Depression

A smartphone-based self-management intervention developed for patients with bipolar disorder (BD) can help decrease depressive symptoms and improve quality of life, new research suggests.

In a randomized clinical trial of usual care plus the experimental smartphone-based intervention known as LiveWell vs. usual care alone, participants in the smartphone group who were categorized as low-risk or in asymptomatic recovery at baseline also showed reduced manic symptom severity.

The results suggest that “apps for individuals with bipolar disorder will likely be useful for some people in managing medication use, sleep duration, routine, and monitoring for and managing signs and symptoms” of the disorder, coinvestigator Evan H. Goulding, MD, PhD, assistant professor of psychiatry and behavioral sciences, Northwestern University, Chicago, told this news organization.

Use of the app may also “lead to decreased recurrence of mood episodes, impact overall depressive and manic symptom levels, and improve some aspects of quality of life,” Dr. Goulding added.

The findings were published online in JAMA Psychiatry.
 

Daily check-ins

The researchers randomly assigned 205 patients with BD to receive either usual care (n = 81; 56% women; mean age, 39 years) or usual care plus the smartphone-based self-management intervention LiveWell (n = 124; 65% women; mean age, 43 years) between March 2017 and April 2020. To be included, participants could not be experiencing a current mood episode or suicidal ideation.

The smartphone intervention included a daily check-in to monitor medication adherence, sleep, and wellness levels; coach visits to support adherence to the app; six phone calls over 16 weeks; and support from mental health professionals whenever needed. Participants in this group were asked to engage their mental health providers in the intervention as well.

Each participant in the control group had a visit with a coach who facilitated self-management support.

Investigators assessed all participants every 8 weeks until week 48 to gather information on mood symptoms and severity over the past 2 weeks and on quality of life.

The patients were also stratified into high- and low-risk relapse groups. The low-risk group was in asymptomatic recovery, meaning that they experienced two or fewer moderate symptoms of mania or depression in the previous 8 weeks. In addition, they had no moderate symptoms of mania or depression at study enrollment.

Patients in the high-risk group were recovering from an episode of mania or depression. They also had two or fewer moderate symptoms, but for 8 weeks or less.
 

Low-risk group fares better

Results showed that the smartphone intervention was significantly associated with a reduction in depressive symptoms vs. usual care (P = .02), as well as improvement in one aspect of the World Health Organization Quality of Life Assessment that measures social relationships (P = .02).

When the investigators stratified participants into risk groups, they found that for those in the low-risk group the smartphone-based intervention was associated with lower episode-relapse rates, lower mean percentage time symptomatic, and decreased manic symptom severity.

Mean estimated relapse rates by 48 weeks for the low-risk group were 12% for those in the intervention group and 37.2% for those in the control group. No differences were noted for the high-risk group.

Low-risk patients in the intervention group also had lower mean percentage-time symptomatic (17.9%) than those in the control group (26.1%) (Cohen d = .31).

“Our results are consistent with literature emphasizing the identification and facilitation of management plans for early warning signs of mood episodes and using these plans as an important self-management technique for avoiding relapse,” Dr. Goulding said.

Study limitations included low engagement by mental health professionals and low data generalizability to other populations, as the sample was mostly White (84% of the app group and 81% of the control group).

“There is a fairly large literature on risk factors, longitudinal trajectories, and stages of diseases that suggest we should already be able to predict relapse risk for individuals,” Dr. Goulding said.

“However, moving from overall risk to individual risk is trickier and will require larger datasets with longer follow-up to better understand what types of help should be delivered when and to whom,” he added.
 

‘Requires commitment’

John Torous, MD, director of the division of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, noted that mental health apps such as LiveWell require “time and energy devoted by both the patient and their clinician for maximal efficacy, which requires commitment from and training for both parties as well.

“But with such an investment in people, there is good evidence apps can help people with bipolar disorder even during the more severe periods of the illness,” added Dr. Torous, who was not involved with the research.

The study was funded by the National Institute of Mental Health.

Dr. Goulding reports having received honoraria from Otsuka. Dr. Torous has reported no relevant financial relationships.

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

A smartphone-based self-management intervention developed for patients with bipolar disorder (BD) can help decrease depressive symptoms and improve quality of life, new research suggests.

In a randomized clinical trial of usual care plus the experimental smartphone-based intervention known as LiveWell vs. usual care alone, participants in the smartphone group who were categorized as low-risk or in asymptomatic recovery at baseline also showed reduced manic symptom severity.

The results suggest that “apps for individuals with bipolar disorder will likely be useful for some people in managing medication use, sleep duration, routine, and monitoring for and managing signs and symptoms” of the disorder, coinvestigator Evan H. Goulding, MD, PhD, assistant professor of psychiatry and behavioral sciences, Northwestern University, Chicago, told this news organization.

Use of the app may also “lead to decreased recurrence of mood episodes, impact overall depressive and manic symptom levels, and improve some aspects of quality of life,” Dr. Goulding added.

The findings were published online in JAMA Psychiatry.
 

Daily check-ins

The researchers randomly assigned 205 patients with BD to receive either usual care (n = 81; 56% women; mean age, 39 years) or usual care plus the smartphone-based self-management intervention LiveWell (n = 124; 65% women; mean age, 43 years) between March 2017 and April 2020. To be included, participants could not be experiencing a current mood episode or suicidal ideation.

The smartphone intervention included a daily check-in to monitor medication adherence, sleep, and wellness levels; coach visits to support adherence to the app; six phone calls over 16 weeks; and support from mental health professionals whenever needed. Participants in this group were asked to engage their mental health providers in the intervention as well.

Each participant in the control group had a visit with a coach who facilitated self-management support.

Investigators assessed all participants every 8 weeks until week 48 to gather information on mood symptoms and severity over the past 2 weeks and on quality of life.

The patients were also stratified into high- and low-risk relapse groups. The low-risk group was in asymptomatic recovery, meaning that they experienced two or fewer moderate symptoms of mania or depression in the previous 8 weeks. In addition, they had no moderate symptoms of mania or depression at study enrollment.

Patients in the high-risk group were recovering from an episode of mania or depression. They also had two or fewer moderate symptoms, but for 8 weeks or less.
 

Low-risk group fares better

Results showed that the smartphone intervention was significantly associated with a reduction in depressive symptoms vs. usual care (P = .02), as well as improvement in one aspect of the World Health Organization Quality of Life Assessment that measures social relationships (P = .02).

When the investigators stratified participants into risk groups, they found that for those in the low-risk group the smartphone-based intervention was associated with lower episode-relapse rates, lower mean percentage time symptomatic, and decreased manic symptom severity.

Mean estimated relapse rates by 48 weeks for the low-risk group were 12% for those in the intervention group and 37.2% for those in the control group. No differences were noted for the high-risk group.

Low-risk patients in the intervention group also had lower mean percentage-time symptomatic (17.9%) than those in the control group (26.1%) (Cohen d = .31).

“Our results are consistent with literature emphasizing the identification and facilitation of management plans for early warning signs of mood episodes and using these plans as an important self-management technique for avoiding relapse,” Dr. Goulding said.

Study limitations included low engagement by mental health professionals and low data generalizability to other populations, as the sample was mostly White (84% of the app group and 81% of the control group).

“There is a fairly large literature on risk factors, longitudinal trajectories, and stages of diseases that suggest we should already be able to predict relapse risk for individuals,” Dr. Goulding said.

“However, moving from overall risk to individual risk is trickier and will require larger datasets with longer follow-up to better understand what types of help should be delivered when and to whom,” he added.
 

‘Requires commitment’

John Torous, MD, director of the division of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, noted that mental health apps such as LiveWell require “time and energy devoted by both the patient and their clinician for maximal efficacy, which requires commitment from and training for both parties as well.

“But with such an investment in people, there is good evidence apps can help people with bipolar disorder even during the more severe periods of the illness,” added Dr. Torous, who was not involved with the research.

The study was funded by the National Institute of Mental Health.

Dr. Goulding reports having received honoraria from Otsuka. Dr. Torous has reported no relevant financial relationships.

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

A smartphone-based self-management intervention developed for patients with bipolar disorder (BD) can help decrease depressive symptoms and improve quality of life, new research suggests.

In a randomized clinical trial of usual care plus the experimental smartphone-based intervention known as LiveWell vs. usual care alone, participants in the smartphone group who were categorized as low-risk or in asymptomatic recovery at baseline also showed reduced manic symptom severity.

The results suggest that “apps for individuals with bipolar disorder will likely be useful for some people in managing medication use, sleep duration, routine, and monitoring for and managing signs and symptoms” of the disorder, coinvestigator Evan H. Goulding, MD, PhD, assistant professor of psychiatry and behavioral sciences, Northwestern University, Chicago, told this news organization.

Use of the app may also “lead to decreased recurrence of mood episodes, impact overall depressive and manic symptom levels, and improve some aspects of quality of life,” Dr. Goulding added.

The findings were published online in JAMA Psychiatry.
 

Daily check-ins

The researchers randomly assigned 205 patients with BD to receive either usual care (n = 81; 56% women; mean age, 39 years) or usual care plus the smartphone-based self-management intervention LiveWell (n = 124; 65% women; mean age, 43 years) between March 2017 and April 2020. To be included, participants could not be experiencing a current mood episode or suicidal ideation.

The smartphone intervention included a daily check-in to monitor medication adherence, sleep, and wellness levels; coach visits to support adherence to the app; six phone calls over 16 weeks; and support from mental health professionals whenever needed. Participants in this group were asked to engage their mental health providers in the intervention as well.

Each participant in the control group had a visit with a coach who facilitated self-management support.

Investigators assessed all participants every 8 weeks until week 48 to gather information on mood symptoms and severity over the past 2 weeks and on quality of life.

The patients were also stratified into high- and low-risk relapse groups. The low-risk group was in asymptomatic recovery, meaning that they experienced two or fewer moderate symptoms of mania or depression in the previous 8 weeks. In addition, they had no moderate symptoms of mania or depression at study enrollment.

Patients in the high-risk group were recovering from an episode of mania or depression. They also had two or fewer moderate symptoms, but for 8 weeks or less.
 

Low-risk group fares better

Results showed that the smartphone intervention was significantly associated with a reduction in depressive symptoms vs. usual care (P = .02), as well as improvement in one aspect of the World Health Organization Quality of Life Assessment that measures social relationships (P = .02).

When the investigators stratified participants into risk groups, they found that for those in the low-risk group the smartphone-based intervention was associated with lower episode-relapse rates, lower mean percentage time symptomatic, and decreased manic symptom severity.

Mean estimated relapse rates by 48 weeks for the low-risk group were 12% for those in the intervention group and 37.2% for those in the control group. No differences were noted for the high-risk group.

Low-risk patients in the intervention group also had lower mean percentage-time symptomatic (17.9%) than those in the control group (26.1%) (Cohen d = .31).

“Our results are consistent with literature emphasizing the identification and facilitation of management plans for early warning signs of mood episodes and using these plans as an important self-management technique for avoiding relapse,” Dr. Goulding said.

Study limitations included low engagement by mental health professionals and low data generalizability to other populations, as the sample was mostly White (84% of the app group and 81% of the control group).

“There is a fairly large literature on risk factors, longitudinal trajectories, and stages of diseases that suggest we should already be able to predict relapse risk for individuals,” Dr. Goulding said.

