groups. Three patients in the home treatment group and two in the usual care group died by suicide.

“Future research should focus on which components of intensive home treatment or hospitalization can be used when, for whom, and meet which goals, so that both hospital care and intensive home treatment can be used proportionally and efficiently for patients in psychiatric crisis,” the investigators write.
 

Not generalizable?

In an accompanying editorial, Claire Henderson, PhD, Institute of Psychiatry, Psychology, and Neuroscience at King’s College London, noted that generalizing the study’s results to other countries could be problematic, especially to regions such as North America, which have shorter lengths of stay for psychiatric hospitalization.

“Future trials looking at intensive home treatment would be most informative if done in countries with relatively short lengths of stay, and without separate crisis services for people receiving assertive community treatment,” Dr. Henderson writes.

The study was funded by De Stichting tot Steun Vereniging voor Christelijke Verzorging van Geestes-en Zenuwzieken. The investigators and Dr. Henderson have reported no relevant financial relationships.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

In September 2022, the University of California, Berkeley, will start training its first class of “trip facilitators,” who will learn how to guide individuals through therapeutic psychedelic experiences aimed at addressing a variety of mental health problems.

The UC Berkeley Center for the Science of Psychedelics (BCSP) training program aims to create a cadre of facilitators who will be ready to help if, and when, substances such as psilocybin, MDMA, and LSD are approved in the United States, Tina Trujillo, PhD, an associate professor at UC Berkeley’s School of Education, told reporters at a press briefing.

Hallucinogenic drugs are on the Drug Enforcement Administration’s (DEA) Schedule I list because they are considered to have no currently accepted medical use and high abuse potential. But there has been an explosion of research into psychedelics – combined with therapy – as treatment for severe depression, posttraumatic stress disorder, substance-use disorder, and other mental health conditions. Some 100 clinical trials are underway.

“The estimates are that we’re going to need 100,000 trained psychedelic facilitators once psilocybin and MDMA are approved by the [U.S. Food and Drug Administration] FDA, which is expected to happen within the next 5 years or so,” said Michael Pollan, co-founder of the BCSP. He is author of “How to Change Your Mind,” a 2018 book about psychedelics, which has been adapted into a four-part docuseries currently streaming on Netflix.

Courtesy Alia Malley

Nine-month program

The first 24 trainees – a mix of physicians, nurses, psychotherapists, and social workers – will undergo 9 months of education and preparation in “the technical, the cultural, the mystical, and the ethical dimensions of psychedelic facilitation,” said Dr. Trujillo.

The BCSP’s Certificate Program in Psychedelic Facilitation will have “an emphasis on both western science and spiritual care traditions,” she said.

Trainees will receive 150 instructional hours and a 25-hour practicum and will take part in a final 5-day retreat. The program will initially focus only on psilocybin, in part because the BCSP is involved in several FDA-approved trials testing the drug.

In one study – which aims to enroll participants in the fall – researchers will use functional MRI to examine the neural correlates of the psychedelic experience in individuals receiving low-dose psilocybin.

Eligible trainees will have an opportunity to participate in the Berkeley psilocybin trials and “increase their first-hand knowledge,” Dr. Trujillo said.

At the conclusion of the training, students will receive a certificate, “not a license or sanction to go off and practice,” she said. She noted that eventually, when facilitation is legal, certificate holders will be able to practice in clinical research settings or in health care settings.
 

Growing acceptance in psychiatry

Mr. Pollan said there has been a radical change in acceptance of psychedelics as potential therapies.

“The shift from destroyer of young minds in the ‘60s to effective medicine in the 2020s is as sudden as it is confusing for many people,” he said. He noted that the Berkeley center hopes to provide evidence-based information for journalists, the public, and clinicians.

He said that after his book was released, he expected pushback from “mainstream psychiatry.” Instead, he was invited to give grand rounds talks. Psychiatrists are “very open to the potential of psychedelics,” Mr. Pollan said.

