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Confronting physician depression and suicide
Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.
Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats
Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.
“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.
One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.
In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.
Topics of conversation
Question 1: What are the causes of physician depression and suicide in training and practice?
Question 2: How can we end stigma against seeking mental health treatment among physicians?
Question 3: How can we prevent depression and suicide among medical students and physicians?
Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?
Question 5: What organizational and political changes are likely to reduce physician suicides?
Resources
1. Getting Back to Medicine as a Community
2. What stops physicians from getting mental health care?
3. Risk considerations for suicidal physicians
4. Two more and counting: Suicide in medical trainees
5. How to talk with a struggling physician colleague
6. Healthcare industry takes on high physician suicide rates, mental health stigma
7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine
8. Creating Joy in Medicine in St. Paul, MN: A Case Study
About Dr. Poorman
Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.
Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.
About Dr. Candler
Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.
She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.
Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.
Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats
Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.
“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.
One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.
In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.
Topics of conversation
Question 1: What are the causes of physician depression and suicide in training and practice?
Question 2: How can we end stigma against seeking mental health treatment among physicians?
Question 3: How can we prevent depression and suicide among medical students and physicians?
Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?
Question 5: What organizational and political changes are likely to reduce physician suicides?
Resources
1. Getting Back to Medicine as a Community
2. What stops physicians from getting mental health care?
3. Risk considerations for suicidal physicians
4. Two more and counting: Suicide in medical trainees
5. How to talk with a struggling physician colleague
6. Healthcare industry takes on high physician suicide rates, mental health stigma
7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine
8. Creating Joy in Medicine in St. Paul, MN: A Case Study
About Dr. Poorman
Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.
Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.
About Dr. Candler
Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.
She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.
Please join us Monday, June 3, at 8:00 p.m. ET as we discuss depression in physicians and the resulting tragedies, as well as how to help physicians receive the treatment they need to prevent suicide.
Our special guests include physicians with expertise on the triggers of physician depression and solutions for fighting this epidemic, Sarah Candler, MD, (@sarahgcandler) and Elisabeth Poorman, MD, (@DrPoorman). We hope you will participate in our Twitter chat on June 3 at 8 p.m. ET. #MDedgeChats
Physicians have higher rates of depression and suicide, compared with the general population, according to the American Foundation for Suicide Prevention. Suicide rates for male physicians are 1.41 times higher than in the general population and, for female physicians, 2.27 times greater.
“But these numbers come from only those deaths that are reported publicly,” Dr. Poorman wrote in an article that was published by WBUR, Boston’s NPR News Station. In fact, as Dr. Poorman was writing this story, she learned of five separate deaths that were widely known to be suicides, but never publicly identified as such, she said.
One possible explanation for physicians’ higher likelihood of becoming depressed or dying by suicide, compared with other professionals, is their hesitance to receive mental health treatment, experts have suggested. Psychiatrist Michael F. Myers, MD, found anecdotal evidence of this tendency when he interviewed the loved ones, friends, and colleagues of physicians who took their own lives.
In this chat we will discuss this topic and other possible reasons for the high rate of depression and suicide among physicians.
Topics of conversation
Question 1: What are the causes of physician depression and suicide in training and practice?
Question 2: How can we end stigma against seeking mental health treatment among physicians?
Question 3: How can we prevent depression and suicide among medical students and physicians?
Question 4: Which institutions or programs are exemplars in providing resources to improve mental health?
Question 5: What organizational and political changes are likely to reduce physician suicides?
Resources
1. Getting Back to Medicine as a Community
2. What stops physicians from getting mental health care?
3. Risk considerations for suicidal physicians
4. Two more and counting: Suicide in medical trainees
5. How to talk with a struggling physician colleague
6. Healthcare industry takes on high physician suicide rates, mental health stigma
7. The Curbsiders episode #129 Depression and Suicide: Occupational Hazards of Practicing Medicine
8. Creating Joy in Medicine in St. Paul, MN: A Case Study
About Dr. Poorman
Dr. Poorman (@DrPoorman) is a primary care physician at the University of Washington in Seattle, a freelance journalist covering issues related to medicine, and a frequent speaker on the causes of and solutions to mental illness among providers.
Her writing has been featured in Self, The Guardian. Medpage Today’s KevinMD.com, and other publications. She produces the blog: https://www.drpoorman.org/what-we-do.
About Dr. Candler
Dr. Candler (@sarahgcandler) is a primary care physician in Houston. She is coeditor of the Annals Fresh Look blog, and a member of Internal Medicine News’ Editorial Advisory Board.
She is currently consulting for a tech firm and will later be joining Iora Health to start a Medicare Advantage clinic.
Psychiatrists urged to raise awareness about human trafficking
SAN FRANCISCO – Psychiatrists see and interact with people who are being sex and labor trafficked “all the time” – and can learn more about how to identify these individuals, Rachel Robitz, MD, said at the annual meeting of the American Psychiatric Association.
In an exclusive video, Mollie Gordon, MD, interviewed Dr. Robitz about the intersection between trafficking and mental health. “What scares me the most is some of the statistics about self-harm,” said Dr. Robitz. “One study of sex-trafficked adults found that about 40% of them had a history of a suicide attempt. A study of sex-trafficked minors found that about 30% of them had a history of moderate to severe self-harm behavior.”
Dr. Robitz said. Other resources include those provided by the Department of Health & Human Services’s Office on Trafficking in Persons.
Dr. Robitz, who is double boarded in psychiatry and family medicine, is with the University of California, Davis. She previously worked for a program for homeless youth and for many programs aimed at helping adult and youth survivors of human trafficking. Dr. Robitz has no disclosures. Dr. Gordon is associate professor of psychiatry in the Menninger department of behavioral health at Baylor College of Medicine, Houston. She is a founding member of the Houston Area Human Trafficking Health Care Consortium. Dr. Gordon has no disclosures.
SAN FRANCISCO – Psychiatrists see and interact with people who are being sex and labor trafficked “all the time” – and can learn more about how to identify these individuals, Rachel Robitz, MD, said at the annual meeting of the American Psychiatric Association.