“However, moving from overall risk to individual risk is trickier and will require larger datasets with longer follow-up to better understand what types of help should be delivered when and to whom,” he added.
 

‘Requires commitment’

John Torous, MD, director of the division of digital psychiatry at Beth Israel Deaconess Medical Center, Boston, noted that mental health apps such as LiveWell require “time and energy devoted by both the patient and their clinician for maximal efficacy, which requires commitment from and training for both parties as well.

“But with such an investment in people, there is good evidence apps can help people with bipolar disorder even during the more severe periods of the illness,” added Dr. Torous, who was not involved with the research.

The study was funded by the National Institute of Mental Health.

Dr. Goulding reports having received honoraria from Otsuka. Dr. Torous has reported no relevant financial relationships.

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

Persistent postconcussion symptoms (PPCS) are tied to a significantly increased risk of developing subsequent depressive symptoms, new research shows.

Results of a large meta-analysis that included 18 studies and more than 9,000 patients showed a fourfold higher risk of developing depressive symptoms in those with PPCS versus those without PPCS.

“In this meta-analysis, experiencing PPCS was associated with a higher risk of experiencing depressive symptoms,” write the investigators, led by Maude Lambert, PhD, of the School of Psychology, University of Ottawa, and Bloorview Research Institute, Toronto.

“There are several important clinical and health policy implications of the findings. Most notably, the development of strategies for effective prevention and earlier intervention to optimize mental health recovery following a concussion should be supported,” they add.

The study was published online  in JAMA Network Open.
 

‘Important minority’

An “important minority” of 15%-30% of those with concussions continue to experience symptoms for months, or even years, following the injury, the investigators note.

Symptoms vary but can include headaches, fatigue, dizziness, cognitive difficulties, and emotional changes, which can “significantly impact an individual’s everyday functioning.”

The association between PPCS and mental health outcomes “has emerged as an area of interest” over the past decade, with multiple studies pointing to bidirectional associations between depressive symptoms and PPCS, the researchers note. Individuals with PPCS are at significantly higher risk of experiencing depressive symptoms, and depressive symptoms, in turn, predict more prolonged postconcussion recovery, they add.

The authors conducted a previous scoping review that showed individuals with PPCS had “greater mental health difficulties than individuals who recovered from concussion or healthy controls.”

But “quantitative summaries evaluating the magnitude and nature of the association between PPCS and mental health outcomes were not conducted,” so they decided to conduct a follow-up meta-analysis to corroborate the hypothesis that PPCS may be associated with depressive symptoms.

The researchers also wanted to “investigate potential moderators of that association and determine whether the association between depressive symptoms and PPCS differed based on age, sex, mental illness, history of concussion, and time since the injury.”

This could have “significant public health implications” as it represents an “important step” toward understanding the association between PPCS and mental health, paving the way for the “development of optimal postconcussion intervention strategies, targeting effective prevention and earlier intervention to enhance recovery trajectories, improve mental health, and promote well-being following concussion.”

To be included in the meta-analysis, a study had to focus on participants who had experienced a concussion, diagnosed by a health care professional, or as classified by diagnostic measures, and who experienced greater than or equal to 1 concussion symptom lasting greater than 4 weeks.

There was no explicit upper limit on duration, and individuals of all ages were eligible.

Depressive symptoms were defined as “an outcome that must be measured by a validated and standardized measure of depression.”
 

Biopsychosocial model

Of 580 reports assessed for eligibility, 18 were included in the meta-analysis, incorporating a total of 9,101 participants, with a median (range) sample size of 154 (48-4,462) participants and a mean (SD) participant age of 33.7 (14.4) years.

The mean length of time since the concussion was 21.3 (18.7) weeks. Of the participants, a mean of 36.1% (11.1%) had a history of greater than or equal to 2 concussions.

Close to three-quarters of the studies (72%) used a cross-sectional design, with most studies conducted in North America, and the remaining conducted in Europe, China, and New Zealand.

The researchers found a “significant positive association” between PPCS and postinjury depressive symptoms (odds ratio, 4.87; 95% confidence interval, 3.01-7.90; P < .001), “representing a large effect size.”

Funnel plot and Egger test analyses “suggested the presence of a publication bias.” However, even after accounting for publication bias, the effect size “of large magnitude” remained, the authors report (OR, 4.56; 95% CI, 2.82-7.37; P < .001).

No significant moderators were identified, “likely due to the small number of studies included,” they speculate.

They note that the current study “does not allow inference about the causal directionality of the association” between PPCS and postinjury depressive symptoms, so the question remains: Do PPCS induce depressive symptoms, or do depressive symptoms induce PPCS?”

Despite this unanswered question, the findings still have important clinical and public health implications, highlighting “the need for a greater understanding of the mechanisms of development and etiology of depressive symptoms postconcussion” and emphasizing “the necessary emergence for timely and effective treatment interventions for depressive symptoms to optimize the long-term prognosis of concussion,” the authors note.

They add that several research teams “have aimed to gain more insight into the etiology and underlying mechanisms of development and course of mental health difficulties in individuals who experience a concussion” and have arrived at a biopsychosocial framework, in light of “the myriad of contributing physiological, biological, and psychosocial factors.”

They recommend the establishment of “specialized multidisciplinary or interdisciplinary concussion care programs should include health care professionals with strong clinical foundations and training in mental health conditions.”
 

Speedy multidisciplinary care

Commenting on the research, Charles Tator, MD, PhD, professor of neurosurgery, University of Toronto, Division of Neurosurgery, Toronto Western Hospital, said the researchers “performed a thorough systematic review” showing “emphatically that depression occurs in this population.”

Dr. Tator, the director of the Canadian Concussion Centre, who was not involved with the current study, continued: “Nowadays clinical discoveries are validated through a progression of case reports, single-center retrospective cohort studies like ours, referenced by [Dr.] Lambert et al., and then confirmatory systematic reviews, each adding important layers of evidence.”

“This evaluative process has now endorsed the importance of early treatment of mental health symptoms in patients with persisting symptoms, which can include depression, anxiety, and PTSD,” he said.

He recommended that treatment should start with family physicians and nurse practitioners “but may require escalation to psychologists and social workers and then to psychiatrists who are often more skilled in medication selection.”

He encouraged “speedy multidisciplinary care,” noting that the possibility of suicide is worrisome.

No source of study funding was listed. A study coauthor, Shannon Scratch, PhD, has reported receiving funds from the Holland Bloorview Kids Rehabilitation Hospital Foundation (via the Holland Family Professorship in Acquired Brain Injury) during the conduct of this study. No other disclosures were reported. Dr. Tator has reported no relevant financial relationships.

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

Persistent postconcussion symptoms (PPCS) are tied to a significantly increased risk of developing subsequent depressive symptoms, new research shows.

Results of a large meta-analysis that included 18 studies and more than 9,000 patients showed a fourfold higher risk of developing depressive symptoms in those with PPCS versus those without PPCS.

“In this meta-analysis, experiencing PPCS was associated with a higher risk of experiencing depressive symptoms,” write the investigators, led by Maude Lambert, PhD, of the School of Psychology, University of Ottawa, and Bloorview Research Institute, Toronto.

“There are several important clinical and health policy implications of the findings. Most notably, the development of strategies for effective prevention and earlier intervention to optimize mental health recovery following a concussion should be supported,” they add.

The study was published online  in JAMA Network Open.
 

‘Important minority’

An “important minority” of 15%-30% of those with concussions continue to experience symptoms for months, or even years, following the injury, the investigators note.

Symptoms vary but can include headaches, fatigue, dizziness, cognitive difficulties, and emotional changes, which can “significantly impact an individual’s everyday functioning.”

The association between PPCS and mental health outcomes “has emerged as an area of interest” over the past decade, with multiple studies pointing to bidirectional associations between depressive symptoms and PPCS, the researchers note. Individuals with PPCS are at significantly higher risk of experiencing depressive symptoms, and depressive symptoms, in turn, predict more prolonged postconcussion recovery, they add.

The authors conducted a previous scoping review that showed individuals with PPCS had “greater mental health difficulties than individuals who recovered from concussion or healthy controls.”

But “quantitative summaries evaluating the magnitude and nature of the association between PPCS and mental health outcomes were not conducted,” so they decided to conduct a follow-up meta-analysis to corroborate the hypothesis that PPCS may be associated with depressive symptoms.

The researchers also wanted to “investigate potential moderators of that association and determine whether the association between depressive symptoms and PPCS differed based on age, sex, mental illness, history of concussion, and time since the injury.”

This could have “significant public health implications” as it represents an “important step” toward understanding the association between PPCS and mental health, paving the way for the “development of optimal postconcussion intervention strategies, targeting effective prevention and earlier intervention to enhance recovery trajectories, improve mental health, and promote well-being following concussion.”

To be included in the meta-analysis, a study had to focus on participants who had experienced a concussion, diagnosed by a health care professional, or as classified by diagnostic measures, and who experienced greater than or equal to 1 concussion symptom lasting greater than 4 weeks.

There was no explicit upper limit on duration, and individuals of all ages were eligible.

Depressive symptoms were defined as “an outcome that must be measured by a validated and standardized measure of depression.”
 

Biopsychosocial model

Of 580 reports assessed for eligibility, 18 were included in the meta-analysis, incorporating a total of 9,101 participants, with a median (range) sample size of 154 (48-4,462) participants and a mean (SD) participant age of 33.7 (14.4) years.

The mean length of time since the concussion was 21.3 (18.7) weeks. Of the participants, a mean of 36.1% (11.1%) had a history of greater than or equal to 2 concussions.

Close to three-quarters of the studies (72%) used a cross-sectional design, with most studies conducted in North America, and the remaining conducted in Europe, China, and New Zealand.

The researchers found a “significant positive association” between PPCS and postinjury depressive symptoms (odds ratio, 4.87; 95% confidence interval, 3.01-7.90; P < .001), “representing a large effect size.”

Funnel plot and Egger test analyses “suggested the presence of a publication bias.” However, even after accounting for publication bias, the effect size “of large magnitude” remained, the authors report (OR, 4.56; 95% CI, 2.82-7.37; P < .001).

No significant moderators were identified, “likely due to the small number of studies included,” they speculate.

They note that the current study “does not allow inference about the causal directionality of the association” between PPCS and postinjury depressive symptoms, so the question remains: Do PPCS induce depressive symptoms, or do depressive symptoms induce PPCS?”

Despite this unanswered question, the findings still have important clinical and public health implications, highlighting “the need for a greater understanding of the mechanisms of development and etiology of depressive symptoms postconcussion” and emphasizing “the necessary emergence for timely and effective treatment interventions for depressive symptoms to optimize the long-term prognosis of concussion,” the authors note.

They add that several research teams “have aimed to gain more insight into the etiology and underlying mechanisms of development and course of mental health difficulties in individuals who experience a concussion” and have arrived at a biopsychosocial framework, in light of “the myriad of contributing physiological, biological, and psychosocial factors.”

They recommend the establishment of “specialized multidisciplinary or interdisciplinary concussion care programs should include health care professionals with strong clinical foundations and training in mental health conditions.”
 

Speedy multidisciplinary care

Commenting on the research, Charles Tator, MD, PhD, professor of neurosurgery, University of Toronto, Division of Neurosurgery, Toronto Western Hospital, said the researchers “performed a thorough systematic review” showing “emphatically that depression occurs in this population.”