“The reason for that, quite frankly, is because they are desperate,” he said. “The tools of conventional psychiatry to deal with things like depression and anxiety and addiction are not very good, and some of them are failing,” he said.

Mr. Pollan cited some other indicators of acceptance. In Oregon, beginning in 2023, psilocybin will be available to anyone older than 21 years but only for use in licensed facilities with licensed facilitators, and the substance must be produced by a licensed manufacturer.

In November, Colorado will ask voters whether they want to follow the Oregon model and legalize psilocybin. If approved, another Colorado ballot initiative would decriminalize possession.

Mr. Pollan noted that Cory Booker, the Democratic Senator from New Jersey, and Rand Paul, a conservative Republican Senator from Kentucky, have found a common cause, introducing legislation to let select terminally ill patients have access to psychedelics and other Schedule I drugs.

Some 400 companies are conducting research on psychedelics. Researchers must have a license from the DEA to obtain and study the substances, Andrea Gomez, assistant professor of neurobiology at UC Berkeley, told reporters.

She said growing interest in the potential of these drugs might lead more researchers to “jump through the hoops” to get the licenses. The floodgates would truly open if the National Institutes of Health started funding studies, she said.

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

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

INDIANAPOLIS – Despite the common prevalence of skin-picking disorder and trichotillomania (hair pulling), no Food and Drug Administration–approved treatments exist for either condition.

And while both body-focused repetitive behavior disorders affect a greater proportion of females than males, “we have no current information that is useful about what hormonal influences may or may not play in terms of picking and pulling behaviors,” Jon E. Grant, MD, JD, MPH, professor of psychiatry and behavioral neuroscience at the University of Chicago, said at the annual meeting of the Society for Pediatric Dermatology. “On a cognitive level, affected children and adolescents often have impaired inhibitory control but they are often 1-2 standard deviations above average IQ. They have Type A personalities [and are] very driven young kids. They also do not tolerate any down time or boredom. They need to be doing something all the time.”

According to the DSM-5, the diagnostic criteria for skin picking includes recurrent skin picking that results in skin lesions and is not attributable to another medical condition or substance. It also involves repeated attempts to decrease or stop the behavior and causes clinically significant distress or impairment.

“The other medical condition that we are interested in is the misuse of or dependence upon amphetamines or other prescription-based or illicit stimulants,” Dr. Grant said. “I saw a young man who was using about 600 mg of Ritalin a day, and he was picking all over the place. He did not have a primary skin disorder.”

The lifetime prevalence of skin picking disorder ranges between 1.4% and 5.4% of the general population. However, about 63% of people in a community sample endorsed some form of skin picking, and in a study of 105 college students, almost 40% said they picked their skin and had noticeable tissue damage as a result.

“Skin picking is not the same as self-injury,” Dr. Grant said. “It is also not simply an anxiety disorder. Anxiety will make people who pick worse, so people will say that they pick when they’re under stress. I can give them benzodiazepines and they’re still going to pick.”

Animal and human studies demonstrate that skin picking and hair pulling primarily affect females. “You will encounter young boys that pick and pull, but it largely affects females, and it tends to start around puberty,” he said. “Picking can have an onset after the age of 30, which is quite uncommon.”

From a cognitive standpoint, pathological skin pickers demonstrate impaired inhibitory control, impaired stop signal reaction time, increased rates of negative urgency (a tendency to act impulsively in response to negative emotions), and increased rates of positive urgency (a tendency to act impulsively in response to exciting or pleasurable emotions).

Trichotillomania

The lifetime prevalence of trichotillomania ranges between 0.6% and 3.9%. The onset is typically from ages 10-13 years, and the mean duration of illness is 22 years.

The DSM-5 criteria for trichotillomania are similar to that of skin-picking disorder, “although we don’t really worry about the substance use issue with people who pull their hair,” Dr. Grant said. “It doesn’t seem to have a correlation.” In addition, sometimes, children “will worsen pulling or picking when they have co-occurring ADHD and they’ve been started on a stimulant, even at a typical dose. For kids who have those issues, we prefer to try nonstimulant options for their ADHD such as bupropion or atomoxetine.”