In an exclusive video, Mollie Gordon, MD, interviewed Dr. Robitz about the intersection between trafficking and mental health. “What scares me the most is some of the statistics about self-harm,” said Dr. Robitz. “One study of sex-trafficked adults found that about 40% of them had a history of a suicide attempt. A study of sex-trafficked minors found that about 30% of them had a history of moderate to severe self-harm behavior.”
Dr. Robitz said. Other resources include those provided by the Department of Health & Human Services’s Office on Trafficking in Persons.
Dr. Robitz, who is double boarded in psychiatry and family medicine, is with the University of California, Davis. She previously worked for a program for homeless youth and for many programs aimed at helping adult and youth survivors of human trafficking. Dr. Robitz has no disclosures. Dr. Gordon is associate professor of psychiatry in the Menninger department of behavioral health at Baylor College of Medicine, Houston. She is a founding member of the Houston Area Human Trafficking Health Care Consortium. Dr. Gordon has no disclosures.
SAN FRANCISCO – Psychiatrists see and interact with people who are being sex and labor trafficked “all the time” – and can learn more about how to identify these individuals, Rachel Robitz, MD, said at the annual meeting of the American Psychiatric Association.
In an exclusive video, Mollie Gordon, MD, interviewed Dr. Robitz about the intersection between trafficking and mental health. “What scares me the most is some of the statistics about self-harm,” said Dr. Robitz. “One study of sex-trafficked adults found that about 40% of them had a history of a suicide attempt. A study of sex-trafficked minors found that about 30% of them had a history of moderate to severe self-harm behavior.”
Dr. Robitz said. Other resources include those provided by the Department of Health & Human Services’s Office on Trafficking in Persons.
Dr. Robitz, who is double boarded in psychiatry and family medicine, is with the University of California, Davis. She previously worked for a program for homeless youth and for many programs aimed at helping adult and youth survivors of human trafficking. Dr. Robitz has no disclosures. Dr. Gordon is associate professor of psychiatry in the Menninger department of behavioral health at Baylor College of Medicine, Houston. She is a founding member of the Houston Area Human Trafficking Health Care Consortium. Dr. Gordon has no disclosures.
REPORTING FROM APA 2019
Intranasal esketamine combo tied to symptom improvement
Concern raised about drug’s abuse potential
SAN FRANCISCO – In treatment-resistant depression, a switch to a new antidepressant combined with inhaled esketamine (Spravato) led to better symptom improvement than did a switch to a new antidepressant plus placebo, results from a new trial show. The treatment effect of esketamine was modest but had a number needed to treat for remission of just five.
About 30% of patients with major depressive disorder are treatment resistant. They are at risk of suicidal behavior and self-harm during the interval between starting a new medication and onset of efficacy. Esketamine, with its rapid onset of efficacy associated with its stimulation of synaptogenesis through inhibition of the N-methyl-D-aspartate receptor, gained Food and Drug Administration approval in March for the treatment of treatment-resistant depression in adults.
The findings were part of a phase 3 study presented at a press conference at the annual meeting of the American Psychiatric Association and simultaneously published in the American Journal of Psychiatry (2019. doi: 10.1176/appi.ajp.2019.19020172).
Adding esketamine to the start of a new antidepressant was associated with a small improvement in symptoms (effect size, 0.30), and this benefit did not continue to accrue further advantage past the original separation, which led to some skepticism from the author of an accompanying editorial (Am J Psychiatry. 2019 May. doi: 10.1176/appi.ajp.2019.19040423). “The question is, do you need to keep a patient on the drug past 48 hours? There is no statistically significant difference (in patient response) past the first 48 hours. That to me is a concern,” said Alan F. Schatzberg, MD, at the press conference.
Dr. Schatzberg, who is a professor of psychiatry at the Stanford (Calif.) University, also expressed concern about the potential for abuse with esketamine, as well as withdrawal after discontinuation. “I think the drug ought to be used, but it needs to be recommended with considerable caution. We have not answered the many questions that are needed in a drug of potential abuse,” Dr. Schatzberg added.
Study coauthor Michael E. Thase, MD, who also presented at the press conference, discussed the possibility of alterations to the treatment regimen. “I have a hunch you can see this (positive response) within first week or 2, and you can at least concentrate the resource on patients that gain the largest benefit. We can be smarter about it,” said Dr. Thase, who is a professor of psychiatry at the University of Pennsylvania, Philadelphia. He predicted that protocols eventually will be put in place to streamline intranasal ketamine treatment.
Regardless of the effect size, the study produced high remission and response rates in this difficult to treat population, which is welcome news to Gerard Sanacora, MD, PhD, a professor of psychiatry at Yale University, New Haven, Conn., and director of the Yale Depression Research Program. he said in an interview.
In the phase 3 study, researchers randomized 223 patients from five countries to receive esketamine or placebo, along with either an SSRI (escitalopram or sertraline) or a selective norepinephrine reuptake inhibitor (duloxetine or venlafaxine extended release), based on investigator choice.
To be eligible, participants had to have failed two previous trials of antidepressants. After a 4-week observation period, patients began a 4-week regimen of a new antidepressant combined with twice-weekly nasal esketamine or a placebo.
Subjects in the treatment arm received esketamine on day 1 of the treatment phase with a 56-mg dose. On day 4, 45.8% were increased to a dose of 84 mg, and 66.7% were at the 84-mg dose at the end of the treatment phase.
From baseline to day 28, the esketamine group had a greater decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score (difference of least square means, –4.0; P = .020; effect size, 0.30). A scatter plot of individual MADRS data during that period revealed rapid onset and increasing rapid response during repeated dosing 24 hours after dosing (least square mean between-group difference, –3.3), day 8 (–2.9), day 15 (–2.0), and day 22 (–4.0; P = .020).
Researchers also examined subjects who achieved at least a 50% reduction MADRS score at day 2 and maintained the improvement at day 28, and the difference was not significant between the two groups. At day 2, 16.5% of esketamine patients achieved a 50% or greater reduction in MADRS, compared with 10.8% in the placebo arm, though the significance of this difference could not be determined.