Dr. Tator, the director of the Canadian Concussion Centre, who was not involved with the current study, continued: “Nowadays clinical discoveries are validated through a progression of case reports, single-center retrospective cohort studies like ours, referenced by [Dr.] Lambert et al., and then confirmatory systematic reviews, each adding important layers of evidence.”

“This evaluative process has now endorsed the importance of early treatment of mental health symptoms in patients with persisting symptoms, which can include depression, anxiety, and PTSD,” he said.

He recommended that treatment should start with family physicians and nurse practitioners “but may require escalation to psychologists and social workers and then to psychiatrists who are often more skilled in medication selection.”

He encouraged “speedy multidisciplinary care,” noting that the possibility of suicide is worrisome.

No source of study funding was listed. A study coauthor, Shannon Scratch, PhD, has reported receiving funds from the Holland Bloorview Kids Rehabilitation Hospital Foundation (via the Holland Family Professorship in Acquired Brain Injury) during the conduct of this study. No other disclosures were reported. Dr. Tator has reported no relevant financial relationships.

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

Persistent postconcussion symptoms (PPCS) are tied to a significantly increased risk of developing subsequent depressive symptoms, new research shows.

Results of a large meta-analysis that included 18 studies and more than 9,000 patients showed a fourfold higher risk of developing depressive symptoms in those with PPCS versus those without PPCS.

“In this meta-analysis, experiencing PPCS was associated with a higher risk of experiencing depressive symptoms,” write the investigators, led by Maude Lambert, PhD, of the School of Psychology, University of Ottawa, and Bloorview Research Institute, Toronto.

“There are several important clinical and health policy implications of the findings. Most notably, the development of strategies for effective prevention and earlier intervention to optimize mental health recovery following a concussion should be supported,” they add.

The study was published online  in JAMA Network Open.
 

‘Important minority’

An “important minority” of 15%-30% of those with concussions continue to experience symptoms for months, or even years, following the injury, the investigators note.

Symptoms vary but can include headaches, fatigue, dizziness, cognitive difficulties, and emotional changes, which can “significantly impact an individual’s everyday functioning.”

The association between PPCS and mental health outcomes “has emerged as an area of interest” over the past decade, with multiple studies pointing to bidirectional associations between depressive symptoms and PPCS, the researchers note. Individuals with PPCS are at significantly higher risk of experiencing depressive symptoms, and depressive symptoms, in turn, predict more prolonged postconcussion recovery, they add.

The authors conducted a previous scoping review that showed individuals with PPCS had “greater mental health difficulties than individuals who recovered from concussion or healthy controls.”

But “quantitative summaries evaluating the magnitude and nature of the association between PPCS and mental health outcomes were not conducted,” so they decided to conduct a follow-up meta-analysis to corroborate the hypothesis that PPCS may be associated with depressive symptoms.

The researchers also wanted to “investigate potential moderators of that association and determine whether the association between depressive symptoms and PPCS differed based on age, sex, mental illness, history of concussion, and time since the injury.”

This could have “significant public health implications” as it represents an “important step” toward understanding the association between PPCS and mental health, paving the way for the “development of optimal postconcussion intervention strategies, targeting effective prevention and earlier intervention to enhance recovery trajectories, improve mental health, and promote well-being following concussion.”

To be included in the meta-analysis, a study had to focus on participants who had experienced a concussion, diagnosed by a health care professional, or as classified by diagnostic measures, and who experienced greater than or equal to 1 concussion symptom lasting greater than 4 weeks.

There was no explicit upper limit on duration, and individuals of all ages were eligible.

Depressive symptoms were defined as “an outcome that must be measured by a validated and standardized measure of depression.”
 

Biopsychosocial model

Of 580 reports assessed for eligibility, 18 were included in the meta-analysis, incorporating a total of 9,101 participants, with a median (range) sample size of 154 (48-4,462) participants and a mean (SD) participant age of 33.7 (14.4) years.

The mean length of time since the concussion was 21.3 (18.7) weeks. Of the participants, a mean of 36.1% (11.1%) had a history of greater than or equal to 2 concussions.

Close to three-quarters of the studies (72%) used a cross-sectional design, with most studies conducted in North America, and the remaining conducted in Europe, China, and New Zealand.

The researchers found a “significant positive association” between PPCS and postinjury depressive symptoms (odds ratio, 4.87; 95% confidence interval, 3.01-7.90; P < .001), “representing a large effect size.”

Funnel plot and Egger test analyses “suggested the presence of a publication bias.” However, even after accounting for publication bias, the effect size “of large magnitude” remained, the authors report (OR, 4.56; 95% CI, 2.82-7.37; P < .001).

No significant moderators were identified, “likely due to the small number of studies included,” they speculate.

They note that the current study “does not allow inference about the causal directionality of the association” between PPCS and postinjury depressive symptoms, so the question remains: Do PPCS induce depressive symptoms, or do depressive symptoms induce PPCS?”

Despite this unanswered question, the findings still have important clinical and public health implications, highlighting “the need for a greater understanding of the mechanisms of development and etiology of depressive symptoms postconcussion” and emphasizing “the necessary emergence for timely and effective treatment interventions for depressive symptoms to optimize the long-term prognosis of concussion,” the authors note.

They add that several research teams “have aimed to gain more insight into the etiology and underlying mechanisms of development and course of mental health difficulties in individuals who experience a concussion” and have arrived at a biopsychosocial framework, in light of “the myriad of contributing physiological, biological, and psychosocial factors.”

They recommend the establishment of “specialized multidisciplinary or interdisciplinary concussion care programs should include health care professionals with strong clinical foundations and training in mental health conditions.”
 

Speedy multidisciplinary care

Commenting on the research, Charles Tator, MD, PhD, professor of neurosurgery, University of Toronto, Division of Neurosurgery, Toronto Western Hospital, said the researchers “performed a thorough systematic review” showing “emphatically that depression occurs in this population.”

Dr. Tator, the director of the Canadian Concussion Centre, who was not involved with the current study, continued: “Nowadays clinical discoveries are validated through a progression of case reports, single-center retrospective cohort studies like ours, referenced by [Dr.] Lambert et al., and then confirmatory systematic reviews, each adding important layers of evidence.”

“This evaluative process has now endorsed the importance of early treatment of mental health symptoms in patients with persisting symptoms, which can include depression, anxiety, and PTSD,” he said.

He recommended that treatment should start with family physicians and nurse practitioners “but may require escalation to psychologists and social workers and then to psychiatrists who are often more skilled in medication selection.”

He encouraged “speedy multidisciplinary care,” noting that the possibility of suicide is worrisome.

No source of study funding was listed. A study coauthor, Shannon Scratch, PhD, has reported receiving funds from the Holland Bloorview Kids Rehabilitation Hospital Foundation (via the Holland Family Professorship in Acquired Brain Injury) during the conduct of this study. No other disclosures were reported. Dr. Tator has reported no relevant financial relationships.

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

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

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

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

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

Sleep complaints by patients with a major depressive episode (MDE) may be a red flag signaling a higher risk for developing other psychiatric disorders, new research suggests.

Investigators studied 3-year incidence rates of psychiatric disorders in almost 3,000 patients experiencing an MDE. Results showed that having a history of difficulty falling asleep, early morning awakening, and hypersomnia increased risk for incident psychiatric disorders.

“The findings of this study suggest the potential value of including insomnia and hypersomnia in clinical assessments of all psychiatric disorders,” write the investigators, led by Bénédicte Barbotin, MD, Département de Psychiatrie et d’Addictologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, France.

“Insomnia and hypersomnia symptoms may be prodromal transdiagnostic biomarkers and easily modifiable therapeutic targets for the prevention of psychiatric disorders,” they add.

The findings were published online recently in the Journal of Clinical Psychiatry.


 

Bidirectional association

The researchers note that sleep disturbance is “one of the most common symptoms” associated with major depressive disorder (MDD) and may be “both a consequence and a cause.”

Moreover, improving sleep disturbances for patients with an MDE “tends to improve depressive symptom and outcomes,” they add.

Although the possibility of a bidirectional association between MDEs and sleep disturbances “offers a new perspective that sleep complaints might be a predictive prodromal symptom,” the association of sleep complaints with the subsequent development of other psychiatric disorders in MDEs “remains poorly documented,” the investigators write.

The observation that sleep complaints are associated with psychiatric complications and adverse outcomes, such as suicidality and substance overdose, suggests that longitudinal studies “may help to better understand these relationships.”

To investigate these issues, the researchers examined three sleep complaints among patients with MDE: trouble falling asleep, early morning awakening, and hypersomnia. They adjusted for an array of variables, including antisocial personality disorders, use of sedatives or tranquilizers, sociodemographic characteristics, MDE severity, poverty, obesity, educational level, and stressful life events.

They also used a “bifactor latent variable approach” to “disentangle” a number of effects, including those shared by all psychiatric disorders; those specific to dimensions of psychopathology, such as internalizing dimension; and those specific to individual psychiatric disorders, such as dysthymia.

“To our knowledge, this is the most extensive prospective assessment [ever conducted] of associations between sleep complaints and incident psychiatric disorders,” the investigators write.

They drew on data from Waves 1 and 2 of the National Epidemiological Survey on Alcohol and Related Conditions, a large nationally representative survey conducted in 2001-2002 (Wave 1) and 2004-2005 (Wave 2) by the National Institute on Alcoholism and Alcohol Abuse.

The analysis included 2,864 participants who experienced MDE in the year prior to Wave 1 and who completed interviews at both waves.

Researchers assessed past-year DSM-IV Axis I disorders and baseline sleep complaints at Wave 1, as well as incident DSM-IV Axis I disorders between the two waves – including substance use, mood, and anxiety disorders.
 

Screening needed?

Results showed a wide range of incidence rates for psychiatric disorders between Wave 1 and Wave 2, ranging from 2.7% for cannabis use to 8.2% for generalized anxiety disorder.

The lifetime prevalence of sleep complaints was higher among participants who developed a psychiatric disorder between the two waves than among those who did not have sleep complaints. The range (from lowest to highest percentage) is shown in the accompanying table.

A higher number of sleep complaints was also associated with higher percentages of psychiatric disorders.

Hypersomnia, in particular, significantly increased the odds of having another psychiatric disorder. For patients with MDD who reported hypersomnia, the mean number of sleep disorders was significantly higher than for patients without hypersomnia (2.08 vs. 1.32; P < .001).

“This explains why hypersomnia appears more strongly associated with the incidence of psychiatric disorders,” the investigators write.

After adjusting for sociodemographic and clinical characteristics and antisocial personality disorder, the effects shared across all sleep complaints were “significantly associated with the incident general psychopathology factor, representing mechanisms that may lead to incidence of all psychiatric disorder in the model,” they add.

The researchers note that insomnia and hypersomnia can impair cognitive function, decision-making, problem-solving, and emotion processing networks, thereby increasing the onset of psychiatric disorders in vulnerable individuals.

Shared biological determinants, such as monoamine neurotransmitters that play a major role in depression, anxiety, substance use disorders, and the regulation of sleep stages, may also underlie both sleep disturbances and psychiatric disorders, they speculate.

