Depression

In 2019, the U.S. suicide rate dropped for the first time in 14 years, driven largely by a significant decline in firearm-related deaths, according to a new analysis of National Vital Statistics System data.

Since firearms are the “most common and most lethal” mechanism of suicide, the drop in deaths is “particularly encouraging,” Deborah M. Stone, ScD, MSW, MPH, and associates wrote in the Morbidity and Mortality Weekly Report.

The national suicide rate decreased from 14.2 per 100,000 population in 2018 to 13.9 per 100,000 in 2019, a statistically significant drop of 2.1% that reversed a 20-year trend that saw the rate increase by 33% since 1999, they said.

The rate for firearm use, which is involved in half of all suicides, declined from 7.0 per 100,000 to 6.8, for a significant change of 2.9%, said Dr. Stone and associates at the Centers for Disease Control and Prevention’s National Center for Injury Prevention and Control.

The only other method with a drop in suicide rate from 2018 to 2019 was suffocation – the second most common mechanism of injury – but the relative change of 2.3% was not significant, they noted.

Significant declines also occurred in several subgroups: Whites; those aged 15-24, 55-64, and 65-74 years; and those living in counties classified as large fringe metropolitan or micropolitan (urban cluster of ≥ 10,000 but less than 50,000 population), they said, based on data from the National Vital Statistics System.

“These declines, although encouraging, were not uniform, and several states experienced significant rate increases,” the investigators wrote.

The states with significant increases were Hawaii (30.3%) and Nebraska (20.1%), while declines in the suicide rate were significant in five states – Idaho, Indiana, Massachusetts, North Carolina, and Virginia, Dr. Stone and associates reported. Altogether, the rate fell in 31 states, increased in 18, and did not change in 2.

The significance of those changes varied between males and females. Declines were significant for females in Indiana, Massachusetts, and Washington, and for males in Florida, Kentucky, Massachusetts, North Carolina, and West Virginia. Minnesota was the only state with a significant increase among females, with Hawaii and Wyoming posting increases for males, they said.

As the response to the COVID-19 pandemic continues, the investigators pointed out, “prevention is more important than ever. Past research indicates that suicide rates remain stable or decline during infrastructure disruption (e.g., natural disasters), only to rise afterwards as the longer-term sequelae unfold in persons, families, and communities.”

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In 2019, the U.S. suicide rate dropped for the first time in 14 years, driven largely by a significant decline in firearm-related deaths, according to a new analysis of National Vital Statistics System data.

Since firearms are the “most common and most lethal” mechanism of suicide, the drop in deaths is “particularly encouraging,” Deborah M. Stone, ScD, MSW, MPH, and associates wrote in the Morbidity and Mortality Weekly Report.

The national suicide rate decreased from 14.2 per 100,000 population in 2018 to 13.9 per 100,000 in 2019, a statistically significant drop of 2.1% that reversed a 20-year trend that saw the rate increase by 33% since 1999, they said.

The rate for firearm use, which is involved in half of all suicides, declined from 7.0 per 100,000 to 6.8, for a significant change of 2.9%, said Dr. Stone and associates at the Centers for Disease Control and Prevention’s National Center for Injury Prevention and Control.

The only other method with a drop in suicide rate from 2018 to 2019 was suffocation – the second most common mechanism of injury – but the relative change of 2.3% was not significant, they noted.

Significant declines also occurred in several subgroups: Whites; those aged 15-24, 55-64, and 65-74 years; and those living in counties classified as large fringe metropolitan or micropolitan (urban cluster of ≥ 10,000 but less than 50,000 population), they said, based on data from the National Vital Statistics System.

“These declines, although encouraging, were not uniform, and several states experienced significant rate increases,” the investigators wrote.

The states with significant increases were Hawaii (30.3%) and Nebraska (20.1%), while declines in the suicide rate were significant in five states – Idaho, Indiana, Massachusetts, North Carolina, and Virginia, Dr. Stone and associates reported. Altogether, the rate fell in 31 states, increased in 18, and did not change in 2.

The significance of those changes varied between males and females. Declines were significant for females in Indiana, Massachusetts, and Washington, and for males in Florida, Kentucky, Massachusetts, North Carolina, and West Virginia. Minnesota was the only state with a significant increase among females, with Hawaii and Wyoming posting increases for males, they said.

As the response to the COVID-19 pandemic continues, the investigators pointed out, “prevention is more important than ever. Past research indicates that suicide rates remain stable or decline during infrastructure disruption (e.g., natural disasters), only to rise afterwards as the longer-term sequelae unfold in persons, families, and communities.”

[email protected]

In 2019, the U.S. suicide rate dropped for the first time in 14 years, driven largely by a significant decline in firearm-related deaths, according to a new analysis of National Vital Statistics System data.

Since firearms are the “most common and most lethal” mechanism of suicide, the drop in deaths is “particularly encouraging,” Deborah M. Stone, ScD, MSW, MPH, and associates wrote in the Morbidity and Mortality Weekly Report.

The national suicide rate decreased from 14.2 per 100,000 population in 2018 to 13.9 per 100,000 in 2019, a statistically significant drop of 2.1% that reversed a 20-year trend that saw the rate increase by 33% since 1999, they said.

The rate for firearm use, which is involved in half of all suicides, declined from 7.0 per 100,000 to 6.8, for a significant change of 2.9%, said Dr. Stone and associates at the Centers for Disease Control and Prevention’s National Center for Injury Prevention and Control.

The only other method with a drop in suicide rate from 2018 to 2019 was suffocation – the second most common mechanism of injury – but the relative change of 2.3% was not significant, they noted.