A post hoc analysis showed that 69.3% of participants in the esketamine group had responded by day 28, compared with 52.0% (odds ratio, 2.4; 95% confidence interval, 1.30-4.54; number needed to treat, 6). More subjects in the treatment group were in remission at day 28 (52.5% vs. 31.0%; NNT, 5).
The most common treatment-emergent adverse events in the esketamine group were dizziness (20.9%), dissociation (26.1%), dysgeusia (24.3%), vertigo (26.1%), and nausea (26.1%).
The study was funded by Janssen Research and Development. Dr. Sanacora was an investigator on previous Janssen-funded studies and has consulted for Janssen. Dr. Schatzberg has received research support from and consulted for Janssen, and has consulted for numerous other companies. Dr. Thase has received research support from Janssen and consulted for a wide range of pharmaceutical companies.
SOURCE: Popova V et al. APA 2019, Am J Psychiatry 2019 May. doi: 10.1176/appi.ajp.2019.19020172.
Concern raised about drug’s abuse potential
Concern raised about drug’s abuse potential
SAN FRANCISCO – In treatment-resistant depression, a switch to a new antidepressant combined with inhaled esketamine (Spravato) led to better symptom improvement than did a switch to a new antidepressant plus placebo, results from a new trial show. The treatment effect of esketamine was modest but had a number needed to treat for remission of just five.
About 30% of patients with major depressive disorder are treatment resistant. They are at risk of suicidal behavior and self-harm during the interval between starting a new medication and onset of efficacy. Esketamine, with its rapid onset of efficacy associated with its stimulation of synaptogenesis through inhibition of the N-methyl-D-aspartate receptor, gained Food and Drug Administration approval in March for the treatment of treatment-resistant depression in adults.
The findings were part of a phase 3 study presented at a press conference at the annual meeting of the American Psychiatric Association and simultaneously published in the American Journal of Psychiatry (2019. doi: 10.1176/appi.ajp.2019.19020172).
Adding esketamine to the start of a new antidepressant was associated with a small improvement in symptoms (effect size, 0.30), and this benefit did not continue to accrue further advantage past the original separation, which led to some skepticism from the author of an accompanying editorial (Am J Psychiatry. 2019 May. doi: 10.1176/appi.ajp.2019.19040423). “The question is, do you need to keep a patient on the drug past 48 hours? There is no statistically significant difference (in patient response) past the first 48 hours. That to me is a concern,” said Alan F. Schatzberg, MD, at the press conference.
Dr. Schatzberg, who is a professor of psychiatry at the Stanford (Calif.) University, also expressed concern about the potential for abuse with esketamine, as well as withdrawal after discontinuation. “I think the drug ought to be used, but it needs to be recommended with considerable caution. We have not answered the many questions that are needed in a drug of potential abuse,” Dr. Schatzberg added.
Study coauthor Michael E. Thase, MD, who also presented at the press conference, discussed the possibility of alterations to the treatment regimen. “I have a hunch you can see this (positive response) within first week or 2, and you can at least concentrate the resource on patients that gain the largest benefit. We can be smarter about it,” said Dr. Thase, who is a professor of psychiatry at the University of Pennsylvania, Philadelphia. He predicted that protocols eventually will be put in place to streamline intranasal ketamine treatment.
Regardless of the effect size, the study produced high remission and response rates in this difficult to treat population, which is welcome news to Gerard Sanacora, MD, PhD, a professor of psychiatry at Yale University, New Haven, Conn., and director of the Yale Depression Research Program. he said in an interview.
In the phase 3 study, researchers randomized 223 patients from five countries to receive esketamine or placebo, along with either an SSRI (escitalopram or sertraline) or a selective norepinephrine reuptake inhibitor (duloxetine or venlafaxine extended release), based on investigator choice.
To be eligible, participants had to have failed two previous trials of antidepressants. After a 4-week observation period, patients began a 4-week regimen of a new antidepressant combined with twice-weekly nasal esketamine or a placebo.
Subjects in the treatment arm received esketamine on day 1 of the treatment phase with a 56-mg dose. On day 4, 45.8% were increased to a dose of 84 mg, and 66.7% were at the 84-mg dose at the end of the treatment phase.
From baseline to day 28, the esketamine group had a greater decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score (difference of least square means, –4.0; P = .020; effect size, 0.30). A scatter plot of individual MADRS data during that period revealed rapid onset and increasing rapid response during repeated dosing 24 hours after dosing (least square mean between-group difference, –3.3), day 8 (–2.9), day 15 (–2.0), and day 22 (–4.0; P = .020).
Researchers also examined subjects who achieved at least a 50% reduction MADRS score at day 2 and maintained the improvement at day 28, and the difference was not significant between the two groups. At day 2, 16.5% of esketamine patients achieved a 50% or greater reduction in MADRS, compared with 10.8% in the placebo arm, though the significance of this difference could not be determined.
A post hoc analysis showed that 69.3% of participants in the esketamine group had responded by day 28, compared with 52.0% (odds ratio, 2.4; 95% confidence interval, 1.30-4.54; number needed to treat, 6). More subjects in the treatment group were in remission at day 28 (52.5% vs. 31.0%; NNT, 5).
The most common treatment-emergent adverse events in the esketamine group were dizziness (20.9%), dissociation (26.1%), dysgeusia (24.3%), vertigo (26.1%), and nausea (26.1%).
The study was funded by Janssen Research and Development. Dr. Sanacora was an investigator on previous Janssen-funded studies and has consulted for Janssen. Dr. Schatzberg has received research support from and consulted for Janssen, and has consulted for numerous other companies. Dr. Thase has received research support from Janssen and consulted for a wide range of pharmaceutical companies.
SOURCE: Popova V et al. APA 2019, Am J Psychiatry 2019 May. doi: 10.1176/appi.ajp.2019.19020172.
SAN FRANCISCO – In treatment-resistant depression, a switch to a new antidepressant combined with inhaled esketamine (Spravato) led to better symptom improvement than did a switch to a new antidepressant plus placebo, results from a new trial show. The treatment effect of esketamine was modest but had a number needed to treat for remission of just five.