“These results suggest the importance of systematically assessing insomnia and hypersomnia when evaluating psychiatric disorders and considering these symptoms as nonspecific prodromal or at-risk symptoms, also shared with suicidal behaviors,” the investigators write.

“In addition, since most individuals who developed a psychiatric disorder had at least one sleep complaint, all psychiatric disorders should be carefully screened among individuals with sleep complaints,” they add.
 

Transdiagnostic phenomenon

In a comment, Roger McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, and head of the Mood Disorders Psychopharmacology Unit, noted that the study replicates previous observations that a bidirectional relationship exists between sleep disturbances and mental disorders and that there “seems to be a relationship between sleep disturbance and suicidality that is bidirectional.”

He added that he appreciated the fact that the investigators “took this knowledge one step further; and what they are saying is that within the syndrome of depression, it is the sleep disturbance that is predicting future problems.”

Dr. McIntyre, who is also chairman and executive director of the Brain and Cognitive Discover Foundation in Toronto, was not involved with the study.

The data suggest that, “conceptually, sleep disturbance is a transdiagnostic phenomenon that may also be the nexus when multiple comorbid mental disorders occur,” he said.

“If this is the case, clinically, there is an opportunity here to prevent incident mental disorders in persons with depression and sleep disturbance, prioritizing sleep management in any patient with a mood disorder,” Dr. McIntyre added.

He noted that “the testable hypothesis” is how this is occurring mechanistically.

“I would conjecture that it could be inflammation and/or insulin resistance that is part of sleep disturbance that could predispose and portend other mental illnesses – and likely other medical conditions too, such as obesity and diabetes,” he said.

The study received no specific funding from any funding agency, commercial, or not-for-profit sectors. The investigators’ relevant financial relationships are listed in the original article. Dr. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; has received speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and Atai Life Sciences; and is a CEO of Braxia Scientific Corp.

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

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

During the initial stage of the COVID-19 pandemic U.S. medical students were suspended from in-person clinical interaction. This decision was based on specific guidance from the Association of American Medical Colleges and subsequently implemented in medical schools across the United States.¹ Our research project addressed students’ stress level before and after clinical in-person suspension and assessed medical students perceived COVID-19–related risk level. We were particularly curious to learn about students’ emotional struggles as they navigated the initial pedagogical uncertainty associated with the pandemic.

Our study showed that students had a significantly higher stress level after the clinical suspension of in-person clinical interaction as compared with the time before the suspension of clinical in-person interaction. It is likely that heightened stress was greater than before and the rationale was likely multifactorial in nature.²

One key stressor U.S. medical students faced was the negative impacts of COVID-19 on medical education. U.S. Medical Licensing Examination exam-taking was severely impacted, and some students needed to reschedule their test dates because of increased restrictions at testing centers. Third-year medical students in particular were worried about how COVID-19 would influence their residency application; for example, in-person residency interviews and away rotations as fourth-year medical students. Another concern was not being able to be involved in clinical work during the direst stage of this public health emergency because of personal protective equipment shortages and attempts to reduce community spread of COVID-19.

Our study also showed that students had a relatively lower perceived risk level when it comes to COVID-19 than health care workers in the 2003 SARS epidemic, which we suspect is mostly attributable to the suspension of clinical in-person interaction. We also found that female gender and self-reported mental illness diagnosis were two risk factors for perceived stress level, consistent with our current literature.

The reality of clinical in-person inaction caused by PPE shortage and limited telehealth options, together with social isolation and uncertainty regarding future education opportunities, appear to have had a detrimental effect on medical students’ psychological wellbeing. This did not have to be the case. Some medical students found innovative ways to stay involved.

For example, in 2020 some of Dr. Zhang’s classmates helped proctor virtual group therapy sessions held by the local National Alliance on Mental Illness chapter. Medical students at the Icahn School of Medicine at Mount Sinai, New York were not only able to engage in telehealth but also join other task forces, such as PPE supply, distribution, and coordination, morale promotion, and administrative services.³ Finally, many medical students in New York volunteered in providing child care for frontline doctors to help relieve their burden.⁴ These actions, if implemented more widely, may have had a protective effect on the stress and well-being of medical students at that time.

While our study focused on the academic side of things, the personal impacts from COVID-19 need to be acknowledged – sickness from COVID-19 and its sequelae, family loss fromCOVID-19, financial struggle, and racial targeting of Asians to name a few. COVID-19 has influenced many families’ livelihood and changed our understanding of ourselves, others, and the world in unprecedented ways.

Fast forward to today – medical students are used to learning and living in a world with an ongoing pandemic, and medical education and residency application process have adapted to this new normal. The once-crippling uncertainty surrounding COVID-19 and disastrous PPE shortages have passed. Yet, COVID-19 continues to be a stressor. In fact, burnout related to “COVID-19 fatigue” has been on the rise and one recent national survey shows one in five physicians intends to leave practice within 2 years.⁵

Meanwhile, uncertainty continued to persist, as in August 2022 monkeypox was declared a public health emergency in the United States.⁶ What Dr. Zhang learned as a medical student during the initial months of COVID-19 continues to be relevant: connect with loved ones, understand the changing reality, process the emotions, recognize what is under one’s control, have a solution-oriented mindset, and be forgiving and patient with oneself and others.

Dr. Zhang is a second-year psychiatry resident physician at Saint Elizabeth’s Hospital/DC DBH, Washington. Dr. Himelhoch serves as professor and chair of the department of psychiatry at the University of Kentucky, Lexington. His research focuses on developing and studying the efficacy of innovative strategies aimed at improving the health and welfare among people with co-occurring psychiatric and substance use disorders.

References

1. Association of American Medical Colleges. Important Guidance for Medical Students on Clinical Rotations During the Coronavirus (COVID-19) Outbreak. 2020 Mar 17.

2. Zhang Y et al. Psychiatry Res. 2022;313:114595. doi: 10.1016/j.psychres.2022.114595.

3. Bahethi RR et al. Acad Med. 2021 Jun 1;96(6):859-63. doi: 10.1097/ACM.0000000000003863.

4. Krieger P and Goodnough A. Medical Students, Sidelined for Now, Find New Ways to Fight Coronavirus. The New York Times. 2020 Mar 23.

5. Abbasi J. JAMA. 2022 Apr 19;327(15):1435-7. doi: 10.1001/jama.2022.5074.

6. Department of Health & Human Services. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. 2022 Aug 4.

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The oral antibiotic linezolid does not increase risk for serotonin syndrome in patients taking antidepressants, new research suggests – contradicting a U.S. Food and Drug Administration 2020 warning.

Results from a study that included more than 1,100 patients who were prescribed linezolid, about 20% of whom were also taking antidepressants, showed that serotonin syndrome occurred in fewer than 0.5% of participants – and that the percentage was actually lower among those who took antidepressants, compared with those who did not.

A comparison of participants who took antidepressants to propensity-matched patients who did not take antidepressants showed similar rates of altered mental status, hospitalization, and death between the two groups.

“In this cohort study of older patients who were prescribed linezolid, serotonin syndrome occurred rarely [and] concurrent antidepressants did not significantly increase the risk of serotonin syndrome,” Anthony Bai, MD, division of infectious diseases, department of medicine, Queen’s University, Kingston, Ont., and colleagues write.

“These findings suggested that linezolid is likely safe for patients receiving antidepressants. Nevertheless, prescribers should remain vigilant for this potential drug interaction,” they warn.

The findings were published online in JAMA Network Open.
 

Scarce data

Linezolid, a synthetic oxazolidinone antibiotic active against resistant gram-positive bacteria, has bioavailability of 100%, “making it ideal as first-line or step-down oral antibiotic therapy for bacteremia and pneumonia as well as skin and soft tissue infections,” the researchers write.

However, they note its use has been “limited because of concerns of drug interactions,” since it can reversibly inhibit monoamine oxidase (MAO).

Thus, “coadministration with antidepressants, such as nonselective MAO inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and bupropion, may precipitate serotonin syndrome,” they write.

The investigators note that many patients who were taking antidepressants and who also needed linezolid for an infection “could not receive it because of this relative contraindication.” They add that data on the risk of serotonin syndrome associated with linezolid are “scarce” and are based largely on case reports or case series from passive surveillance.

Although a previous review of linezolid trials found “no conclusive evidence” that it increased risk for serotonin syndrome in patients taking serotonergic medication, data on patients outside of trials “are lacking.” In addition, an observational study suggested that an increased risk had a small sample size that “likely led to imprecise estimates with a wide CI and inconclusive results,” the researchers write.

Therefore, they sought to fill the knowledge gap by retrospectively analyzing data drawn from the ICES database, an independent nonprofit research institute funded by the Ontario Ministry of Health. This was done in order to “estimate the incidence of serotonin syndrome and how this risk changes because of concomitant antidepressant use in patients receiving linezolid treatment,” they write.

The study included a convenience sample of Ontario-based adults (n = 1,134, 52.5% men) who were dispensed oral linezolid 600 mg twice daily between Oct. 1, 2014, and Jan. 1, 2021. All patients were followed for 30 days.

Of these participants, 19% were also taking antidepressants. Close to half (47.9%) were taking an SSRI, 16.7% were taking an SNRI, 7% were taking a tricyclic antidepressant, and 3.3% were taking a norepinephrine and dopamine reuptake inhibitor.

Patients were divided into groups on the basis of age: 66-69 years (19.8%), 70-79 years (41.7%), and 80 years or older (38.4%).
 

Reassuring findings

Serotonin syndrome occurred in fewer than six patients (< .5%), although the exact numbers were not reported, owing to patient privacy concerns. However, on the basis of fewer than six events, the investigators calculated the risk difference for serotonin syndrome as ranging from −0.5% to 2.3%.

Fewer patients who were taking antidepressants experienced serotonin syndrome, compared with those who were not taking antidepressants.

The investigators estimated a propensity score for antidepressant use that incorporated several patient baseline characteristics, including age, sex, rural home address, Charlson Comorbidity Index, estimated glomerular filtration rate, history of substance use disorder, and days of use of linezolid and other serotonergic medications. They then matched patients who were not taking antidepressants with those who were taking antidepressants (n = 166 each).

The adjusted risk difference for serotonin syndrome was lower in the antidepressant group than in the no-antidepressant group (−1.2%; 95% confidence interval, −2.9% to 0.5%).

“Within this 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200,” the researchers write.

For secondary outcomes, they found “similar rates” of altered mental status or confusion, hospitalization, and death within 30 days between the two propensity score–matched groups.

The investigators note that their findings have “limitations, due to the nature of retrospective observational studies.” Moreover, these types of studies are “not efficient because they often focus on a particular adverse event.”

Future research should move beyond observational studies to phase 4 studies, which would “prospectively monitor for all types of adverse events,” they write.

Still, “while waiting for higher-quality evidence, our study adds to the existing evidence for the safety of linezolid even in the context of concomitant antidepressants,” the researchers note.

“Based on the existing evidence, clinicians should be reassured that it appears safe to prescribe oral linezolid to patients taking antidepressants, especially if there are limited antibiotic options or alternative antibiotic options would be inferior,” they add.
 

‘Consequential relevance’

Commenting on the study, Ipsit Vahia, MD, associate chief of geriatric psychiatry and director of digital psychiatry translation at McLean Hospital, Boston, noted that although studies of drug interactions across age groups “may not accurately reflect the rates of risk for older adults,” the current study focused on linezolid use among older patients.