Significant declines also occurred in several subgroups: Whites; those aged 15-24, 55-64, and 65-74 years; and those living in counties classified as large fringe metropolitan or micropolitan (urban cluster of ≥ 10,000 but less than 50,000 population), they said, based on data from the National Vital Statistics System.

“These declines, although encouraging, were not uniform, and several states experienced significant rate increases,” the investigators wrote.

The states with significant increases were Hawaii (30.3%) and Nebraska (20.1%), while declines in the suicide rate were significant in five states – Idaho, Indiana, Massachusetts, North Carolina, and Virginia, Dr. Stone and associates reported. Altogether, the rate fell in 31 states, increased in 18, and did not change in 2.

The significance of those changes varied between males and females. Declines were significant for females in Indiana, Massachusetts, and Washington, and for males in Florida, Kentucky, Massachusetts, North Carolina, and West Virginia. Minnesota was the only state with a significant increase among females, with Hawaii and Wyoming posting increases for males, they said.

As the response to the COVID-19 pandemic continues, the investigators pointed out, “prevention is more important than ever. Past research indicates that suicide rates remain stable or decline during infrastructure disruption (e.g., natural disasters), only to rise afterwards as the longer-term sequelae unfold in persons, families, and communities.”

[email protected]

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

In his role as head of the division of pediatric behavioral health at National Jewish Health, Denver, Bruce G. Bender, PhD, helps children and adults navigate the adverse effects of severe atopic dermatitis (AD) on their quality of life.

“There have been many surveys of adults with AD who report impairment of their sleep, reduced activity level, increased work absence, financial burden, emotional distress, and social avoidance,” he said at the Revolutionizing Atopic Dermatitis virtual symposium. “Similarly, children with AD or their parents report emotional distress, reduced activity, and increased school absence, social avoidance, and sleep disturbance. Families report financial burdens, conflict, particularly among the adults, social avoidance, sleep disturbance in the parents, and reduction of well-being in the siblings.”

Getting adequate sleep is especially challenging for patients with AD, and loss of sleep can have serious daytime consequences. In an effort to objectively measure sleep change in this population, Dr. Bender and colleagues recruited 14 adults with AD and 14 healthy controls who wore an ActiGraph for 1 week and completed questionnaires about sleep, itch, and quality of life. Patients with AD were awake almost twice as many minutes each night as the healthy controls (a mean of 57.3 vs. 32.3 minutes, respectively; P = .0480). Consequently, their sleep efficiency was significantly reduced based on the Pittsburgh sleep quality index (a mean of 90.6 vs. 95; P = .0305).

In another study, Dr. Bender and colleagues enrolled 20 adults with AD who underwent 2 nights of polysomnography and actigraphy. The lab was set up to measure a scratching event, which was recorded when a burst of electromyographic activity of at least 3 seconds was accompanied by a visible scratching motion. “We learned that sleep efficiency as measured by both PSG and actigraphy correlated with total body surface area and scratching index,” he said. “As we might assume, the more skin involved, the more patients scratch, the less well they sleep.”
 

Behavioral, neurocognitive effects

In a separate study of AD, sleep, and behavior, the researchers studied 1,041 children with asthma who were enrolled in the Childhood Asthma Management Program at eight North American sites. They used baseline parent ratings on standardized sleep and behavior rating scales and found that increased awakenings were associated with increased school absence and daytime behavior problems. “So, not only do children with AD sleep less well, but this shows up to impair their functioning during the day,” said Dr. Bender, professor of psychiatry at the University of Colorado, Denver.

In a report from Australia, researchers set out to explore the association between sleep and neurocognitive function in 21 children with eczema and 20 healthy controls. Participants underwent cognitive testing and polysomnography. The authors found that the children with eczema demonstrated lower test scores. Reduced scores were correlated with parental reports of sleep problems but not polysomnography.

In a much larger study funded by the Agency for Healthcare Research and Quality, investigators analyzed data on 354,416 children and 34,613 adults from 19 U.S. population surveys including the National Health Interview Survey 1997-2013 and the National Survey of Children’s Health 2003/4 and 2007/8. They found that AD was associated with ADHD in children (adjusted odds ratio, 1.14) and adults (aOR, 1.61). Higher odds of ADHD were found in children who had significant sleep disturbance (aOR, 16.83) and other allergic disease and asthma (aOR, 1.61).

“All of these findings show that AD can impact quality of life, especially sleep, with the result of poorer daytime functioning,” Dr. Bender said. “But those studies don’t answer this question: Are patients with AD at increased risk for psychological disorders such as depression and anxiety?”
 

Impact on depression, anxiety

Two systematic reviews on the topic suggest that patients with AD are twice as likely to experience depression. One was published in 2018 and the other in 2019. The 2018 review reported a little more than a twofold increase (OR, 2.19), the 2019 review a little bit less (OR, 1.71).

“At the more severe end of the depression continuum, we sometimes see suicidal ideation and suicide attempts,” Dr. Bender said. “A number of studies have asked whether these are increased in patients with AD. Quite a few studies collectively show an increased incidence of suicidal ideation. The question of suicide attempts is reflected in fewer studies. And while the result is small, it is significant. There is a significant increase reported of suicide attempts in AD patients.”

The 2018 review also found an increased incidence of anxiety in AD patients: a little more than twofold in adults (OR, 2.19) and a little less than twofold in children (OR, 1.81).

“It’s a two-way relationship between AD and psychological factors,” Dr. Bender said. “We generally think about AD – the stress that it brings, the burden that it puts on children, adults, and families. But it can work the other way around,” he said, referring to patients who have psychological problems, experience a great deal of stress, have trouble being adherent to their treatment regimen, and find it difficult to resist scratching. “The behavioral/psychological characteristics of the patient also drive the AD. It is well established that acute and chronic stress can result in a worsening of skin conditions in AD patients.”