Individuals with trichotillomania also tend to have low self-esteem and increased social anxiety, he added, and about one-third report low or very low quality of life. “When you notice alopecia, particularly in young girls who often have longer hair, up to 20% will eat their hair,” Dr. Grant said. “We don’t know why. It’s not related to vitamin deficiencies; it’s not a pica type of iron deficiency. There seems to be a shame piece about eating one’s own hair, but it’s important to assess that. Ask about constipation or overflow incontinence because they can get a bezoar, which can rupture” and can be fatal.

Skin-picking disorder and trichotillomania co-occur in up to 20% of cases. “When they do it tends to be a more difficult problem,” he said. These patients often come for mental health care because of depression, and most, he added, say “I don’t think I would be depressed if I wasn’t covered with excoriations or missing most of my hair.”
 

Treatment for both conditions

According to Dr. Grant, the treatment of choice for skin-picking disorder and trichotillomania is a specific psychotherapy known as “habit reversal therapy,” which involves helping the patient gain better self-control. The drawback is that it’s difficult to find someone trained in habit reversal therapy, “who know anything about skin picking and hair pulling,” he said. “That has been a huge challenge in the field.”

In his experience, the medical treatment of choice for skin-picking disorder and trichotillomania is N-acetylcysteine, an over-the-counter amino acid and antioxidant, which has been shown to be helpful at a dose of 2,400 mg per day. “Patients report to me that some of the excoriations clear up a little quicker as they’re taking it,” Dr. Grant said.

There may also be a role for antipsychotic therapy, he said, “but because of the associated weight gain with most antipsychotics we prefer not to use them.”

The opioid antagonist naltrexone has been shown to be effective in the subset of patients with skin-picking or hair-pulling disorders whose parents have a substance use disorder, Dr. Grant said. “The thought is that there’s something addictive about this behavior in some kids. These kids will look forward to picking and find it rewarding and exciting.”

Dr. Grant reported having no relevant financial disclosures.

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

High-dose vitamin B6 supplements may reduce feelings of anxiety and depression, new research suggests.

Investigators compared supplementation with a 1-month course of vitamin B6 or B12 to supplementation with placebo in almost 500 adults. Results showed that vitamin B6 supplementation was associated with reductions in self-reported anxiety and a trend toward decreased depressive symptoms.

In addition, the vitamin B6 group showed increased levels of gamma-aminobutyric acid (GABA), as indicated by results on a visual test that was administered at the end of the trial. The test results demonstrated subtle changes in participants’ visual performance. The researchers considered this to be consistent with controlled levels of GABA-related brain activity.

However, “before practicing clinicians would recommend taking high doses of vitamin B6, a full-scale clinical trial would have to be carried out to verify the findings, assess any side effects, and find out which types of patients do or don’t benefit,” study investigator David Field, PhD, associate professor, School of Psychological and Clinical Language Sciences, University of Reading (England), told this news organization.

“My relatively small study can only be considered as an initial proof of concept,” Dr. Field said.

The findings were published online in the Journal of Human Psychopharmacology: Clinical and Experimental.
 

Eat Marmite?

“Recent research has connected mood disorders and some other neuropsychiatric conditions with disturbance in this balance, often in the direction of raised levels of brain activity,” Dr. Field noted.

Vitamin B6 is a coenzyme in the synthesis of GABA, an inhibitory neurotransmitter, from glutamate. Some previous research has suggested that vitamins B6 and B12 have a role in improving mood-related outcomes.

Dr. Field had reviewed a 2017 study of the effects on visual processing of eating Marmite, a type of food spread rich in vitamin B, every day for a few weeks.

“Remarkably, the results of that study suggested that eating Marmite had increased the level of the inhibitory neurotransmitter GABA in the visual part of the brain, damping down the level of neural activity slightly,” he said.

However, Marmite contains other B vitamins and other ingredients that might potentially account for this result, “plus, a lot of people don’t like the taste of Marmite,” Dr. Field noted.