“One may expect higher rates of serotonin syndrome in older adults, who generally tend to be more sensitive to adverse reactions,” said Dr. Vahia, who is also director of the Technology and Aging Lab at McLean and was not involved with the current research.

“However, the study finds the risk to be low with a number needed to harm of 200,” Dr. Vahia said.

“This retrospective epidemiologic study does not shed light on why this number may be lower than expected, but it has consequential relevance in clinical practice for the management of severe infections among older adults using antidepressants,” he added.

The study was funded by a Queen’s University Research Initiation Grant. Dr. Bai and three of the four other investigators report no relevant financial relationships. Coinvestigator Mark Loeb, MD, reports having received personal fees from the Paladin Labs Advisory Committee, the International Centre for Professional Development in Health and Medicine Advisory Committee, and the Sunovion Advisory Committee outside the submitted work. Dr. Vahia serves as a consultant for Otsuka, has a research collaboration with Emerald Innovations, and receives honorarium as editor for The American Journal of Geriatric Psychiatry.

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

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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

Treatment-resistant depression (TRD) is significantly linked to comorbid psychiatric conditions and a higher risk for mortality and can take more than a year to be diagnosed, new research shows.

In a population study of more than 145,000 patients, participants with TRD used outpatient resources and missed work at twice the rate as patients with treatment-responsive depression. They also had a threefold higher number of days spent in hospital.

Patients with TRD also had a 23% higher risk of dying during the time they were observed, compared with their matched counterparts with non-TRD depression, and their self-harm rates were twice as high.

In addition, it took an average of 1.5 years for patients with TRD to undergo two unsuccessful treatment attempts and reach their third treatment trial, which is several months longer than is recommended for assessing the efficacy of a treatment for depression.

“It seemed like ineffective treatments were allowed to continue for longer than should be needed and what is recommended in current guidelines,” lead investigator Johan Lundberg, MD, PhD, adjunct professor of psychiatry in the department of clinical neuroscience and head of the mood disorder section at the Northern Stockholm Psychiatry Clinic, told this news organization.

“If this is true, patients would most likely benefit from a more frequent evaluation of treatment effect and, when needed, optimization of ineffective treatments,” Dr. Lundberg said.

The findings were published online in JAMA Psychiatry.
 

More anxiety, sleep disorders, substance use

Using data from the Region Stockholm’s administrative health care database and the Swedish social insurance agency, the investigators identified nearly 160,000 unipolar major depressive disorder (MDD) episodes in 145,577 patients who sought treatment between January 2012 and December 2017.

Of those episodes, 12,800 fulfilled criteria for TRD, which meant there were three or more treatment trials with antidepressants, add-on medication (aripiprazole, lithium, olanzapine, quetiapine, and/or risperidone), electroshock therapy, or repetitive transcranial magnetic stimulation.

Each new treatment had to be initiated within the MDD episode more than 28 days after previous treatment initiation.

Investigators matched each TRD episode with up to five non-TRD episodes and found that patients with TRD were more likely to have comorbid psychiatric conditions than were their non-TRD counterparts.

This included anxiety (60% vs. 44%, respectively), sleep disorders (28% vs. 19%), substance use (15% vs. 11%) or alcohol use (10% vs. 7%) disorders, and personality disorders (6% vs. 3%). Rates of intentional self-harm were also higher in the TRD group (5% vs. 2%).

Perhaps in part because of the comorbid problems, patients with TRD had a more than 50% higher mean number of outpatient physician visits 1 year before and after the index date, defined as the date of the initiation of the third treatment trial.

The most important predictor of TRD depression was the severity of depression at diagnosis on the self-rated Montgomery Åsberg Depression Rating Scale, the researchers report.
 

Not generalizable?

Patients with TRD also had three times the number of inpatient bed days as did those with depression that responded to treatment (mean, 3.9 days vs. 1.3 days, respectively) and significantly more lost workdays (132.3 days vs. 58.7 days).

Most notably, patients with TRD episodes had a 23% higher risk of dying during the time they were observed than did their non-TRD counterparts.

“This finding in itself could be a reason to focus on how to avoid putting a patient on the TRD path. This could be done through prospective studies comparing different treatment options and their risk of leading to TRD,” Dr. Lundberg said.

Interestingly, he noted that the study results may not be generalizable to other populations, such as the United States.

“The biggest difference between Stockholm and the U.S. may not be the demographics, but the access to health care,” Dr. Lundberg said.

“In Stockholm, there is a universal access health care system, meaning that these results are what you can expect if you are able to get care. In the U.S., this is not the case, meaning that people outside the health care system may fare worse than what our study suggests,” he added.
 

Quality over quantity

In a comment, Sidney Zisook, MD, distinguished professor of psychiatry at the University of California, San Diego, said that the findings “highlight the need for our field to develop better-tolerated, more effective, and sustainable treatments for major depressive disorder and for better education of clinicians so they can employ up-to-date, evidence-based treatments and integrate sound clinical guidelines into clinical practice.”

Dr. Zisook has independently researched TRD but was not involved with the current study.

He noted that it was “striking how long patients remained on the same antidepressant, apparently despite suboptimal outcomes, without taking next steps.”

However, Dr. Zisook expressed concern that the diagnosis of TRD in the study was solely on the basis of the number of treatment trials for an episode.

“Somebody might have had three different antidepressant trials because they had had three episodes with interepisode periods of recovery followed by recurrent episodes. That would not be considered treatment-resistant depression,” he said.

Dr. Zisook also noted that patients might be given a new antidepressant for reasons other than treatment resistance. “For example, they lost an initial good response – this used to be called Prozac poop out, were nonadherent, or had troublesome side effects,” he said.

“We usually define treatment-resistant depression not only on the basis of number of trials but also the quality of the trial, taking both dose and duration into account,” Dr. Zisook added.

The study was funded by Region Stockholm. Dr. Zisook reports receiving research funding from COMPASS Pathways.

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

Intervening with physical activity appears to mitigate depressive symptoms in children and adolescents, a systematic review and meta-analysis of almost 2,500 participants found. Greater reductions were observed for children older than 13 years and those having a diagnosis of mental illness and/or depression versus other conditions, according to Hong Kong researchers reporting in JAMA Pediatrics.

“There is an urgent need to explore novel treatment approaches that can be safely, feasibly, and widely implemented in the daily routine of depressed children and adolescents,” said study coauthor Parco M. Siu, PhD, exercise physiologist and associate professor in the school of public health at the University of Hong Kong, in an interview. “Given the observed association with significant reductions in symptoms, clinical practice guidelines should consider the role of physical activity for improving the mental health of young populations.”

Dr. Siu further noted that while current guidelines suggest psychotherapy and/or pharmacotherapy for children with this common mood disorder, adherence to these can be problematic, and surveys show that nearly 80% do not receive appropriate disorder-specific medical care.

The analysis

Dr. Siu’s team drew on 21 international studies, including 17 randomized controlled trials, published from 1987 to 2021 and comprising 2,444 young participants, mean age 14, 53% girls. Eligible studies compared the effect of exercise on depression versus a control condition.

In 12 studies, participants had a somatic or psychiatric disorder such as obesity, diabetes, depression, and attention-deficit/hyperactivity disorder. The mean duration of the prescribed physical activity program was 22 weeks (6-144 weeks), while the frequency of weekly sessions ranged from 2 to 5 days, with 3 days per week most common and mean duration of 50 minutes (30-120 minutes). Regimens ranged from aerobic exercise on fitness equipment such as treadmills, stationary bikes, and ellipticals, to running, swimming, dancing, sports, and exercise games.

In meta-analysis of postintervention differences, physical activity was associated with a significant reduction in the pooled estimate of depressive symptoms compared with the control condition (Hedges g statistic [effect size] = −0.29; 95% confidence interval, −0.47 to −0.10; P = .004). This was driven by moderate to large effect sizes in adolescents (g = −0.44) and children with diagnosed depression (g = −0.75).The differences, however, were not detectable after a mean follow-up of 21 weeks, possibly owing to the limited number of studies with follow-up outcomes, the authors conceded.

Despite the strong association, the mechanisms underlying the antidepressant properties of physical activity remain uncertain. “Potential pathways include the activation of the endocannabinoid system to stimulate the release of endorphins, an increase in the bioavailability of brain neurotransmitters such as serotonin, dopamine, and noradrenaline, which are reduced in depression, as well as long-term changes in brain plasticity,” Dr. Siu said.

In addition, psychosocial and behavioral hypotheses suggest that physical activity can lead to improvements in self-perception, social interactions, and self-confidence. However, he added, depressive phenomenology is multifaceted and individual, so isolating the effects that physical activity have on specific symptoms may not be possible.

Physical activity appears to enhance the treatment of cognitive and affective symptoms in depression, Dr. Siu continued, and a combination of physical activity and pharmacotherapy may also reduce relapse risk, improve adherence to antidepressants, and promote better management of adverse effects, compared with pharmacotherapy alone. “More research is warranted to explain if and how these mechanisms moderate the effect of physical activity, and whether these changes are also present in younger populations,” he said.

Still unanswered is the question of how vigorous activity has to be in order to have an effect, Dr. Siu said. “Future studies should investigate the influence of parameters such as frequency, duration, and supervision of exercise sessions to determine the optimal dose and mode of delivery of the intervention for depressive symptom management.”

But would group activity likely have broader benefits than solitary exercise? “It is still unclear whether there’s a difference between the effect of solitary activities and team sports,” Dr. Siu said.

In an accompanying editorial on the meta-analysis, Eduardo E. Bustamante, PhD, an exercise psychologist in the department of kinesiology and nutrition at the University of Illinois at Chicago, and colleagues called the meta-analysis “part of a potential watershed moment” in the field of exercise as therapy for psychological disorders. “The work is timely, aligning with the rise of mental health disorders in adolescents, and the methods are rigorous (e.g., random-effects models, risk-of-bias assessment, sensitivity analyses).”

Dr. Bustamante said the literature on physical activity in children has lagged behind that for adults, so this meta-analysis provides a welcome “critical mass” of evidence of benefit in children, in an interview. “Though the benefit is relatively small, it’s exciting to see the results come in positive specifically to depression.” In his view, the effect of exercise is likely to be less pronounced in children than in adults, especially older ones, as they have fewer inflammatory and other systemic health problems that might improve with exercise. “And we tend to see bigger effects in children with a diagnosis like ADHD or clinical depression.”

But the bottom line is clear: “The evidence that physical activity is effective medicine for mental health is robust; now we need to find ways to get people to take it.”

This work was supported by the Health and Medical Research Fund of the Food and Health Bureau, Hong Kong Special Administrative Region Government, and the Seed Fund for Basic Research of the University of Hong Kong. The authors and editorial commentators disclosed no conflicts of interest.

Intervening with physical activity appears to mitigate depressive symptoms in children and adolescents, a systematic review and meta-analysis of almost 2,500 participants found. Greater reductions were observed for children older than 13 years and those having a diagnosis of mental illness and/or depression versus other conditions, according to Hong Kong researchers reporting in JAMA Pediatrics.