Behavioral health interventions that have been described in the literature include cognitive therapy, stress management, biofeedback, hypnotherapy, relaxation training, mindfulness, habit reversal, and patient education – some of which have been tested in randomized trials. “All of them report a decrease in scratching as a consequence of the behavioral intervention,” Dr. Bender said.

“Other studies have been reported that look at the impact of behavioral interventions on the severity of the skin condition. Most report an improvement in the skin condition from these behavioral interventions but it’s not a perfect literature.” Critiques of these studies include the fact that there is often not enough detail about the intervention or the framework for the intervention that would allow a clinician to test an intervention in another study or actually pull that intervention into clinical practice (Cochrane Database Syst Rev. 2014 Jan 7;2014[1]:CD004054), (Int Arch Allergy Immunol.2007;144[1]:1-9).

“Some of the studies lack rigorous designs, some have sampling bias, and some have inadequate outcome measurements,” he said. “We really need additional, high-quality studies to look at what is helpful for patients with AD.”

Dr. Bender reported having no financial disclosures.

[email protected]

Patients with severe asthma and comorbid atopy, obesity, and depression/anxiety had fewer annual exacerbations after receiving mepolizumab, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”

Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.

The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.

At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.

Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).

In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.

The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).

The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).

The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.

“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”

This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.

Patients with severe asthma and comorbid atopy, obesity, and depression/anxiety had fewer annual exacerbations after receiving mepolizumab, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”

Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.

The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.

At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.

Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).

In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.

The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).

The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).

The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.

“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”

This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.

Patients with severe asthma and comorbid atopy, obesity, and depression/anxiety had fewer annual exacerbations after receiving mepolizumab, according to research from the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

“Mepolizumab has clearly been shown to improve severe asthma control in many clinical trials, but atopy, obesity, and depression/anxiety affect patients with asthma at an increased rate,” Thomas B. Casale, MD, former AAAAI president and professor of medicine and pediatrics at the University of South Florida in Tampa, said in a presentation at the meeting. “Yet, few studies have examined whether asthma therapy with these comorbidities works.”

Dr. Casale and colleagues performed a retrospective analysis of patients in the United States from the MarketScan Commercial and Medicare Supplemental Database between November 2014 and December 2018 who had atopy, obesity, or depression/anxiety in addition to asthma and were receiving mepolizumab. Atopy in the study was defined as allergic rhinitis, anaphylaxis, atopic dermatitis, conjunctivitis, eosinophilic esophagitis, and food allergies. Patients were at least age 12 years, had at least one diagnosis for asthma, at least one diagnosis code for atopic disease, obesity, or depression/anxiety at baseline, and at least two administrations of mepolizumab within 180 days.

The researchers examined the number of exacerbations, oral corticosteroid (OCS) claims, and OCS bursts per year at 12-month follow-up, compared with baseline. They identified exacerbations by examining patients who had an emergency department or outpatient claim related to their asthma, and a claim for systemic corticosteroids made in the 4 days prior to or 5 days after a visit, or if their inpatient hospital admission contained a primary asthma diagnosis. Dr. Casale and colleagues measured OCS bursts as a pharmacy claim of at least 20 mg of prednisone per day for between 3 and 28 days plus a claim for an emergency department visit related to asthma in the 7 days prior or 6 days after the claim.

At baseline, patients across all groups were mean age 50.5-52.4 years with a Charleson Comorbidity Index score between 1.1 and 1.4, a majority were women (59.0%-72.0%) and nearly all were commercially insured (88.0%-90.0%). Patients who used biologics at baseline and/or used a biologic that wasn’t mepolizumab during the follow-up period were excluded.

Medication claims in the groups included inhaled corticosteroids (ICS) (36.8%-48.6%), ICS/long-acting beta-agonist (LABA) (60.2%-63.0%), LABA/ long-acting muscarinic antagonist (LAMA) (1.2%-3.5%), ICS/LABA/LAMA (21.2%-25.1%), short-acting beta-agonist (SABA) (83.2%-87.7%), LAMA alone (33.5%-42.1%), or leukotriene receptor antagonist (LTRA).

In the non–mutually exclusive group of patients with atopy (468 patients), 28.0% had comorbid obesity and 26.0% had comorbid depression/anxiety. For patients with obesity categorized in a non–mutually exclusive subgroup (171 patients), 79.0% had comorbid atopy and 32.0% had comorbid depression/anxiety. Among patients with non–mutually exclusive depression/anxiety (173 patients), 70.0% had comorbid atopy, while 32.0% had comorbid obesity.

The results showed the mean number of overall exacerbations decreased by 48% at 12 months in the atopic group (2.3 vs. 1.2; P < .001), 52% in the group with obesity (2.5 vs. 1.2; P < .001), and 38% in the depression/anxiety group (2.4 vs. 1.5; P < .001). The mean number of exacerbations leading to hospitalizations decreased by 64% in the atopic group (0.11 vs. 0.04; P < .001), 65% in the group with obesity (0.20 vs. 0.07; P < .001), and 68% in the group with depression/anxiety (0.22 vs. 0.07; P < .001).

The researchers also found the mean number of OCS claims and OCS bursts also significantly decreased over the 12-month follow-up period. Mean OCS claims decreased by 33% for patients in the atopic group (5.5 vs. 3.7; P < .001), by 38% in the group with obesity (6.1 vs. 3.8; P < .001), and by 31% in the group with depression/anxiety (6.2 vs. 4.3; P < .001).