Therefore, he wanted to “find out which individual ingredients were driving the effect, and B6 and B12 were the most plausible candidates.”

He decided to test these vitamins individually and to compare them to placebo. “I added the measures of anxiety and depression that were not in the Marmite study because I reasoned that if GABA levels were altered, this could improve those disorders, because we know that decreased levels of GABA in the brain occur in both of those conditions,” Dr. Field added.

Over the course of 5 years, investigators recruited 478 participants aged 18-58 years (mean age, 23 years; 381 women). Of these, 265 reported having anxiety, and 146 reported having depression.

The study participants were randomly assigned to receive either vitamin B6 (100 mg pyroxidine hydrochloride), vitamin B12 (1,000 mg methylcobalmin), or placebo tablets once daily for a month.

They also completed the Screen for Adult Anxiety Related Disorders (SCAARED) and the Mood and Feelings Questionnaire (MFQ) long version at baseline and following supplementation (“post test”), and they underwent three sensory tests that acted as assays of inhibitory function at post test.

In addition, 307 participants completed the Visual Contrast Sensitivity and Surround Suppression, which “measures the minimum percentage contrast between the lighter and darker regions of a striped pattern that can be detected (called the contrast threshold),” the investigators note.

The contrast threshold was measured with and without a suppressive surround mask that increases the threshold – an effect mediated by GABAergic connections in the visual cortex.

Participants (n = 172) also completed the Binocular Rivalry test and the Tactile Test Battery (n = 180). Both tests are designed to measure responses requiring GABAergic inhibitory activity.
 

‘Subtle changes’

ANOVA analyses revealed a “highly significant” reduction in anxiety at post test (F[1,173] = 10.03; P = .002; np 2 = .055), driven primarily by reduced anxiety in the B6 group (t[88] = 3.51; P < .001; d = .37). The placebo group also showed some reduction in anxiety, but it was not deemed significant, and the overall interaction itself did not reach significance.

A comparison of the B12 group with the group that received placebo revealed a significant reduction in anxiety at post test (F[1,175] = 4.08; P = .045; np 2 = .023), similarly driven by reduced anxiety in the B12 group (t[89] = 1.84; P = .069; d = .19) – but the interaction was not significant.

Among the B6 group, there was a highly significant reduction in scores on the generalized anxiety disorder and social anxiety subscales of the SCAARED, and there was a trend toward reductions on the other subscales. Among the B12 group, there was a significant reduction only on scores on the separation anxiety subscale. No significant changes were found in the placebo group.

The ANOVA test analysis of the B6 and placebo group data showed “no uniform direction of change” in depression at post test. The researchers found a “tendency” for depression scores to decrease between baseline and post test in the B6 group but to increase in the placebo group – an interaction that “approached” significance (F[1,96] = 3.08; P = .083; np 2 = .031), they report.

The ANOVA analysis of the B12 and placebo group data revealed no significant or trending effects, and the t-test comparing baseline and post-test scores in the B12 group was similarly nonsignificant.

B6 supplementation did change visual contrast thresholds, but only when a suppressive surround was present. There were “no clear effects” of B6 supplementation on other outcome measures, including binocular rivalry reversal rate and the tactile test battery, the investigators note.

“We found that supplementation with B6 produced subtle changes in tests of visual processing in a way that suggested an increase in the level of the inhibitory neurotransmitter GABA,” Dr. Field reported.

Vitamin B6 is a “cofactor for a metabolic pathway in the brain that converts the excitatory neurotransmitter glutamate into the inhibitory/calming GABA,” he said.

“By increasing the quantity of the cofactor, we slightly speed up the rate of this metabolic process, and so you end up with a bit more of the GABA neurotransmitter and a bit less glutamate. The net effect of this is to slightly reduce the amount of activity in the brain,” Dr. Field added.
 