About 30% of patients with major depressive disorder are treatment resistant. They are at risk of suicidal behavior and self-harm during the interval between starting a new medication and onset of efficacy. Esketamine, with its rapid onset of efficacy associated with its stimulation of synaptogenesis through inhibition of the N-methyl-D-aspartate receptor, gained Food and Drug Administration approval in March for the treatment of treatment-resistant depression in adults.
The findings were part of a phase 3 study presented at a press conference at the annual meeting of the American Psychiatric Association and simultaneously published in the American Journal of Psychiatry (2019. doi: 10.1176/appi.ajp.2019.19020172).
Adding esketamine to the start of a new antidepressant was associated with a small improvement in symptoms (effect size, 0.30), and this benefit did not continue to accrue further advantage past the original separation, which led to some skepticism from the author of an accompanying editorial (Am J Psychiatry. 2019 May. doi: 10.1176/appi.ajp.2019.19040423). “The question is, do you need to keep a patient on the drug past 48 hours? There is no statistically significant difference (in patient response) past the first 48 hours. That to me is a concern,” said Alan F. Schatzberg, MD, at the press conference.
Dr. Schatzberg, who is a professor of psychiatry at the Stanford (Calif.) University, also expressed concern about the potential for abuse with esketamine, as well as withdrawal after discontinuation. “I think the drug ought to be used, but it needs to be recommended with considerable caution. We have not answered the many questions that are needed in a drug of potential abuse,” Dr. Schatzberg added.
Study coauthor Michael E. Thase, MD, who also presented at the press conference, discussed the possibility of alterations to the treatment regimen. “I have a hunch you can see this (positive response) within first week or 2, and you can at least concentrate the resource on patients that gain the largest benefit. We can be smarter about it,” said Dr. Thase, who is a professor of psychiatry at the University of Pennsylvania, Philadelphia. He predicted that protocols eventually will be put in place to streamline intranasal ketamine treatment.
Regardless of the effect size, the study produced high remission and response rates in this difficult to treat population, which is welcome news to Gerard Sanacora, MD, PhD, a professor of psychiatry at Yale University, New Haven, Conn., and director of the Yale Depression Research Program. he said in an interview.
In the phase 3 study, researchers randomized 223 patients from five countries to receive esketamine or placebo, along with either an SSRI (escitalopram or sertraline) or a selective norepinephrine reuptake inhibitor (duloxetine or venlafaxine extended release), based on investigator choice.
To be eligible, participants had to have failed two previous trials of antidepressants. After a 4-week observation period, patients began a 4-week regimen of a new antidepressant combined with twice-weekly nasal esketamine or a placebo.
Subjects in the treatment arm received esketamine on day 1 of the treatment phase with a 56-mg dose. On day 4, 45.8% were increased to a dose of 84 mg, and 66.7% were at the 84-mg dose at the end of the treatment phase.
From baseline to day 28, the esketamine group had a greater decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) score (difference of least square means, –4.0; P = .020; effect size, 0.30). A scatter plot of individual MADRS data during that period revealed rapid onset and increasing rapid response during repeated dosing 24 hours after dosing (least square mean between-group difference, –3.3), day 8 (–2.9), day 15 (–2.0), and day 22 (–4.0; P = .020).
Researchers also examined subjects who achieved at least a 50% reduction MADRS score at day 2 and maintained the improvement at day 28, and the difference was not significant between the two groups. At day 2, 16.5% of esketamine patients achieved a 50% or greater reduction in MADRS, compared with 10.8% in the placebo arm, though the significance of this difference could not be determined.
A post hoc analysis showed that 69.3% of participants in the esketamine group had responded by day 28, compared with 52.0% (odds ratio, 2.4; 95% confidence interval, 1.30-4.54; number needed to treat, 6). More subjects in the treatment group were in remission at day 28 (52.5% vs. 31.0%; NNT, 5).
The most common treatment-emergent adverse events in the esketamine group were dizziness (20.9%), dissociation (26.1%), dysgeusia (24.3%), vertigo (26.1%), and nausea (26.1%).
The study was funded by Janssen Research and Development. Dr. Sanacora was an investigator on previous Janssen-funded studies and has consulted for Janssen. Dr. Schatzberg has received research support from and consulted for Janssen, and has consulted for numerous other companies. Dr. Thase has received research support from Janssen and consulted for a wide range of pharmaceutical companies.
SOURCE: Popova V et al. APA 2019, Am J Psychiatry 2019 May. doi: 10.1176/appi.ajp.2019.19020172.
REPORTING FROM APA 2019
Key clinical point: Pivotal study reports a modest benefit to symptoms when inhaled esketamine is combined with a new antidepressant in treatment-resistant depression.
Major finding: Combining esketamine with a new antidepressant led to a small improvement in symptoms, compared with the antidepressant alone (effect size, 0.30).
Study details: Results of a randomized, controlled trial (n = 223).
Disclosures: The study was funded by Janssen Research and Development. Dr. Sanacora was an investigator on previous Janssen-funded studies and has consulted for Janssen. Dr. Schatzberg has received research support from and consulted for Janssen, and has consulted for numerous other companies. Dr. Thase has received research support from Janssen and consulted for a wide range of pharmaceutical companies.
Source: Popova V et al. APA 2019, Am J Psychiatry. 2019 May. doi: 10.1176/appi.ajp.2019.19020172.
The effects persist for children who witnessed 9/11
SAN FRANCISCO – according to a case-control study presented at the American Psychiatric Association annual meeting.
The investigation included 942 people who, as children under 18 years old, were in school below Canal Street in lower Manhattan when the World Trade Center was attacked. They saw the towers collapse and were evacuated from the area, but did not lose a parent. Now 18-36 years old, they were interviewed in their homes and asked to filled out questionnaires about psychiatric and physical problems. The outcomes were compared with 563 age- and gender-matched controls who were in school in Queens at the time.
In turns out that “it made a huge difference whether you were there or not. Being there had much more impact than hearing about it or watching it on TV,” said lead investigator Lawrence Amsel, MD, an assistant professor of clinical psychiatry at Columbia University in New York.