“There is an urgent need to explore novel treatment approaches that can be safely, feasibly, and widely implemented in the daily routine of depressed children and adolescents,” said study coauthor Parco M. Siu, PhD, exercise physiologist and associate professor in the school of public health at the University of Hong Kong, in an interview. “Given the observed association with significant reductions in symptoms, clinical practice guidelines should consider the role of physical activity for improving the mental health of young populations.”

Dr. Siu further noted that while current guidelines suggest psychotherapy and/or pharmacotherapy for children with this common mood disorder, adherence to these can be problematic, and surveys show that nearly 80% do not receive appropriate disorder-specific medical care.

The analysis

Dr. Siu’s team drew on 21 international studies, including 17 randomized controlled trials, published from 1987 to 2021 and comprising 2,444 young participants, mean age 14, 53% girls. Eligible studies compared the effect of exercise on depression versus a control condition.

In 12 studies, participants had a somatic or psychiatric disorder such as obesity, diabetes, depression, and attention-deficit/hyperactivity disorder. The mean duration of the prescribed physical activity program was 22 weeks (6-144 weeks), while the frequency of weekly sessions ranged from 2 to 5 days, with 3 days per week most common and mean duration of 50 minutes (30-120 minutes). Regimens ranged from aerobic exercise on fitness equipment such as treadmills, stationary bikes, and ellipticals, to running, swimming, dancing, sports, and exercise games.

In meta-analysis of postintervention differences, physical activity was associated with a significant reduction in the pooled estimate of depressive symptoms compared with the control condition (Hedges g statistic [effect size] = −0.29; 95% confidence interval, −0.47 to −0.10; P = .004). This was driven by moderate to large effect sizes in adolescents (g = −0.44) and children with diagnosed depression (g = −0.75).The differences, however, were not detectable after a mean follow-up of 21 weeks, possibly owing to the limited number of studies with follow-up outcomes, the authors conceded.

Despite the strong association, the mechanisms underlying the antidepressant properties of physical activity remain uncertain. “Potential pathways include the activation of the endocannabinoid system to stimulate the release of endorphins, an increase in the bioavailability of brain neurotransmitters such as serotonin, dopamine, and noradrenaline, which are reduced in depression, as well as long-term changes in brain plasticity,” Dr. Siu said.

In addition, psychosocial and behavioral hypotheses suggest that physical activity can lead to improvements in self-perception, social interactions, and self-confidence. However, he added, depressive phenomenology is multifaceted and individual, so isolating the effects that physical activity have on specific symptoms may not be possible.

Physical activity appears to enhance the treatment of cognitive and affective symptoms in depression, Dr. Siu continued, and a combination of physical activity and pharmacotherapy may also reduce relapse risk, improve adherence to antidepressants, and promote better management of adverse effects, compared with pharmacotherapy alone. “More research is warranted to explain if and how these mechanisms moderate the effect of physical activity, and whether these changes are also present in younger populations,” he said.

Still unanswered is the question of how vigorous activity has to be in order to have an effect, Dr. Siu said. “Future studies should investigate the influence of parameters such as frequency, duration, and supervision of exercise sessions to determine the optimal dose and mode of delivery of the intervention for depressive symptom management.”

But would group activity likely have broader benefits than solitary exercise? “It is still unclear whether there’s a difference between the effect of solitary activities and team sports,” Dr. Siu said.

In an accompanying editorial on the meta-analysis, Eduardo E. Bustamante, PhD, an exercise psychologist in the department of kinesiology and nutrition at the University of Illinois at Chicago, and colleagues called the meta-analysis “part of a potential watershed moment” in the field of exercise as therapy for psychological disorders. “The work is timely, aligning with the rise of mental health disorders in adolescents, and the methods are rigorous (e.g., random-effects models, risk-of-bias assessment, sensitivity analyses).”

Dr. Bustamante said the literature on physical activity in children has lagged behind that for adults, so this meta-analysis provides a welcome “critical mass” of evidence of benefit in children, in an interview. “Though the benefit is relatively small, it’s exciting to see the results come in positive specifically to depression.” In his view, the effect of exercise is likely to be less pronounced in children than in adults, especially older ones, as they have fewer inflammatory and other systemic health problems that might improve with exercise. “And we tend to see bigger effects in children with a diagnosis like ADHD or clinical depression.”

But the bottom line is clear: “The evidence that physical activity is effective medicine for mental health is robust; now we need to find ways to get people to take it.”

This work was supported by the Health and Medical Research Fund of the Food and Health Bureau, Hong Kong Special Administrative Region Government, and the Seed Fund for Basic Research of the University of Hong Kong. The authors and editorial commentators disclosed no conflicts of interest.

Intervening with physical activity appears to mitigate depressive symptoms in children and adolescents, a systematic review and meta-analysis of almost 2,500 participants found. Greater reductions were observed for children older than 13 years and those having a diagnosis of mental illness and/or depression versus other conditions, according to Hong Kong researchers reporting in JAMA Pediatrics.

“There is an urgent need to explore novel treatment approaches that can be safely, feasibly, and widely implemented in the daily routine of depressed children and adolescents,” said study coauthor Parco M. Siu, PhD, exercise physiologist and associate professor in the school of public health at the University of Hong Kong, in an interview. “Given the observed association with significant reductions in symptoms, clinical practice guidelines should consider the role of physical activity for improving the mental health of young populations.”

Dr. Siu further noted that while current guidelines suggest psychotherapy and/or pharmacotherapy for children with this common mood disorder, adherence to these can be problematic, and surveys show that nearly 80% do not receive appropriate disorder-specific medical care.

The analysis

Dr. Siu’s team drew on 21 international studies, including 17 randomized controlled trials, published from 1987 to 2021 and comprising 2,444 young participants, mean age 14, 53% girls. Eligible studies compared the effect of exercise on depression versus a control condition.

In 12 studies, participants had a somatic or psychiatric disorder such as obesity, diabetes, depression, and attention-deficit/hyperactivity disorder. The mean duration of the prescribed physical activity program was 22 weeks (6-144 weeks), while the frequency of weekly sessions ranged from 2 to 5 days, with 3 days per week most common and mean duration of 50 minutes (30-120 minutes). Regimens ranged from aerobic exercise on fitness equipment such as treadmills, stationary bikes, and ellipticals, to running, swimming, dancing, sports, and exercise games.

In meta-analysis of postintervention differences, physical activity was associated with a significant reduction in the pooled estimate of depressive symptoms compared with the control condition (Hedges g statistic [effect size] = −0.29; 95% confidence interval, −0.47 to −0.10; P = .004). This was driven by moderate to large effect sizes in adolescents (g = −0.44) and children with diagnosed depression (g = −0.75).The differences, however, were not detectable after a mean follow-up of 21 weeks, possibly owing to the limited number of studies with follow-up outcomes, the authors conceded.

Despite the strong association, the mechanisms underlying the antidepressant properties of physical activity remain uncertain. “Potential pathways include the activation of the endocannabinoid system to stimulate the release of endorphins, an increase in the bioavailability of brain neurotransmitters such as serotonin, dopamine, and noradrenaline, which are reduced in depression, as well as long-term changes in brain plasticity,” Dr. Siu said.

In addition, psychosocial and behavioral hypotheses suggest that physical activity can lead to improvements in self-perception, social interactions, and self-confidence. However, he added, depressive phenomenology is multifaceted and individual, so isolating the effects that physical activity have on specific symptoms may not be possible.

Physical activity appears to enhance the treatment of cognitive and affective symptoms in depression, Dr. Siu continued, and a combination of physical activity and pharmacotherapy may also reduce relapse risk, improve adherence to antidepressants, and promote better management of adverse effects, compared with pharmacotherapy alone. “More research is warranted to explain if and how these mechanisms moderate the effect of physical activity, and whether these changes are also present in younger populations,” he said.

Still unanswered is the question of how vigorous activity has to be in order to have an effect, Dr. Siu said. “Future studies should investigate the influence of parameters such as frequency, duration, and supervision of exercise sessions to determine the optimal dose and mode of delivery of the intervention for depressive symptom management.”

But would group activity likely have broader benefits than solitary exercise? “It is still unclear whether there’s a difference between the effect of solitary activities and team sports,” Dr. Siu said.

In an accompanying editorial on the meta-analysis, Eduardo E. Bustamante, PhD, an exercise psychologist in the department of kinesiology and nutrition at the University of Illinois at Chicago, and colleagues called the meta-analysis “part of a potential watershed moment” in the field of exercise as therapy for psychological disorders. “The work is timely, aligning with the rise of mental health disorders in adolescents, and the methods are rigorous (e.g., random-effects models, risk-of-bias assessment, sensitivity analyses).”

Dr. Bustamante said the literature on physical activity in children has lagged behind that for adults, so this meta-analysis provides a welcome “critical mass” of evidence of benefit in children, in an interview. “Though the benefit is relatively small, it’s exciting to see the results come in positive specifically to depression.” In his view, the effect of exercise is likely to be less pronounced in children than in adults, especially older ones, as they have fewer inflammatory and other systemic health problems that might improve with exercise. “And we tend to see bigger effects in children with a diagnosis like ADHD or clinical depression.”

But the bottom line is clear: “The evidence that physical activity is effective medicine for mental health is robust; now we need to find ways to get people to take it.”

This work was supported by the Health and Medical Research Fund of the Food and Health Bureau, Hong Kong Special Administrative Region Government, and the Seed Fund for Basic Research of the University of Hong Kong. The authors and editorial commentators disclosed no conflicts of interest.

A common refrain in psychiatry is that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, (DSM-5-TR), published in 2022, is the best we can do.

Since the DSM-III was released in 1980, the American Psychiatric Association, which publishes the manual, has espoused the position that we should list symptoms, in a manner that is reminiscent of a checklist. For example, having a depressed mood on most days for a 2-week period, or a loss of interest in pleasurable things, as well as 4 additional symptoms – among them changes in appetite, changes in sleep, changes in psychomotor activity, fatigue, worthlessness, poor concentration, or thoughts of death – can lead to a diagnosis of a major depressive episode as part of a major depressive disorder.

Criticisms of this approach can be apparent. Patients subjected to such checklists, including being repeatedly asked to complete the Patient Health Questionnaire 9 (PHQ-9), which closely follows those criteria, can feel lost and even alienated by their providers. After all, one can ask all those questions and make a diagnosis of depression without even knowing about the patient’s stressors, their history, or their social context.

The DSM permits the diagnosis of psychiatric disorders without an understanding of the narrative of the patient. In its defense, the DSM is not a textbook of psychiatry, it is a guide on how to diagnose individuals. The DSM does not demand that psychiatrists only ask about the symptoms on the checklists; it is the providers who can choose to dismiss asking about the important facets of one’s life.

Yet every time we attend a lecture that starts by enumerating the DSM symptoms of the disorder being discussed, we are left with the dissatisfying impression that a specialist of this disorder should have a more nuanced and interesting description of their disorder of study. This feeling of discontent is compounded when we see a movie that encompasses so much of what is missing in today’s psychiatric parlance, and even more so if that movie is ostensibly made for children. Movies, by design, are particularly adept at encapsulating the narrative of someone’s life in a way that psychiatry can learn from.