Most common nutrient deficiency

Carol Johnston, PhD, professor and associate dean for faculty success, College of Health Solutions, Arizona State University, Phoenix, said vitamin B6 is “the most common nutrient deficiency in the United States;” 16% of men and 32% of women are reportedly B6 deficient.

“Young women on birth control are at higher risk for B6 deficiency due to effects of oral contraceptives on B6 metabolism,” whereas vitamin B12 deficiency is more common in older adults, said Dr. Johnston, who was not involved with the study.

The current study’s population mainly consisted of young women, and the interpretation of the data is “limited” because the researchers did not measure blood status for B6 and B12, Dr. Johnston noted. It is possible the sample was low in B6 and that the supplements “improved cognitive measures.”

Because the population was young – no one was older than 60 years – B12 status was likely “adequate in the sample, and supplementation did not have an impact,” she said.

Overall, Dr. Johnston cautioned that it is important to “alert clinicians and the general public about the concerns of overdosing B6.” For example, supplementation at high amounts can cause potentially irreversible sensory neuropathy, she noted.

“The safe upper limit defined by experts is 100 mg per day – the dosage used in this trial. Daily supplementation should not exceed this level,” Dr. Johnston said.

The vitamin tablets used in the study were supplied by Innopure. The investigators and Dr. Johnston have reported no relevant financial relationships.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Pharmacogenetic testing, which is used to classify how patients with major depressive disorder (MDD) metabolize medications, reduces adverse drug-gene interactions, new research shows.

In a randomized clinical trial that included almost 2,000 adults with MDD, patients in the pharmacogenomics-guided group were more likely to receive an antidepressant that had no potential drug-gene interaction than the patients who received usual care.

In addition, among the intervention group, the rate of remission over 24 weeks was significantly greater.

“These tests can be helpful in rethinking choices of antidepressants, but clinicians should not expect them to be helpful for every patient,” study investigator David W. Oslin, MD, Corporal Michael J. Crescenz VA Medical Center and professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, said in an interview.

The findings were published online  in JAMA.

Less trial and error

Pharmacogenomic testing can provide information to inform drug selection or dosing for patients with a genetic variation that alters pharmacokinetics or pharmacodynamics. Such testing may be particularly useful for patients with MDD, as fewer than 40% of these patients achieve clinical remission after an initial treatment with an antidepressant, the investigators note.

“To get to a treatment that works for an individual, it’s not unusual to have to try two or three or four antidepressants,” said Dr. Oslin. “If we could reduce that variance a little bit with a test like this, that would be huge from a public health perspective.”

The study included 676 physicians and 1,944 adults with MDD (mean age, 48 years; 24% women) who were receiving care at 22 Department of Veterans Affairs medical centers. Eligible patients were set to start a new antidepressant monotherapy, and all underwent a pharmacogenomic test using a cheek swab.

Investigators randomly assigned patients to receive test results when available (pharmacogenomic-guided group) or 24 weeks later (usual-care group). For the former group, clinicians were asked to initiate treatment when test results were available, typically within 2-3 days. For the latter group, they were asked to initiate treatment on a day of randomization.

Assessments included the 9-item Patient Health questionnaire (PHQ-9), scores for which range from 0-27 points, with higher scores indicating worse symptoms.

Of the total patient population, 79% completed the 24-week assessment.

Researchers characterized antidepressant medications on the basis of drug-gene interaction categories: no known interactions, moderate interactions, and substantial interactions.

The co-primary outcomes were treatment initiation within 30 days, determined on the basis of drug-gene interaction categories, and remission from depression symptoms, defined as a PHQ-9 score of less than or equal to 5.

Raters who were blinded to clinical care and study randomization assessed outcomes at 4, 8, 12, 18, and 24 weeks.
 

Significant impact?

Results showed that the pharmacogenomic-guided group was more likely to receive an antidepressant that had no potential drug-gene interaction, as opposed to one with a moderate/substantial interaction (odds ratio, 4.32; 95% confidence interval, 3.47-5.39; P < .001).