Adults who witnessed the attacks as children were more than twice as likely to have panic disorder, marijuana use disorder, and separation anxiety, which is uncommon in adults; anxiety disorders were more prevalent, as well.
They also were almost half as likely to be living with a spouse or partner, and half as likely to be living independently. “That kind of goes along with the separation anxiety; these kids were more likely to be afraid of moving away from their family and breaking out into their own lives,” Dr. Amsel said.
Overall, 36% had a psychiatric disorder, and 27% had a physical problem, such as diabetes, asthma, or eczema; 14% had both. Among adults who were in Queens during the attacks, 28% had a psychiatric disorder, and 11% a physical problem; 4% were comorbid.
The increased odds of physical-psychiatric comorbidity among witnesses (adjusted odds ratio, 4.60; 95% confidence interval, 2.75- 7.71; P less than .0001) “was not due simply to an increase in physical conditions,” according to the study team.
“This was a single event,” Dr. Amsel said, but for children who witnessed it, “it’s had effects for decades. There were huge amounts of money sent in, and lots of health care for kids who were down there, but despite that, we have this. We think the PTSD morphed into” long-term issues, Dr. Amsel said.
“We know that one of the reasons people get psychiatric disorders” after trauma “is that they generalize the fear; the message to your brain is that everything is dangerous. You’ve got to intervene there and break the association between the fear system and everything else, so that life is still safe,” he said.
There’s an added element with human violence. “Life may be unsafe” after a natural disaster, “but you know that human beings are good and helpful. With a terrorist attack, you stop trusting people,” he said.
Cognitive behavioral therapy could help, among other approaches. It also might be helpful to teach resilience to schoolchildren, just like biology and algebra, he said.
Cases and controls were evenly split between the sexes. Just over 40% of subjects in both groups were white, followed by Hispanics, Asians, and blacks. The majority of households were middle income.
The next step is to break the results down by age, ethnicity, socioeconomic factors, and support systems. The team will run blood work and heart and lung tests on the subjects to nail down the physical problems reported by witnesses. There are concerns about the lingering effects of the dust plume.
The work is funded by the federal government. Dr. Amsel didn’t have any relevant financial disclosures.
SAN FRANCISCO – according to a case-control study presented at the American Psychiatric Association annual meeting.
The investigation included 942 people who, as children under 18 years old, were in school below Canal Street in lower Manhattan when the World Trade Center was attacked. They saw the towers collapse and were evacuated from the area, but did not lose a parent. Now 18-36 years old, they were interviewed in their homes and asked to filled out questionnaires about psychiatric and physical problems. The outcomes were compared with 563 age- and gender-matched controls who were in school in Queens at the time.
In turns out that “it made a huge difference whether you were there or not. Being there had much more impact than hearing about it or watching it on TV,” said lead investigator Lawrence Amsel, MD, an assistant professor of clinical psychiatry at Columbia University in New York.
Adults who witnessed the attacks as children were more than twice as likely to have panic disorder, marijuana use disorder, and separation anxiety, which is uncommon in adults; anxiety disorders were more prevalent, as well.
They also were almost half as likely to be living with a spouse or partner, and half as likely to be living independently. “That kind of goes along with the separation anxiety; these kids were more likely to be afraid of moving away from their family and breaking out into their own lives,” Dr. Amsel said.
Overall, 36% had a psychiatric disorder, and 27% had a physical problem, such as diabetes, asthma, or eczema; 14% had both. Among adults who were in Queens during the attacks, 28% had a psychiatric disorder, and 11% a physical problem; 4% were comorbid.
The increased odds of physical-psychiatric comorbidity among witnesses (adjusted odds ratio, 4.60; 95% confidence interval, 2.75- 7.71; P less than .0001) “was not due simply to an increase in physical conditions,” according to the study team.
“This was a single event,” Dr. Amsel said, but for children who witnessed it, “it’s had effects for decades. There were huge amounts of money sent in, and lots of health care for kids who were down there, but despite that, we have this. We think the PTSD morphed into” long-term issues, Dr. Amsel said.
“We know that one of the reasons people get psychiatric disorders” after trauma “is that they generalize the fear; the message to your brain is that everything is dangerous. You’ve got to intervene there and break the association between the fear system and everything else, so that life is still safe,” he said.
There’s an added element with human violence. “Life may be unsafe” after a natural disaster, “but you know that human beings are good and helpful. With a terrorist attack, you stop trusting people,” he said.
Cognitive behavioral therapy could help, among other approaches. It also might be helpful to teach resilience to schoolchildren, just like biology and algebra, he said.
Cases and controls were evenly split between the sexes. Just over 40% of subjects in both groups were white, followed by Hispanics, Asians, and blacks. The majority of households were middle income.
The next step is to break the results down by age, ethnicity, socioeconomic factors, and support systems. The team will run blood work and heart and lung tests on the subjects to nail down the physical problems reported by witnesses. There are concerns about the lingering effects of the dust plume.
The work is funded by the federal government. Dr. Amsel didn’t have any relevant financial disclosures.
SAN FRANCISCO – according to a case-control study presented at the American Psychiatric Association annual meeting.
The investigation included 942 people who, as children under 18 years old, were in school below Canal Street in lower Manhattan when the World Trade Center was attacked. They saw the towers collapse and were evacuated from the area, but did not lose a parent. Now 18-36 years old, they were interviewed in their homes and asked to filled out questionnaires about psychiatric and physical problems. The outcomes were compared with 563 age- and gender-matched controls who were in school in Queens at the time.
In turns out that “it made a huge difference whether you were there or not. Being there had much more impact than hearing about it or watching it on TV,” said lead investigator Lawrence Amsel, MD, an assistant professor of clinical psychiatry at Columbia University in New York.
Adults who witnessed the attacks as children were more than twice as likely to have panic disorder, marijuana use disorder, and separation anxiety, which is uncommon in adults; anxiety disorders were more prevalent, as well.
They also were almost half as likely to be living with a spouse or partner, and half as likely to be living independently. “That kind of goes along with the separation anxiety; these kids were more likely to be afraid of moving away from their family and breaking out into their own lives,” Dr. Amsel said.