Other than the embarrassment of not knowing a patient outside the checklist, the importance of narrative cannot be understated. Dr. Erik Erikson rightfully suggested that the point of life is “the acceptance of one’s one and only life cycle”¹ or rather to know it was okay to have been oneself without additions or substitutions. Therefore, one must know what it has meant to be themselves to reconcile this question and achieve Ego Integrity rather than disgust and despair. Narrative is the way in which we understand who we are and what it has meant to be ourselves. An understanding of our personal narrative presents a unique opportunity in expressing what is missing in the DSM. Below, we provide two of our favorite examples in Disney films, among many.
 

‘Ratatouille’ (2007)

One of the missing features of the DSM is its inability to explain to patients the intrapsychic processes that guide us. One of these processes is how our values can lead us to a deep sense of guilt, shame, and the resulting feelings of alienation. It is extremely common for patients to enter our clinical practice feeling shackled by beliefs that they should accomplish more and be more than they are.

The animated film “Ratatouille” does an excellent job at addressing this feeling. The film follows Remy, the protagonist rat, and his adventures as he explores his passion for cooking. Remy teams up with the inept but good-natured human Alfredo Linguini and guides him through cooking while hiding under his chef’s hat. The primary antagonist, Anton Ego, is a particularly harsh food critic. His presence and appearance are somber. He exudes disdain. His trim physique and scarf suggest a man that will break and react to anything, and his skull-shaped typewriter in his coffin-shaped office informs the viewer that he is out to kill with his cruel words. Anton Ego serves as our projected super-ego. He is not an external judge but the judgment deep inside ourselves, goading us to be better with such severity that we are ultimately left feeling condemned.

Remy is the younger of two siblings. He is less physically adept but more intellectual than his older brother, who does not understand why Remy isn’t content eating scraps from the garbage like the rest of their rat clan. Remy is the creative part within us that wants to challenge the status quo and try something new. Remy also represents our shame and guilt for leaving our home. On one hand, we want to dare greatly, in this case at being an extraordinary chef, but on the other we are shy and cook in secret, hiding within the hat of another person. Remy struggles with the deep feeling that we do not deserve our success, that our family will leave us for being who we are, and that we are better off isolating and segregating from our challenges.

The movie concludes that through talent and hard work, our critics will accept us. Furthermore, once accepted for what we do, we can be further accepted for who we are. The movie ends with Remy cooking the eponymous dish ratatouille. He prepares it so remarkably well, the dish transports Anton Ego back to a sublime experience of eating ratatouille as a child, a touching moment which not only underscores food’s evocative link to memory but gives a glimpse at Anton Ego’s own narrative.

Ego is first won over by the dish, and only afterward learns of Remy’s true identity. Remy’s talent is undeniable though, and even the stuffy Ego must accept the film’s theme that “Anyone can cook,” even a rat – the rat that we all sometimes feel we are deep inside, rotten to the core but trying so hard to be accepted by others, and ultimately by ourselves. In the end, we overcome the disgust inherent in the imagery of a rat in a kitchen and instead embrace our hero’s achievement of ego integrity as he combines his identities as a member of a clan of rats, and one of Paris’s finest chefs.

While modern psychiatry can favor looking at people through the lens of biology rather than narrative, “Ratatouille” can serve as a reminder of the powerful unconscious forces that guide our lives. “Ratatouille” is not a successful movie only because of the compelling narrative, but also because the narrative matches the important psychic paradigms that psychiatry once embraced.
 

‘Inside Out’ (2015)

Another missing feature of the DSM is its inability to explain how symptoms feel and manifest psychologically. One such feeling is that of control – whether one is in control of one’s life, feelings, and action or rather a victim of external forces. It is extremely common for patients to enter our clinical practice feeling traumatized by the life they’ve lived and powerless to produce any change. Part of our role is to guide them through this journey from the object of their lives to the subject of their lives.

In the animated feature “Inside Out,” Riley, a preteen girl, goes through the tribulation of growing up and learning about herself. This seemingly happy child, content playing hockey with her best friend, Meg, on the picturesque frozen lakes of Minnesota, reaches her inevitable conflict. Her parents uproot her life, moving the family to San Francisco. By doing so, they disconnect her from her school, her friends, and her hobbies. While all this is happening, we spend time inside Riley’s psyche with the personified characters of Riley’s emotions as they affect her decisions and daily actions amidst the backdrop of her core memories and islands of personality.

During the move, her parents seemingly change and ultimately destroy every facet of Riley’s sense of self, which is animated as the collapse of her personality islands. Her best friend engages Riley in a video call just to inform her that she has a new friend who plays hockey equally well. Her parents do not hear Riley’s concerns and are portrayed as distracted by their adult problems. Riley feels ridiculed in her new school and unable to share her feelings with her parents, who ask her to still be their “happy girl” and indirectly ask her to fake pleasure to alleviate their own anxiety.

The climax of the movie is when Riley decides to run away from San Francisco and her parents, to return to her perceived true home, Minnesota. The climax is resolved when Riley realizes that her parents’ love, representing the connection we have to others, transcends her need for control. To some degree, we are all powerless in the face of the tremendous forces of life and share the difficult task of accepting the cards we were dealt, thus making the story of Riley so compelling.

Additionally, the climax is further resolved by another argument that psychiatry (and the DSM) should consider embracing. Emotions are not all symptoms and living without negative emotion is not the goal of life. Riley grows from preteen to teenager, and from object to subject of her life, by realizing that her symptoms/feelings are not just nuisances to avoid and hide, but the key to meaning. Our anger drives us to try hard. Our fear protects us from harm. Our sadness attracts the warmth and care of others. Our disgust protects us physically from noxious material (symbolized as a dreaded broccoli floret for preteen Riley) and socially by encouraging us to share societal norms. Similarly, patients and people in general would benefit by being taught that, while symptoms may permit the better assessment of psychiatric conditions using the DSM, life is much more than that.

It is unfair to blame the DSM for things it was not designed to do. The DSM doesn’t advertise itself as a guidebook of all behaviors, at all times. However, for a variety of reasons, it has become the main way psychiatry describes people. While we commend the APA for its effort and do not know that we could make it any better, we are frequently happily reminded that in about 90 minutes, filmmakers are able to display an empathic understanding of personal narratives that biologic psychiatry can miss.

Dr. Pulido is a psychiatry resident at the University of California, San Diego. She is interested in women’s mental health, medical education, and outpatient psychiatry. 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. He has no conflicts of interest.

References

1. Erikson, EH. Childhood and society (New York: WW Norton, 1950).

A common refrain in psychiatry is that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, (DSM-5-TR), published in 2022, is the best we can do.

Since the DSM-III was released in 1980, the American Psychiatric Association, which publishes the manual, has espoused the position that we should list symptoms, in a manner that is reminiscent of a checklist. For example, having a depressed mood on most days for a 2-week period, or a loss of interest in pleasurable things, as well as 4 additional symptoms – among them changes in appetite, changes in sleep, changes in psychomotor activity, fatigue, worthlessness, poor concentration, or thoughts of death – can lead to a diagnosis of a major depressive episode as part of a major depressive disorder.

Criticisms of this approach can be apparent. Patients subjected to such checklists, including being repeatedly asked to complete the Patient Health Questionnaire 9 (PHQ-9), which closely follows those criteria, can feel lost and even alienated by their providers. After all, one can ask all those questions and make a diagnosis of depression without even knowing about the patient’s stressors, their history, or their social context.

The DSM permits the diagnosis of psychiatric disorders without an understanding of the narrative of the patient. In its defense, the DSM is not a textbook of psychiatry, it is a guide on how to diagnose individuals. The DSM does not demand that psychiatrists only ask about the symptoms on the checklists; it is the providers who can choose to dismiss asking about the important facets of one’s life.

Yet every time we attend a lecture that starts by enumerating the DSM symptoms of the disorder being discussed, we are left with the dissatisfying impression that a specialist of this disorder should have a more nuanced and interesting description of their disorder of study. This feeling of discontent is compounded when we see a movie that encompasses so much of what is missing in today’s psychiatric parlance, and even more so if that movie is ostensibly made for children. Movies, by design, are particularly adept at encapsulating the narrative of someone’s life in a way that psychiatry can learn from.

Other than the embarrassment of not knowing a patient outside the checklist, the importance of narrative cannot be understated. Dr. Erik Erikson rightfully suggested that the point of life is “the acceptance of one’s one and only life cycle”¹ or rather to know it was okay to have been oneself without additions or substitutions. Therefore, one must know what it has meant to be themselves to reconcile this question and achieve Ego Integrity rather than disgust and despair. Narrative is the way in which we understand who we are and what it has meant to be ourselves. An understanding of our personal narrative presents a unique opportunity in expressing what is missing in the DSM. Below, we provide two of our favorite examples in Disney films, among many.
 

‘Ratatouille’ (2007)

One of the missing features of the DSM is its inability to explain to patients the intrapsychic processes that guide us. One of these processes is how our values can lead us to a deep sense of guilt, shame, and the resulting feelings of alienation. It is extremely common for patients to enter our clinical practice feeling shackled by beliefs that they should accomplish more and be more than they are.

The animated film “Ratatouille” does an excellent job at addressing this feeling. The film follows Remy, the protagonist rat, and his adventures as he explores his passion for cooking. Remy teams up with the inept but good-natured human Alfredo Linguini and guides him through cooking while hiding under his chef’s hat. The primary antagonist, Anton Ego, is a particularly harsh food critic. His presence and appearance are somber. He exudes disdain. His trim physique and scarf suggest a man that will break and react to anything, and his skull-shaped typewriter in his coffin-shaped office informs the viewer that he is out to kill with his cruel words. Anton Ego serves as our projected super-ego. He is not an external judge but the judgment deep inside ourselves, goading us to be better with such severity that we are ultimately left feeling condemned.

Remy is the younger of two siblings. He is less physically adept but more intellectual than his older brother, who does not understand why Remy isn’t content eating scraps from the garbage like the rest of their rat clan. Remy is the creative part within us that wants to challenge the status quo and try something new. Remy also represents our shame and guilt for leaving our home. On one hand, we want to dare greatly, in this case at being an extraordinary chef, but on the other we are shy and cook in secret, hiding within the hat of another person. Remy struggles with the deep feeling that we do not deserve our success, that our family will leave us for being who we are, and that we are better off isolating and segregating from our challenges.

The movie concludes that through talent and hard work, our critics will accept us. Furthermore, once accepted for what we do, we can be further accepted for who we are. The movie ends with Remy cooking the eponymous dish ratatouille. He prepares it so remarkably well, the dish transports Anton Ego back to a sublime experience of eating ratatouille as a child, a touching moment which not only underscores food’s evocative link to memory but gives a glimpse at Anton Ego’s own narrative.

Ego is first won over by the dish, and only afterward learns of Remy’s true identity. Remy’s talent is undeniable though, and even the stuffy Ego must accept the film’s theme that “Anyone can cook,” even a rat – the rat that we all sometimes feel we are deep inside, rotten to the core but trying so hard to be accepted by others, and ultimately by ourselves. In the end, we overcome the disgust inherent in the imagery of a rat in a kitchen and instead embrace our hero’s achievement of ego integrity as he combines his identities as a member of a clan of rats, and one of Paris’s finest chefs.

While modern psychiatry can favor looking at people through the lens of biology rather than narrative, “Ratatouille” can serve as a reminder of the powerful unconscious forces that guide our lives. “Ratatouille” is not a successful movie only because of the compelling narrative, but also because the narrative matches the important psychic paradigms that psychiatry once embraced.
 