The usual-care group was more likely to receive a drug with mild potential drug-gene interaction (no/moderate interaction vs. substantial interaction: OR, 2.08; 95% CI, 1.52-2.84; P = .005).

For the intervention group, the estimated rates of receiving an antidepressant with no, moderate, and substantial drug-gene interactions were 59.3%, 30.0%, and 10.7%, respectively. For the usual-care group, the estimates were 25.7%, 54.6%, and 19.7%.

The finding that 1 in 5 patients who received usual care were initially given a medication for which there were significant drug-gene interactions means it is “not a rare event,” said Dr. Oslin. “If we can make an impact on 20% of the people we prescribe to, that’s actually pretty big.”

Rates of remission were greater in the pharmacogenomic-guided group over 24 weeks (OR, 1.28; 95% CI, 1.05-1.57; P = .02; absolute risk difference, 2.8%; 95% CI, 0.6%-5.1%).

The secondary outcomes of response to treatment, defined as at least a 50% decrease in PHQ-9 score, also favored the pharmacogenomic-guided group. This was also the case for the secondary outcome of reduction in symptom severity on the PHQ-9 score.

Some physicians have expressed skepticism about pharmacogenomic testing, but the study provides additional evidence of its usefulness, Dr. Oslin noted.

“While I don’t think testing should be standard of practice, I also don’t think we should put barriers into the testing until we can better understand how to target the testing” to those who will benefit the most, he added.

The tests are available at a commercial cost of about $1,000 – which may not be that expensive if testing has a significant impact on a patient’s life, said Dr. Oslin.
 

Important research, but with several limitations

In an accompanying editorial, Dan V. Iosifescu, MD, associate professor of psychiatry at New York University School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research, called the study an important addition to the literature on pharmacogenomic testing for patients with MDD.

The study was significantly larger and had broader inclusion criteria and longer follow-up than previous clinical trials and is one of the few investigations not funded by a manufacturer of pharmacogenomic tests, writes Dr. Iosifescu, who was not involved with the research.

However, he notes that an antidepressant was not initiated for 30 days after randomization in 25% of the intervention group and in 31% of the usual-care group, which was “puzzling.” “Because these rates were comparable in the 2 groups, it cannot be explained primarily by the delay of the pharmacogenomic test results in the intervention group,” he writes.

In addition, in the co-primary outcome of symptom remission rate, the difference in clinical improvement in favor of the pharmacogenomic-guided treatment was only “modest” – the gain was of less than 2% in the proportion of patients achieving remission, Dr. Iosifescu adds.

He adds this is “likely not very meaningful clinically despite this difference achieving statistical significance in this large study sample.”

Other potential study limitations he cites include the lack of patient blinding to treatment assignment and the absence of clarity about why rates of MDD response and remission over time were relatively low in both treatment groups.

A possible approach to optimize antidepressant choices could involve integration of pharmacogenomic data into larger predictive models that include clinical and demographic variables, Dr. Iosifescu notes.

“The development of such complex models is challenging, but it is now possible given the recent substantial advances in the proficiency of computational tools,” he writes.

The study was funded by the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, and the Mental Illness Research, Education, and Clinical Center at the Corporal Michael J. Crescenz VA Medical Center. Dr. Oslin reports having received grants from the VA Office of Research and Development and Janssen Pharmaceuticals and nonfinancial support from Myriad Genetics during the conduct of the study. Dr. Iosifescu report having received personal fees from Alkermes, Allergan, Axsome, Biogen, the Centers for Psychiatric Excellence, Jazz, Lundbeck, Precision Neuroscience, Sage, and Sunovion and grants from Alkermes, AstraZeneca, Brainsway, Litecure, Neosync, Otsuka, Roche, and Shire.

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

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.

Despite much progress, major depressive disorder (MDD) continues to be a challenging and life-threatening neuropsychiatric disorder. It is highly prevalent and afflicts tens of millions of Americans.

It is also ranked as the No. 1 disabling medical (not just psychiatric) condition by the World Health Organization.¹ A significant proportion of patients with MDD do not respond adequately to several rounds of antidepressant medications,² and many are labeled as having “treatment-resistant depression” (TRD).