Overall, 36% had a psychiatric disorder, and 27% had a physical problem, such as diabetes, asthma, or eczema; 14% had both. Among adults who were in Queens during the attacks, 28% had a psychiatric disorder, and 11% a physical problem; 4% were comorbid.
The increased odds of physical-psychiatric comorbidity among witnesses (adjusted odds ratio, 4.60; 95% confidence interval, 2.75- 7.71; P less than .0001) “was not due simply to an increase in physical conditions,” according to the study team.
“This was a single event,” Dr. Amsel said, but for children who witnessed it, “it’s had effects for decades. There were huge amounts of money sent in, and lots of health care for kids who were down there, but despite that, we have this. We think the PTSD morphed into” long-term issues, Dr. Amsel said.
“We know that one of the reasons people get psychiatric disorders” after trauma “is that they generalize the fear; the message to your brain is that everything is dangerous. You’ve got to intervene there and break the association between the fear system and everything else, so that life is still safe,” he said.
There’s an added element with human violence. “Life may be unsafe” after a natural disaster, “but you know that human beings are good and helpful. With a terrorist attack, you stop trusting people,” he said.
Cognitive behavioral therapy could help, among other approaches. It also might be helpful to teach resilience to schoolchildren, just like biology and algebra, he said.
Cases and controls were evenly split between the sexes. Just over 40% of subjects in both groups were white, followed by Hispanics, Asians, and blacks. The majority of households were middle income.
The next step is to break the results down by age, ethnicity, socioeconomic factors, and support systems. The team will run blood work and heart and lung tests on the subjects to nail down the physical problems reported by witnesses. There are concerns about the lingering effects of the dust plume.
The work is funded by the federal government. Dr. Amsel didn’t have any relevant financial disclosures.
REPORTING FROM APA 2019
Hip-hop offers lens into psyche of black boys, men
SAN FRANCISCO – The lyrics found in hip-hop can help mental health professionals understand the triumphs and trauma experienced by African American boys and men, Sarah Y. Vinson, MD, said at the annual meeting of the American Psychiatric Association. This understanding can enable clinicians to recognize hopelessness and pain in those patients that they otherwise might have missed.
In this video, Dr. Vinson said her session at the APA meeting looked at the history of hip-hop and focused on the perspectives embedded in the work of several artists/groups, including N.W.A, Tupac Shakur, Childish Gambino (aka Donald Glover), J. Cole, and Kendrick Lamar.
One of the take-home points for clinicians, Dr. Vinson said, is that hip-hop, an art form that has spread across the world, came out of resilience. Another is that suicidality in black men might not look the same as it does in other patients. “It doesn’t necessarily look like cutting your own wrists or having thoughts of killing yourself – it may look like reckless behaviors that put you at risk of being killed by somebody else.”
Dr. Vinson, who is triple boarded in child and adolescent, adult, and forensic psychiatry, is in private practice in Atlanta. She had no financial disclosures.
SAN FRANCISCO – The lyrics found in hip-hop can help mental health professionals understand the triumphs and trauma experienced by African American boys and men, Sarah Y. Vinson, MD, said at the annual meeting of the American Psychiatric Association. This understanding can enable clinicians to recognize hopelessness and pain in those patients that they otherwise might have missed.
In this video, Dr. Vinson said her session at the APA meeting looked at the history of hip-hop and focused on the perspectives embedded in the work of several artists/groups, including N.W.A, Tupac Shakur, Childish Gambino (aka Donald Glover), J. Cole, and Kendrick Lamar.
One of the take-home points for clinicians, Dr. Vinson said, is that hip-hop, an art form that has spread across the world, came out of resilience. Another is that suicidality in black men might not look the same as it does in other patients. “It doesn’t necessarily look like cutting your own wrists or having thoughts of killing yourself – it may look like reckless behaviors that put you at risk of being killed by somebody else.”
Dr. Vinson, who is triple boarded in child and adolescent, adult, and forensic psychiatry, is in private practice in Atlanta. She had no financial disclosures.
SAN FRANCISCO – The lyrics found in hip-hop can help mental health professionals understand the triumphs and trauma experienced by African American boys and men, Sarah Y. Vinson, MD, said at the annual meeting of the American Psychiatric Association. This understanding can enable clinicians to recognize hopelessness and pain in those patients that they otherwise might have missed.
In this video, Dr. Vinson said her session at the APA meeting looked at the history of hip-hop and focused on the perspectives embedded in the work of several artists/groups, including N.W.A, Tupac Shakur, Childish Gambino (aka Donald Glover), J. Cole, and Kendrick Lamar.
One of the take-home points for clinicians, Dr. Vinson said, is that hip-hop, an art form that has spread across the world, came out of resilience. Another is that suicidality in black men might not look the same as it does in other patients. “It doesn’t necessarily look like cutting your own wrists or having thoughts of killing yourself – it may look like reckless behaviors that put you at risk of being killed by somebody else.”
Dr. Vinson, who is triple boarded in child and adolescent, adult, and forensic psychiatry, is in private practice in Atlanta. She had no financial disclosures.
REPORTING FROM APA 2019
Youth suicide: Rates rising more rapidly in girls
Youth suicide rates appear to be increasing faster in girls than in boys, narrowing the historical gap between the two, according to research published in JAMA Network Open.
From 1999 to 2014, suicide rates in the United States have increased by 33%, but the incidence always has been higher among men than women in all age groups.
Recent reports suggesting that suicide rates were increasing in girls prompted Donna A. Ruch, PhD, from the the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, and her coauthors to undertake a cross-sectional study of all suicides in the United States among individuals aged 10-19 years, between 1975 and 2016.
During that time there were a total of 85,051 suicide deaths in youth aged 10-19 years; approximately 80% of the deaths were in males, representing a nearly fourfold higher rate in males than females (incidence rate ratio [IRR], 3.82).
From 1975 to 1993, researchers noted a 5.4% increase each year in suicide rates among girls aged 10-14 years and a 4.5% increase among boys in the same age group. From 2003-2007, suicide rates among both sexes declined until 2007, at which point the suicide rates among girls increased annually by 12.7%, compared with 7.1% among boys.