The mean number of OCS bursts also significantly decreased by 40% in the atopic group (2.0 vs. 2.1; P < .001), 48% in the group with obesity (2.3 vs. 1.2; P < .001), and by 37% in the group with depression/anxiety (1.9 vs. 1.2; P < .001). In total, 69% of patients with comorbid atopy, 70.8% of patients with comorbid obesity, and 68.2% of patients with comorbid depression/anxiety experienced a mean decrease in their OCS dose over 12 months.

“These data demonstrate that patients with asthma and atopy, obesity, or depression and anxiety have significantly fewer exacerbations and reduced OCS use in a real-world setting with treatment of mepolizumab,” Dr. Casale said. “Thus, holistic patient care for severe asthma is critical, and mepolizumab provides tangible clinical benefit despite the complexities of medical comorbidities.”

This study was funded by GlaxoSmithKline, and the company also funded graphic design support of the poster. Dr. Casale reports he has received research funds from GlaxoSmithKline. Four authors report being current or former GlaxoSmithKline employees; three authors report holding stock and/or shares of GlaxoSmithKline. Three authors are IBM Watson Health employees, a company GlaxoSmithKline has provided research funding.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

This past year, the referrals to my private practice have taken a noticeable shift and caused me to pause.

HRAUN/Getty Images

More calls have come from nurses, many who work directly with COVID-19 patients, understandably seeking mental health treatment, or support. Especially in this time, nurses are facing trauma and stress that is unimaginable to many, myself included. Despite the collective efforts we have made as a society to recognize their work, I do not think we have given enough consideration to the enormous sacrifice nurses are currently undertaking to save our collective psyche.

As physicians and mental health providers, we have a glimpse into the complexities and stressors of medical treatment. In our line of work, we support patients with trauma on a regular basis. We feel deeply connected to patients, some of whom we have treated until the end of their lives. Despite that, I am not sure that I, or anyone, can truly comprehend what nurses face in today’s climate of care.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com.

References

1. Rogers CR. J Consult Psychol. 1957;21(2):95-103.

2. Mallo CJ, Mintz DL. Psychodyn Psychiatry. 2013 Mar;41(1):13-37.

3. Resick PA et al. Cognitive Processing Therapy for PTSD: A Comprehensive Manual. Guilford Publications, 2016.

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

Researchers have come a long way in understanding the link between acute inflammation and treatment-resistant depression, but more work needs to be done, according to Mark Hyman Rapaport, MD.

Svisio/Thinkstock

“Inflammation has been a hot topic in the past decade, both because of its impact in medical disorders and in psychiatric disorders,” Dr. Rapaport, CEO of the Huntsman Mental Health Institute in Salt Lake City, Utah, said during an annual psychopharmacology update held by the Nevada Psychiatric Association. “We run into difficulty with chronic inflammation, which we see with rheumatic disorders, and when we think of metabolic syndrome and obesity.”

The immune system helps to control energy regulation and neuroendocrine function in acute inflammation and chronic inflammatory diseases. “We see a variety of effects on the central nervous system or liver function or on homeostasis of the body,” said Dr. Rapaport, who also chairs the department of psychiatry at the University of Utah, also in Salt Lake City. “These are all normal and necessary to channel energy to the immune system in order to fight what’s necessary in acute inflammatory response.”

A chronic state of inflammation can result in prolonged allocation of fuels to the immune system, tissue inflammation, and a chronically aberrant immune reaction, he continued. This can cause depressive symptoms/fatigue, anorexia, malnutrition, muscle wasting, cachectic obesity, insulin resistance, dyslipidemia, increased adipose tissue in the proximity of inflammatory lesion, alterations of steroid hormone axes, elevated sympathetic tone, hypertension, decreased parasympathetic tone, inflammation-related anemia, and osteopenia. “So, chronic inflammation has a lot of long-term sequelae that are detrimental,” he said.

Both physical stress and psychological stress also cause an inflammatory state. After looking at the medical literature, Dr. Rapaport and colleagues began to wonder whether inflammation and immune activation associated with psychiatric disorders are attributable to the stress of acute illness. To find out, they performed a meta-analysis of blood cytokine network alterations in psychiatric patients and evaluated comparisons between schizophrenia, bipolar disorder, and depression. A total of three meta-analyses were performed: one of acute/inpatient studies, one on the impact of acute treatment, and one of outpatient studies. The researchers hypothesized that inflammatory and immune findings in psychiatric illnesses were tied to two distinct etiologies: the acute stress of illness and intrinsic immune dysfunction.

The meta-analyses included 68 studies: 40 involving patients with schizophrenia, 18 involving those with major depressive disorder (MDD) and 10 involving those with bipolar disorder. The researchers found that levels of four cytokines were significantly increased in acutely ill patients with schizophrenia, bipolar mania, and MDD, compared with controls: interleukin-6, tumor necrosis factor–alpha (TNF-alpha), soluble IL-2 receptor (sIL-2R), and IL-1 receptor antagonist (IL-1RA). “There has not been a consistent blood panel used across studies, be it within a disorder itself like depression, or across disorders,” Dr. Rapaport noted. “This is a challenge that we face in looking at these data.”

Following treatment of acute illness, IL-6 levels significantly decreased in schizophrenia and MDD, but no significant changes in TNF-alpha levels were observed in patients with schizophrenia or MDD. In addition, sIL-2R levels increase in schizophrenia but remained unchanged in bipolar and MDD, while IL-1RA levels in bipolar mania decreased but remained unchanged in MDD. Meanwhile, assessment of the study’s 24 outpatient studies revealed that levels of IL-6 were significantly increased in outpatients with schizophrenia, euthymic bipolar disorder, and MDD, compared with controls (P < .01 for each). In addition, levels of IL-1 beta and sIL-2R were significantly increased in outpatients with schizophrenia and bipolar disorder.