In a previous article, I provocatively proposed that TRD is a myth.³ What I meant is that in a heterogeneous syndrome such as depression, failure to respond to 1, 2, or even 3 antidepressants should not imply TRD, because there is a “right treatment” that has not yet been identified for a given depressed patient. Most of those labeled as TRD have simply not yet received the pharmacotherapy or somatic therapy with the requisite mechanism of action for their variant of depression within a heterogeneous syndrome. IV ketamine, which, astonishingly, often reverses severe TRD of chronic duration within a few hours, is a prime example of why the term TRD is often used prematurely. Ketamine’s mechanism of action (immediate neuroplasticity via glutamate N-methyl-d-aspartate receptor antagonism, and stimulation of the mammalian target of rapamycin [mTOR]) was not recognized for decades because of the obsession with the monoamine model of depression.

Some clinicians may not be aware of the abundance of mechanisms of action currently available for the treatment of MDD as well as bipolar depression. Many practitioners, in both psychiatry and primary care, usually start the treatment of depression with a selective serotonin reuptake inhibitor, and if that does not produce a response or remission, they might switch to a serotonin-norepinephrine reuptake inhibitor. If that does not control the patient’s depressive symptoms, they start entertaining the notion that the patient may have TRD, not realizing that they have barely scratched the surface of the many therapeutic options and mechanisms of action, one of which could be the “best match” for a given patient.⁴

There will come a day when “precision psychiatry” finally arrives, and specific biomarkers will be developed to identify the “right” treatment for each patient within the heterogenous syndrome of depression.⁵ Until that day arrives, the treatment of depression will continue to be a process of trial and error, and hit or miss. But research will eventually discover genetic, neuro­chemical, neurophysiological, neuro­imaging, or neuroimmune biomarkers that will rapidly guide clinicians to the correct treatment. This is critical to avoid inordinate delays in achieving remission and avert the ever-present risk of suicidal behavior.

The Table⁶ provides an overview of the numerous treatments currently available to manage depression. All increase brain-derived neurotrophic factor and restore healthy neuroplasticity and neuro­genesis, which are impaired in MDD and currently believed to be a final common pathway for all depression treatments.⁷

These 41 therapeutic approaches to treating MDD or bipolar depression reflect the heterogeneity of mechanisms of action to address an equally heterogeneous syndrome. This implies that clinicians have a wide array of on-label options to manage patients with depression, aiming for remission, not just a good response, which typically is defined as a ≥50% reduction in total score on one of the validated rating scales used to quantify depression severity, such as the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale, or Calgary Depression Scale for Schizophrenia.

Continue to: When several FDA-approved pharmacotherapies...

When several FDA-approved pharmacotherapies fall short and produce a suboptimal response, clinicians can resort to other treatment options known to have a higher efficacy than oral antidepressants. These include electroconvulsive therapy, repetitive transcranial magnetic stimulation, and vagus nerve stimulation. Other on-label options include adjunctive therapy with one of the approved second-generation antipsychotic agents or with adjunctive esketamine.

But if the patient still does not improve, one of many emerging off-label treatment options may work. One of the exciting new discoveries is the hallucinogen psilocybin, whose mechanism of action is truly unique. Unlike standard antidepressant medications, which modulate neurotransmitters, psilocybin increases the brain’s network flexibility, decreases the modularity of several key brain networks (especially the default-brain network, or DMN), and alters the dark and distorted mental perspective of depression to a much healthier and optimistic outlook about the self and the world.⁸ Such novel breakthroughs in the treatment of severe depression will shed some unprecedented insights into the core neurobiology of depression, and may lead to early intervention and prevention.

As the saying goes, all roads lead to Rome. Psychiatric clinicians should rejoice that there are abundant approaches and therapeutic mechanisms to relieve their severely melancholic (and often suicidal) patients from the grips of this disabling and life-altering brain syndrome.