Overall, the male to female incidence rate ratio among youth aged 10-14 decreased from 3.14 in 1975-1991 to 1.80 from 2007-2016, a statistically significant difference.
“The narrowing gap between male and female rates of suicide was most pronounced among youth aged 10 to 14 years, underscoring the importance of early prevention efforts that take both sex and developmental level into consideration,” the authors wrote.
Ethnicity was an influence, with the most consistent declining trend in male to female incidence rate ratio seen in non-Hispanic white youth, and also was significant in non-Hispanic youth of other races. There was no significant change in the male to female incidence rate ratio seen with younger non-Hispanic black youth or Hispanic youth.
Among youth aged 15-19, the differences between male and female suicide rates decreased significantly in non-Hispanic youth of other race, and a significant downward trend also was seen in Hispanic youth.
The analysis also looked at method of suicide. The results showed that while the male to female incidence rate ratio for shooting suicides increased significantly in youth aged 15-19 years, it decreased for suicide by hanging or suffocation across all ages groups.
“Future research to identify sex-specific risk factors for youth suicide and distinct mechanisms of suicide in male and female individuals within racial/ethnic groups could lead to improved suicide prevention strategies and interventions,” the authors wrote.
One author was supported by a grant from the National Institute of Mental Health, and declared unpaid board membership for the scientific advisory board of a mental health company. No other conflicts of interest were declared.
SOURCE: Ruch D et al. JAMA Network Open. 2019, May 17. doi:10.1001/jamanetworkopen.2019.3886.
Rates of suicide among girls aged 10-14 have tripled between 1999-2014, and this new study raises questions about what is driving this trend. Fingers have been pointed at the rise of social media use, particularly among this age group, as a clear and powerful social change that has occurred over the same period. But social media use has risen among both sexes, so why is it disproportionately impacting girls?
It may be that girls’ social media use is more likely to result in interpersonal stress, but also that girls are known to use social media more frequently and are more likely to experience cyberbullying. Research also suggests that girls with depression experience more negative comments from peers on social media compared to boys with depression, suggesting that increasing social media use may make young girls more vulnerable to suicide.
Joan Luby, MD, and Sarah Kertz, PhD, are from the department of psychiatry at Washington University in St. Louis. These comments are adapted from an editorial accompanying the article by Ruch et al. (JAMA Network Open. 2019, May 17. doi: 10.1001/jamanetworkopen.2019.3916). Dr Luby reported grants from the National Institute of Mental Health. No other disclosures were reported.
Rates of suicide among girls aged 10-14 have tripled between 1999-2014, and this new study raises questions about what is driving this trend. Fingers have been pointed at the rise of social media use, particularly among this age group, as a clear and powerful social change that has occurred over the same period. But social media use has risen among both sexes, so why is it disproportionately impacting girls?
It may be that girls’ social media use is more likely to result in interpersonal stress, but also that girls are known to use social media more frequently and are more likely to experience cyberbullying. Research also suggests that girls with depression experience more negative comments from peers on social media compared to boys with depression, suggesting that increasing social media use may make young girls more vulnerable to suicide.
Joan Luby, MD, and Sarah Kertz, PhD, are from the department of psychiatry at Washington University in St. Louis. These comments are adapted from an editorial accompanying the article by Ruch et al. (JAMA Network Open. 2019, May 17. doi: 10.1001/jamanetworkopen.2019.3916). Dr Luby reported grants from the National Institute of Mental Health. No other disclosures were reported.
Rates of suicide among girls aged 10-14 have tripled between 1999-2014, and this new study raises questions about what is driving this trend. Fingers have been pointed at the rise of social media use, particularly among this age group, as a clear and powerful social change that has occurred over the same period. But social media use has risen among both sexes, so why is it disproportionately impacting girls?
It may be that girls’ social media use is more likely to result in interpersonal stress, but also that girls are known to use social media more frequently and are more likely to experience cyberbullying. Research also suggests that girls with depression experience more negative comments from peers on social media compared to boys with depression, suggesting that increasing social media use may make young girls more vulnerable to suicide.
Joan Luby, MD, and Sarah Kertz, PhD, are from the department of psychiatry at Washington University in St. Louis. These comments are adapted from an editorial accompanying the article by Ruch et al. (JAMA Network Open. 2019, May 17. doi: 10.1001/jamanetworkopen.2019.3916). Dr Luby reported grants from the National Institute of Mental Health. No other disclosures were reported.
Youth suicide rates appear to be increasing faster in girls than in boys, narrowing the historical gap between the two, according to research published in JAMA Network Open.
From 1999 to 2014, suicide rates in the United States have increased by 33%, but the incidence always has been higher among men than women in all age groups.
Recent reports suggesting that suicide rates were increasing in girls prompted Donna A. Ruch, PhD, from the the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, and her coauthors to undertake a cross-sectional study of all suicides in the United States among individuals aged 10-19 years, between 1975 and 2016.
During that time there were a total of 85,051 suicide deaths in youth aged 10-19 years; approximately 80% of the deaths were in males, representing a nearly fourfold higher rate in males than females (incidence rate ratio [IRR], 3.82).
From 1975 to 1993, researchers noted a 5.4% increase each year in suicide rates among girls aged 10-14 years and a 4.5% increase among boys in the same age group. From 2003-2007, suicide rates among both sexes declined until 2007, at which point the suicide rates among girls increased annually by 12.7%, compared with 7.1% among boys.
Overall, the male to female incidence rate ratio among youth aged 10-14 decreased from 3.14 in 1975-1991 to 1.80 from 2007-2016, a statistically significant difference.
“The narrowing gap between male and female rates of suicide was most pronounced among youth aged 10 to 14 years, underscoring the importance of early prevention efforts that take both sex and developmental level into consideration,” the authors wrote.
Ethnicity was an influence, with the most consistent declining trend in male to female incidence rate ratio seen in non-Hispanic white youth, and also was significant in non-Hispanic youth of other races. There was no significant change in the male to female incidence rate ratio seen with younger non-Hispanic black youth or Hispanic youth.