According to Dr. Rapaport, these meta-analyses suggest that there are likely inflammatory immune findings present in acutely ill patients with MDD, schizophrenia, and bipolar disorder.

“Some of this activation decreases with effective acute treatment of the disorder,” he said. “The data suggest that immune changes are present in a subset of patients with all three disorders.”

Advancing this area of research requires a better understanding of the bidirectional interactions between the brain and periphery. “We also need to understand the regulatory role that microglia and astroglia play within the brain,” he said. “We need to identify changes in brain circuitry and function associated with inflammation and other immune changes. We also need to carefully scrutinize publications, understand the assumptions behind the statistics, and carry out more research beyond the protein level.”

He concluded his presentation by calling for research to help clinicians differentiate acute from chronic inflammation. “The study of both is important,” he said. “We need to understand the pathophysiology of immune changes in psychiatric disorders. We need to study both the triggers and pathways to resolution.”

Dr. Rapaport disclosed that he has received research support from the National Institutes of Health, the National Institute of Mental Health, and the National Center for Complementary and Integrative Health.

[email protected]

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

[email protected]

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

[email protected]

For many adults, depression and chronic medical conditions are inextricably linked.

In fact, the prevalence of depression is 2-10 times higher among people with chronic medical conditions, particularly in people with chronic pain, where the prevalence reaches 40%-60%, according to Jonathan E. Alpert, MD, PhD.

“About 60% of adults over 65 have two or more chronic conditions, of which depression is the single most common comorbidity,” Dr. Alpert, chair of the department of psychiatry and behavioral sciences at the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, said during an annual psychopharmacology update held by the Nevada Psychiatric Association.

“Premorbid depression is a risk factor for a number of medical conditions, such as heart disease. We also know that medical illness is a risk factor for depression. Comorbid depression predicts poorer health outcomes, including disability, hospital readmission, and mortality. It is also associated with up to severalfold higher general medical costs.”

Despite the pervasive nature of depression on other medical conditions, a limited evidence base exists to guide clinicians on treatment approaches.

“Most major depressive disorder randomized clinical trials exclude individuals with active medical illness, but we do know that medical comorbidity is associated with poorer depression outcomes,” Dr. Alpert said. For example, the STAR*D trial found that people with major depressive disorder plus medical comorbidity had lower remission rates, compared with those who had MDD alone (P < .001), while a large analysis from University of Pittsburgh researchers found that people with medical comorbidities had higher depression recurrence rates.

An assessment of the relationship between medical conditions and depression should include thinking about the association between the medical illness itself and medications with depressive symptoms.

“Are the medications contributing to depressive symptoms?” he asked. “We also want to be thinking of the impact of medical illness and medications on antidepressant pharmacokinetics and pharmacodynamics. We also want to know about the evidence for antidepressant safety, tolerability, efficacy, and anticipated drug-drug interactions among individuals with the medical illness. You also want to enhance focus on treatment adherence and coordination of care.”

Nontraditional routes of antidepressant administration exist for patients who have difficulty swallowing pills. Food and Drug Administration–approved options include transdermal selegiline; intranasal esketamine; liquid forms of fluoxetine, escitalopram, paroxetine, nortriptyline, doxepin, imipramine, and lithium; and oral disintegrating tablet forms of mirtazapine and selegiline. As for non–FDA-approved forms of antidepressant administration, small studies or case reports have appeared in the medical literature regarding intravenous ketamine, citalopram, amitriptyline, mirtazapine, maprotiline, and lithium; intramuscular ketamine and amitriptyline; and rectal forms of antidepressants such as trazodone, amitriptyline, doxepin, fluoxetine, and lamotrigine.

“It’s good to keep in mind that, when you’re not able to use by mouth antidepressants or typical tablet forms of antidepressants, there are other options available,” said Dr. Alpert, who is also chair of the American Psychiatric Association’s Council on Research.

Metabolism of medications occurs primarily in the liver, he continued, but some metabolic enzymes also line the intestinal tract. The metabolism of a substrate may be inhibited or induced by other drugs.

“If someone is on drug A and we give drug B, and drug B is inhibiting the metabolism of drug A, there will be a very rapid impact – hours to just a few days,” Dr. Alpert said. “The substrate levels rise very quickly, so within hours or days of taking drug B, drug A levels can rise steeply.” On the other hand, if someone is on drug A and you give a drug B – which induces the enzymes that usually metabolize drug A – the impact will be gradual. “That’s because induction requires increased synthesis of the metabolic enzyme responsible for metabolizing drug A,” he said. “That happens over days to weeks.”

Medications that are potential inducers of metabolism include carbamazepine, phenobarbital, phenytoin, primidone, prednisone, ritonavir, rifampin, chronic alcohol use, chronic smoking, St. John’s wort, and consumption of large quantities of cruciferous vegetables and charbroiled meats.

On the other hand, potential inhibitors of metabolism include antifungals, macrolide antibiotics, fluoroquinolones, antiretrovirals, isoniazid, antimalarials, disulfiram, SSRIs, phenothiazines, valproic acid, nefazodone, duloxetine, bupropion, beta-blockers, acute alcohol use, cimetidine, quinidine, calcium channel blockers, grapefruit juice, propafenone, and amiodarone.

“When treating people with significant medical comorbidity, start low and go slow, but persevere,” Dr. Alpert advised. “We want to always think about the risk of treating versus the risk of not treating, or not treating actively enough. Often, people with comorbid medical illness require the same or even more assertive treatment with pharmacotherapy for their depression as people without medical illness. So, we don’t want to make the mistake of undertreating depression. We also want to anticipate and address challenges with adherence.”