‘Inside Out’ (2015)

Another missing feature of the DSM is its inability to explain how symptoms feel and manifest psychologically. One such feeling is that of control – whether one is in control of one’s life, feelings, and action or rather a victim of external forces. It is extremely common for patients to enter our clinical practice feeling traumatized by the life they’ve lived and powerless to produce any change. Part of our role is to guide them through this journey from the object of their lives to the subject of their lives.

In the animated feature “Inside Out,” Riley, a preteen girl, goes through the tribulation of growing up and learning about herself. This seemingly happy child, content playing hockey with her best friend, Meg, on the picturesque frozen lakes of Minnesota, reaches her inevitable conflict. Her parents uproot her life, moving the family to San Francisco. By doing so, they disconnect her from her school, her friends, and her hobbies. While all this is happening, we spend time inside Riley’s psyche with the personified characters of Riley’s emotions as they affect her decisions and daily actions amidst the backdrop of her core memories and islands of personality.

During the move, her parents seemingly change and ultimately destroy every facet of Riley’s sense of self, which is animated as the collapse of her personality islands. Her best friend engages Riley in a video call just to inform her that she has a new friend who plays hockey equally well. Her parents do not hear Riley’s concerns and are portrayed as distracted by their adult problems. Riley feels ridiculed in her new school and unable to share her feelings with her parents, who ask her to still be their “happy girl” and indirectly ask her to fake pleasure to alleviate their own anxiety.

The climax of the movie is when Riley decides to run away from San Francisco and her parents, to return to her perceived true home, Minnesota. The climax is resolved when Riley realizes that her parents’ love, representing the connection we have to others, transcends her need for control. To some degree, we are all powerless in the face of the tremendous forces of life and share the difficult task of accepting the cards we were dealt, thus making the story of Riley so compelling.

Additionally, the climax is further resolved by another argument that psychiatry (and the DSM) should consider embracing. Emotions are not all symptoms and living without negative emotion is not the goal of life. Riley grows from preteen to teenager, and from object to subject of her life, by realizing that her symptoms/feelings are not just nuisances to avoid and hide, but the key to meaning. Our anger drives us to try hard. Our fear protects us from harm. Our sadness attracts the warmth and care of others. Our disgust protects us physically from noxious material (symbolized as a dreaded broccoli floret for preteen Riley) and socially by encouraging us to share societal norms. Similarly, patients and people in general would benefit by being taught that, while symptoms may permit the better assessment of psychiatric conditions using the DSM, life is much more than that.

It is unfair to blame the DSM for things it was not designed to do. The DSM doesn’t advertise itself as a guidebook of all behaviors, at all times. However, for a variety of reasons, it has become the main way psychiatry describes people. While we commend the APA for its effort and do not know that we could make it any better, we are frequently happily reminded that in about 90 minutes, filmmakers are able to display an empathic understanding of personal narratives that biologic psychiatry can miss.

Dr. Pulido is a psychiatry resident at the University of California, San Diego. She is interested in women’s mental health, medical education, and outpatient psychiatry. 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. He has no conflicts of interest.

References

1. Erikson, EH. Childhood and society (New York: WW Norton, 1950).

A common refrain in psychiatry is that the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision, (DSM-5-TR), published in 2022, is the best we can do.

Since the DSM-III was released in 1980, the American Psychiatric Association, which publishes the manual, has espoused the position that we should list symptoms, in a manner that is reminiscent of a checklist. For example, having a depressed mood on most days for a 2-week period, or a loss of interest in pleasurable things, as well as 4 additional symptoms – among them changes in appetite, changes in sleep, changes in psychomotor activity, fatigue, worthlessness, poor concentration, or thoughts of death – can lead to a diagnosis of a major depressive episode as part of a major depressive disorder.

Criticisms of this approach can be apparent. Patients subjected to such checklists, including being repeatedly asked to complete the Patient Health Questionnaire 9 (PHQ-9), which closely follows those criteria, can feel lost and even alienated by their providers. After all, one can ask all those questions and make a diagnosis of depression without even knowing about the patient’s stressors, their history, or their social context.

The DSM permits the diagnosis of psychiatric disorders without an understanding of the narrative of the patient. In its defense, the DSM is not a textbook of psychiatry, it is a guide on how to diagnose individuals. The DSM does not demand that psychiatrists only ask about the symptoms on the checklists; it is the providers who can choose to dismiss asking about the important facets of one’s life.

Yet every time we attend a lecture that starts by enumerating the DSM symptoms of the disorder being discussed, we are left with the dissatisfying impression that a specialist of this disorder should have a more nuanced and interesting description of their disorder of study. This feeling of discontent is compounded when we see a movie that encompasses so much of what is missing in today’s psychiatric parlance, and even more so if that movie is ostensibly made for children. Movies, by design, are particularly adept at encapsulating the narrative of someone’s life in a way that psychiatry can learn from.

Other than the embarrassment of not knowing a patient outside the checklist, the importance of narrative cannot be understated. Dr. Erik Erikson rightfully suggested that the point of life is “the acceptance of one’s one and only life cycle”¹ or rather to know it was okay to have been oneself without additions or substitutions. Therefore, one must know what it has meant to be themselves to reconcile this question and achieve Ego Integrity rather than disgust and despair. Narrative is the way in which we understand who we are and what it has meant to be ourselves. An understanding of our personal narrative presents a unique opportunity in expressing what is missing in the DSM. Below, we provide two of our favorite examples in Disney films, among many.
 

‘Ratatouille’ (2007)

One of the missing features of the DSM is its inability to explain to patients the intrapsychic processes that guide us. One of these processes is how our values can lead us to a deep sense of guilt, shame, and the resulting feelings of alienation. It is extremely common for patients to enter our clinical practice feeling shackled by beliefs that they should accomplish more and be more than they are.

The animated film “Ratatouille” does an excellent job at addressing this feeling. The film follows Remy, the protagonist rat, and his adventures as he explores his passion for cooking. Remy teams up with the inept but good-natured human Alfredo Linguini and guides him through cooking while hiding under his chef’s hat. The primary antagonist, Anton Ego, is a particularly harsh food critic. His presence and appearance are somber. He exudes disdain. His trim physique and scarf suggest a man that will break and react to anything, and his skull-shaped typewriter in his coffin-shaped office informs the viewer that he is out to kill with his cruel words. Anton Ego serves as our projected super-ego. He is not an external judge but the judgment deep inside ourselves, goading us to be better with such severity that we are ultimately left feeling condemned.

Remy is the younger of two siblings. He is less physically adept but more intellectual than his older brother, who does not understand why Remy isn’t content eating scraps from the garbage like the rest of their rat clan. Remy is the creative part within us that wants to challenge the status quo and try something new. Remy also represents our shame and guilt for leaving our home. On one hand, we want to dare greatly, in this case at being an extraordinary chef, but on the other we are shy and cook in secret, hiding within the hat of another person. Remy struggles with the deep feeling that we do not deserve our success, that our family will leave us for being who we are, and that we are better off isolating and segregating from our challenges.

The movie concludes that through talent and hard work, our critics will accept us. Furthermore, once accepted for what we do, we can be further accepted for who we are. The movie ends with Remy cooking the eponymous dish ratatouille. He prepares it so remarkably well, the dish transports Anton Ego back to a sublime experience of eating ratatouille as a child, a touching moment which not only underscores food’s evocative link to memory but gives a glimpse at Anton Ego’s own narrative.

Ego is first won over by the dish, and only afterward learns of Remy’s true identity. Remy’s talent is undeniable though, and even the stuffy Ego must accept the film’s theme that “Anyone can cook,” even a rat – the rat that we all sometimes feel we are deep inside, rotten to the core but trying so hard to be accepted by others, and ultimately by ourselves. In the end, we overcome the disgust inherent in the imagery of a rat in a kitchen and instead embrace our hero’s achievement of ego integrity as he combines his identities as a member of a clan of rats, and one of Paris’s finest chefs.

While modern psychiatry can favor looking at people through the lens of biology rather than narrative, “Ratatouille” can serve as a reminder of the powerful unconscious forces that guide our lives. “Ratatouille” is not a successful movie only because of the compelling narrative, but also because the narrative matches the important psychic paradigms that psychiatry once embraced.
 

‘Inside Out’ (2015)

Another missing feature of the DSM is its inability to explain how symptoms feel and manifest psychologically. One such feeling is that of control – whether one is in control of one’s life, feelings, and action or rather a victim of external forces. It is extremely common for patients to enter our clinical practice feeling traumatized by the life they’ve lived and powerless to produce any change. Part of our role is to guide them through this journey from the object of their lives to the subject of their lives.

In the animated feature “Inside Out,” Riley, a preteen girl, goes through the tribulation of growing up and learning about herself. This seemingly happy child, content playing hockey with her best friend, Meg, on the picturesque frozen lakes of Minnesota, reaches her inevitable conflict. Her parents uproot her life, moving the family to San Francisco. By doing so, they disconnect her from her school, her friends, and her hobbies. While all this is happening, we spend time inside Riley’s psyche with the personified characters of Riley’s emotions as they affect her decisions and daily actions amidst the backdrop of her core memories and islands of personality.

During the move, her parents seemingly change and ultimately destroy every facet of Riley’s sense of self, which is animated as the collapse of her personality islands. Her best friend engages Riley in a video call just to inform her that she has a new friend who plays hockey equally well. Her parents do not hear Riley’s concerns and are portrayed as distracted by their adult problems. Riley feels ridiculed in her new school and unable to share her feelings with her parents, who ask her to still be their “happy girl” and indirectly ask her to fake pleasure to alleviate their own anxiety.

The climax of the movie is when Riley decides to run away from San Francisco and her parents, to return to her perceived true home, Minnesota. The climax is resolved when Riley realizes that her parents’ love, representing the connection we have to others, transcends her need for control. To some degree, we are all powerless in the face of the tremendous forces of life and share the difficult task of accepting the cards we were dealt, thus making the story of Riley so compelling.

Additionally, the climax is further resolved by another argument that psychiatry (and the DSM) should consider embracing. Emotions are not all symptoms and living without negative emotion is not the goal of life. Riley grows from preteen to teenager, and from object to subject of her life, by realizing that her symptoms/feelings are not just nuisances to avoid and hide, but the key to meaning. Our anger drives us to try hard. Our fear protects us from harm. Our sadness attracts the warmth and care of others. Our disgust protects us physically from noxious material (symbolized as a dreaded broccoli floret for preteen Riley) and socially by encouraging us to share societal norms. Similarly, patients and people in general would benefit by being taught that, while symptoms may permit the better assessment of psychiatric conditions using the DSM, life is much more than that.

It is unfair to blame the DSM for things it was not designed to do. The DSM doesn’t advertise itself as a guidebook of all behaviors, at all times. However, for a variety of reasons, it has become the main way psychiatry describes people. While we commend the APA for its effort and do not know that we could make it any better, we are frequently happily reminded that in about 90 minutes, filmmakers are able to display an empathic understanding of personal narratives that biologic psychiatry can miss.

Dr. Pulido is a psychiatry resident at the University of California, San Diego. She is interested in women’s mental health, medical education, and outpatient psychiatry. 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. He has no conflicts of interest.

References

1. Erikson, EH. Childhood and society (New York: WW Norton, 1950).