He also recommended being mindful of the most salient side effects for a given condition, such as lowered seizure threshold or QT prolongation in populations with brain injury or with cardiovascular disease, and to leverage dual benefits when they might exist, such as using [selective norepinephrine reuptake inhibitors] for depression and pain or hot flashes, or bupropion for depression and smoking cessation, or mirtazapine, which is effective for nausea, cachexia, or insomnia, as well as depression itself.

“We want to collaborate closely and regularly with other treaters, sharing our notes and diagnostic impressions,” Dr. Alpert said. “We want to use all the tools in the box in addition to pharmacotherapy, thinking about psychotherapy, neuromodulation, and peer navigators. We want to strive for measurement-based care using rating scales when we can, to augment our treatment. And we want to be resourceful. There are very few absolute contraindications in treating the medically ill.”

Dr. Alpert reports having received speaker’s honoraria, consulting fees, and research support from numerous pharmaceutical companies.

[email protected]

Researchers have developed a proprietary computer adaptive screening tool that may help emergency departments more accurately predict suicide attempts in adolescents, according to a recent study in JAMA Psychiatry.

The computerized adaptive screen for suicidal youth (CASSY) had an area under the curve (AUC) of 0.87 in an independent validation cohort that predicted an adolescent suicide attempt within 3 months, according to Cheryl A. King, PhD, of the department of psychiatry at the University of Michigan in Ann Arbor, and colleagues. CASSY’s adaptive design, which presents different questions based on a respondent’s answers, means “an individual’s initial item responses are used to determine a provisional estimate of their standing on the measured trait,” the researchers said.

Dr. King and colleagues evaluated the CASSY algorithm in a first study that consisted of 2,845 adolescents who were mean 15.1 years old, mostly girls (63%) enrolled from 13 different emergency departments across the United States within the Pediatric Emergency Care Applied Research Network (PECARN) between June 2015 and July 2016. To develop the CASSY algorithm, the participants received a 92-item self-report survey at baseline with three “anchor” questions from the Ask Suicide-Screening Questions (ASQ) and Columbia–Suicide Severity Rating Scale (C-SSRS). Based on the answers to the baseline survey, the researchers categorized participants as being at low, medium, or high risk for a suicide attempt, and followed participants for 3 months to record suicide attempts reported by a patient or parent.

Retention of participants at 3 months was 72.9%, leaving data available for 2,075 adolescents for review. The researchers found that the AUC was 0.89 (95% confidence interval, 0.85-0.91) in the first study, with a sensitivity of 82.4% and a specificity of 80%. Participants answered a mean number of 11 items during an assessment (range, 5-21 items) administered in a median time of 1 minute, 24 seconds.

In a second study consisting of a validation cohort, 4,050 adolescents from 14 PECARN emergency departments and 1 Indian Health Service hospital were followed, with a retention of 2,754 participants (69.5%) at the end of 3 months. Of the adolescents available at the end of 3 months, 62.1% were girls with a mean age of 15.0 years. The AUC for this validation group was 0.87 (95% CI, 0.85-0.89). Of these participants, 71.5% reported no previous suicide attempts, 9% reported one prior attempt, 18.2% reported multiple attempts, and 1.2% had an unknown number of suicide attempts. During the 3-month window of the second study, 6.0% of participants had at least one suicide attempt.

The researchers said that while the CASSY instrument may be advantageous for some emergency departments, “a standard screen such as the ASQ, which consists of fewer items, may be preferred in some settings, particularly those in which the cost and technical setup of a computerized adaptive screen poses too high a barrier.”

“Important next steps will be to measure the CASSY’s test-retest reliability and develop triage recommendations and conduct implementation studies,” Dr. King and colleagues concluded.
 

Climbing adolescent suicide rate

In an interview, Igor Galynker, MD, PhD, professor in the department of psychiatry, and director of the suicide lab and the Zirinsky Center for Bipolar Disorder at the Icahn School of Medicine at Mount Sinai, New York, said the study by Dr. King and colleagues is important during a time when the suicide rate for adolescents is substantially increasing.

According to data from the CDC’s Web-based Injury Statistics Query and Reporting System, 1,750 adolescents died of suicide in 2018, and the rate of deaths by suicide has increased by 62% since the year 2000. “The issue really needs to be addressed,” said Dr. Galynker, who was not involved with the study.

Some methods of screening suicidal ideation that open with a direct question can miss suicide attempts in individuals who do not express these suicidal ideations, he explained, and the problem can be magnified in adolescent patients. “This is particularly difficult with adolescents because they’re notoriously poor historians. They cannot describe their feelings as well. It’s even more important to have methods that work for suicide prevention for adolescents and to support those predictors which do not rely on self-report,” he said.

Dr. Galynker said that CASSY is innovative because asking whether the patient is suicidal is not the “gateway question” and does not categorize people into groups determined to be at low, medium, or high risk for a suicide attempt.

“When you categorize people – adolescents in this particular case – you remove clinical judgment from [the] clinician. You deprive [the] clinician of exercising their clinical judgment in terms of somebody is or is not likely to die by suicide. That’s a serious problem,” he said, noting it may be one reason why these screening tools have difficulty identifying patients at risk of suicide.

Regarding limitations, the 3-month follow-up window for patients in the study may be too long to be clinically meaningful.

“If somebody is in treatment, 3 months is a long time. You want to know whether somebody is going to attempt suicide before the next time you see them, which is usually a month or a week,” he said.

But a strength of the CASSY instrument, Dr. Galynker said, is its ability to capture the patient’s mental state in the moment, as opposed to relying only a patient’s electronic medical record. The study also demonstrates “it should be possible to introduce detailed suicide risk assessment in the emergency rooms, and [it] should be done,” he said.

This study was funded with support from the Health Resources and Services Administration, the Maternal and Child Health Bureau, and the Emergency Medical Services for Children Network Development Demonstration Program, and a grant by the National Institute of Mental Health for the Emergency Department Screen for Teens at Risk for Suicide. Twelve authors reported personal and institutional relationships in the form of fees, grants, consultancies, royalties, copyrighted work, founding of technologies, and scientific council memberships for a variety of agencies, societies, foundations, and other organizations inside and outside of the study. Dr. Galynker reported his work unrelated to the study is supported by the National Institute of Mental Health and the American Foundation for Suicide Prevention. But he has no proprietary interests.
 

[email protected]

Researchers have developed a proprietary computer adaptive screening tool that may help emergency departments more accurately predict suicide attempts in adolescents, according to a recent study in JAMA Psychiatry.

The computerized adaptive screen for suicidal youth (CASSY) had an area under the curve (AUC) of 0.87 in an independent validation cohort that predicted an adolescent suicide attempt within 3 months, according to Cheryl A. King, PhD, of the department of psychiatry at the University of Michigan in Ann Arbor, and colleagues. CASSY’s adaptive design, which presents different questions based on a respondent’s answers, means “an individual’s initial item responses are used to determine a provisional estimate of their standing on the measured trait,” the researchers said.

Dr. King and colleagues evaluated the CASSY algorithm in a first study that consisted of 2,845 adolescents who were mean 15.1 years old, mostly girls (63%) enrolled from 13 different emergency departments across the United States within the Pediatric Emergency Care Applied Research Network (PECARN) between June 2015 and July 2016. To develop the CASSY algorithm, the participants received a 92-item self-report survey at baseline with three “anchor” questions from the Ask Suicide-Screening Questions (ASQ) and Columbia–Suicide Severity Rating Scale (C-SSRS). Based on the answers to the baseline survey, the researchers categorized participants as being at low, medium, or high risk for a suicide attempt, and followed participants for 3 months to record suicide attempts reported by a patient or parent.

Retention of participants at 3 months was 72.9%, leaving data available for 2,075 adolescents for review. The researchers found that the AUC was 0.89 (95% confidence interval, 0.85-0.91) in the first study, with a sensitivity of 82.4% and a specificity of 80%. Participants answered a mean number of 11 items during an assessment (range, 5-21 items) administered in a median time of 1 minute, 24 seconds.

In a second study consisting of a validation cohort, 4,050 adolescents from 14 PECARN emergency departments and 1 Indian Health Service hospital were followed, with a retention of 2,754 participants (69.5%) at the end of 3 months. Of the adolescents available at the end of 3 months, 62.1% were girls with a mean age of 15.0 years. The AUC for this validation group was 0.87 (95% CI, 0.85-0.89). Of these participants, 71.5% reported no previous suicide attempts, 9% reported one prior attempt, 18.2% reported multiple attempts, and 1.2% had an unknown number of suicide attempts. During the 3-month window of the second study, 6.0% of participants had at least one suicide attempt.

The researchers said that while the CASSY instrument may be advantageous for some emergency departments, “a standard screen such as the ASQ, which consists of fewer items, may be preferred in some settings, particularly those in which the cost and technical setup of a computerized adaptive screen poses too high a barrier.”

“Important next steps will be to measure the CASSY’s test-retest reliability and develop triage recommendations and conduct implementation studies,” Dr. King and colleagues concluded.
 

Climbing adolescent suicide rate

In an interview, Igor Galynker, MD, PhD, professor in the department of psychiatry, and director of the suicide lab and the Zirinsky Center for Bipolar Disorder at the Icahn School of Medicine at Mount Sinai, New York, said the study by Dr. King and colleagues is important during a time when the suicide rate for adolescents is substantially increasing.

According to data from the CDC’s Web-based Injury Statistics Query and Reporting System, 1,750 adolescents died of suicide in 2018, and the rate of deaths by suicide has increased by 62% since the year 2000. “The issue really needs to be addressed,” said Dr. Galynker, who was not involved with the study.

Some methods of screening suicidal ideation that open with a direct question can miss suicide attempts in individuals who do not express these suicidal ideations, he explained, and the problem can be magnified in adolescent patients. “This is particularly difficult with adolescents because they’re notoriously poor historians. They cannot describe their feelings as well. It’s even more important to have methods that work for suicide prevention for adolescents and to support those predictors which do not rely on self-report,” he said.

Dr. Galynker said that CASSY is innovative because asking whether the patient is suicidal is not the “gateway question” and does not categorize people into groups determined to be at low, medium, or high risk for a suicide attempt.

“When you categorize people – adolescents in this particular case – you remove clinical judgment from [the] clinician. You deprive [the] clinician of exercising their clinical judgment in terms of somebody is or is not likely to die by suicide. That’s a serious problem,” he said, noting it may be one reason why these screening tools have difficulty identifying patients at risk of suicide.

Regarding limitations, the 3-month follow-up window for patients in the study may be too long to be clinically meaningful.

“If somebody is in treatment, 3 months is a long time. You want to know whether somebody is going to attempt suicide before the next time you see them, which is usually a month or a week,” he said.

But a strength of the CASSY instrument, Dr. Galynker said, is its ability to capture the patient’s mental state in the moment, as opposed to relying only a patient’s electronic medical record. The study also demonstrates “it should be possible to introduce detailed suicide risk assessment in the emergency rooms, and [it] should be done,” he said.

This study was funded with support from the Health Resources and Services Administration, the Maternal and Child Health Bureau, and the Emergency Medical Services for Children Network Development Demonstration Program, and a grant by the National Institute of Mental Health for the Emergency Department Screen for Teens at Risk for Suicide. Twelve authors reported personal and institutional relationships in the form of fees, grants, consultancies, royalties, copyrighted work, founding of technologies, and scientific council memberships for a variety of agencies, societies, foundations, and other organizations inside and outside of the study. Dr. Galynker reported his work unrelated to the study is supported by the National Institute of Mental Health and the American Foundation for Suicide Prevention. But he has no proprietary interests.
 

[email protected]

Researchers have developed a proprietary computer adaptive screening tool that may help emergency departments more accurately predict suicide attempts in adolescents, according to a recent study in JAMA Psychiatry.

The computerized adaptive screen for suicidal youth (CASSY) had an area under the curve (AUC) of 0.87 in an independent validation cohort that predicted an adolescent suicide attempt within 3 months, according to Cheryl A. King, PhD, of the department of psychiatry at the University of Michigan in Ann Arbor, and colleagues. CASSY’s adaptive design, which presents different questions based on a respondent’s answers, means “an individual’s initial item responses are used to determine a provisional estimate of their standing on the measured trait,” the researchers said.

Dr. King and colleagues evaluated the CASSY algorithm in a first study that consisted of 2,845 adolescents who were mean 15.1 years old, mostly girls (63%) enrolled from 13 different emergency departments across the United States within the Pediatric Emergency Care Applied Research Network (PECARN) between June 2015 and July 2016. To develop the CASSY algorithm, the participants received a 92-item self-report survey at baseline with three “anchor” questions from the Ask Suicide-Screening Questions (ASQ) and Columbia–Suicide Severity Rating Scale (C-SSRS). Based on the answers to the baseline survey, the researchers categorized participants as being at low, medium, or high risk for a suicide attempt, and followed participants for 3 months to record suicide attempts reported by a patient or parent.

Retention of participants at 3 months was 72.9%, leaving data available for 2,075 adolescents for review. The researchers found that the AUC was 0.89 (95% confidence interval, 0.85-0.91) in the first study, with a sensitivity of 82.4% and a specificity of 80%. Participants answered a mean number of 11 items during an assessment (range, 5-21 items) administered in a median time of 1 minute, 24 seconds.

In a second study consisting of a validation cohort, 4,050 adolescents from 14 PECARN emergency departments and 1 Indian Health Service hospital were followed, with a retention of 2,754 participants (69.5%) at the end of 3 months. Of the adolescents available at the end of 3 months, 62.1% were girls with a mean age of 15.0 years. The AUC for this validation group was 0.87 (95% CI, 0.85-0.89). Of these participants, 71.5% reported no previous suicide attempts, 9% reported one prior attempt, 18.2% reported multiple attempts, and 1.2% had an unknown number of suicide attempts. During the 3-month window of the second study, 6.0% of participants had at least one suicide attempt.

The researchers said that while the CASSY instrument may be advantageous for some emergency departments, “a standard screen such as the ASQ, which consists of fewer items, may be preferred in some settings, particularly those in which the cost and technical setup of a computerized adaptive screen poses too high a barrier.”

“Important next steps will be to measure the CASSY’s test-retest reliability and develop triage recommendations and conduct implementation studies,” Dr. King and colleagues concluded.
 

Climbing adolescent suicide rate

In an interview, Igor Galynker, MD, PhD, professor in the department of psychiatry, and director of the suicide lab and the Zirinsky Center for Bipolar Disorder at the Icahn School of Medicine at Mount Sinai, New York, said the study by Dr. King and colleagues is important during a time when the suicide rate for adolescents is substantially increasing.

According to data from the CDC’s Web-based Injury Statistics Query and Reporting System, 1,750 adolescents died of suicide in 2018, and the rate of deaths by suicide has increased by 62% since the year 2000. “The issue really needs to be addressed,” said Dr. Galynker, who was not involved with the study.

Some methods of screening suicidal ideation that open with a direct question can miss suicide attempts in individuals who do not express these suicidal ideations, he explained, and the problem can be magnified in adolescent patients. “This is particularly difficult with adolescents because they’re notoriously poor historians. They cannot describe their feelings as well. It’s even more important to have methods that work for suicide prevention for adolescents and to support those predictors which do not rely on self-report,” he said.

Dr. Galynker said that CASSY is innovative because asking whether the patient is suicidal is not the “gateway question” and does not categorize people into groups determined to be at low, medium, or high risk for a suicide attempt.

“When you categorize people – adolescents in this particular case – you remove clinical judgment from [the] clinician. You deprive [the] clinician of exercising their clinical judgment in terms of somebody is or is not likely to die by suicide. That’s a serious problem,” he said, noting it may be one reason why these screening tools have difficulty identifying patients at risk of suicide.

Regarding limitations, the 3-month follow-up window for patients in the study may be too long to be clinically meaningful.

“If somebody is in treatment, 3 months is a long time. You want to know whether somebody is going to attempt suicide before the next time you see them, which is usually a month or a week,” he said.

But a strength of the CASSY instrument, Dr. Galynker said, is its ability to capture the patient’s mental state in the moment, as opposed to relying only a patient’s electronic medical record. The study also demonstrates “it should be possible to introduce detailed suicide risk assessment in the emergency rooms, and [it] should be done,” he said.

This study was funded with support from the Health Resources and Services Administration, the Maternal and Child Health Bureau, and the Emergency Medical Services for Children Network Development Demonstration Program, and a grant by the National Institute of Mental Health for the Emergency Department Screen for Teens at Risk for Suicide. Twelve authors reported personal and institutional relationships in the form of fees, grants, consultancies, royalties, copyrighted work, founding of technologies, and scientific council memberships for a variety of agencies, societies, foundations, and other organizations inside and outside of the study. Dr. Galynker reported his work unrelated to the study is supported by the National Institute of Mental Health and the American Foundation for Suicide Prevention. But he has no proprietary interests.
 

[email protected]