Among youth aged 15-19, the differences between male and female suicide rates decreased significantly in non-Hispanic youth of other race, and a significant downward trend also was seen in Hispanic youth.
The analysis also looked at method of suicide. The results showed that while the male to female incidence rate ratio for shooting suicides increased significantly in youth aged 15-19 years, it decreased for suicide by hanging or suffocation across all ages groups.
“Future research to identify sex-specific risk factors for youth suicide and distinct mechanisms of suicide in male and female individuals within racial/ethnic groups could lead to improved suicide prevention strategies and interventions,” the authors wrote.
One author was supported by a grant from the National Institute of Mental Health, and declared unpaid board membership for the scientific advisory board of a mental health company. No other conflicts of interest were declared.
SOURCE: Ruch D et al. JAMA Network Open. 2019, May 17. doi:10.1001/jamanetworkopen.2019.3886.
Youth suicide rates appear to be increasing faster in girls than in boys, narrowing the historical gap between the two, according to research published in JAMA Network Open.
From 1999 to 2014, suicide rates in the United States have increased by 33%, but the incidence always has been higher among men than women in all age groups.
Recent reports suggesting that suicide rates were increasing in girls prompted Donna A. Ruch, PhD, from the the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, and her coauthors to undertake a cross-sectional study of all suicides in the United States among individuals aged 10-19 years, between 1975 and 2016.
During that time there were a total of 85,051 suicide deaths in youth aged 10-19 years; approximately 80% of the deaths were in males, representing a nearly fourfold higher rate in males than females (incidence rate ratio [IRR], 3.82).
From 1975 to 1993, researchers noted a 5.4% increase each year in suicide rates among girls aged 10-14 years and a 4.5% increase among boys in the same age group. From 2003-2007, suicide rates among both sexes declined until 2007, at which point the suicide rates among girls increased annually by 12.7%, compared with 7.1% among boys.
Overall, the male to female incidence rate ratio among youth aged 10-14 decreased from 3.14 in 1975-1991 to 1.80 from 2007-2016, a statistically significant difference.
“The narrowing gap between male and female rates of suicide was most pronounced among youth aged 10 to 14 years, underscoring the importance of early prevention efforts that take both sex and developmental level into consideration,” the authors wrote.
Ethnicity was an influence, with the most consistent declining trend in male to female incidence rate ratio seen in non-Hispanic white youth, and also was significant in non-Hispanic youth of other races. There was no significant change in the male to female incidence rate ratio seen with younger non-Hispanic black youth or Hispanic youth.
Among youth aged 15-19, the differences between male and female suicide rates decreased significantly in non-Hispanic youth of other race, and a significant downward trend also was seen in Hispanic youth.
The analysis also looked at method of suicide. The results showed that while the male to female incidence rate ratio for shooting suicides increased significantly in youth aged 15-19 years, it decreased for suicide by hanging or suffocation across all ages groups.
“Future research to identify sex-specific risk factors for youth suicide and distinct mechanisms of suicide in male and female individuals within racial/ethnic groups could lead to improved suicide prevention strategies and interventions,” the authors wrote.
One author was supported by a grant from the National Institute of Mental Health, and declared unpaid board membership for the scientific advisory board of a mental health company. No other conflicts of interest were declared.
SOURCE: Ruch D et al. JAMA Network Open. 2019, May 17. doi:10.1001/jamanetworkopen.2019.3886.
FROM JAMA NETWORK OPEN
Key clinical point: Suicide rates are rising faster among girls than boys.
Major finding: Suicide rates in girls have increased annually by 12.7% since 2007, compared with 7.1% among boys.
Study details: Cross-sectional study of 85,051 suicide deaths in youth aged 10-19 years.
Disclosures: One author was supported by a grant from the National Institute of Mental Health, and declared unpaid board membership for the scientific advisory board of a mental health company. No other conflicts of interest were declared.
Source: Ruch D et al. JAMA Network Open 2019, May 17. doi: 10.1001/jamanetworkopen.2019.3886.
Is there an epidemic of anxiety and depression among today’s adolescents?
It seems that every week there are fresh headlines about a mental health crisis in children and adolescents, reporting exploding rates of severe anxiety and depression in youth. These reports raise the question of whether or not there has been a significant change in their incidence: Are more children developing depressive and anxiety disorders? Are they having greater difficulty accessing care? Are the disorders more severe than they were in the past? Or are young people failing to develop appropriate skills to manage anxiety, sadness, and other forms of distress that are a normal (if unpleasant) part of life? These are important questions, as they will help us to advocate for the proper services to address the public health challenge that underlies this “epidemic.”
What do the data show?
It is important to start by noting that epidemiologic data on child psychiatry in the United States are not as robust as we might like. It was only in 1999 that the Surgeon General’s Report on Mental Health articulated that there was a need for a more systematic approach to collecting epidemiologic data on psychiatric illness in children and adolescents. At that time, the consensus was that approximately one in five children would develop a psychiatric illness by the age of 18 and that approximately 5% of all children would experience a severe or persistent mental illness.1 In the 2 decades since then there have been expanded efforts to collect data, including the addition of an adolescent supplement to the National Comorbidity Survey sponsored by the National Institute of Mental Health, although our current estimates still are based on representative surveys of thousands of U.S. children and teenagers, often with questionnaires filled out by their parents. Thus, we may have overestimates of some behavioral disorders that are obvious and of concern to parents or underestimates of certain internalizing disorders such as depression that can remain unstated and contained in the mind of the adolescent. And even with accurate current estimates, our ability to make statements about trends or changes in rates of disease is limited by the very short period of time in which we have been studying these disease rates in U.S. youth, some changes in definitions, and the unknown impact of increasing recognition rather than true change in incidence.
What is unequivocally clear is that psychiatric illnesses usually present in youth and that these illnesses are among the most common illnesses of youth. Current estimates are that nearly one in four young people will have a psychiatric illness (by The Diagnostic and Statistical Manual of Mental Disorders [DSM], Fifth Edition criteria) by the time they turn 18,2 although only 10% of youth will experience an illness that meets the Substance Abuse and Mental Health Services Administration criteria for a serious emotional disturbance, or one that has a substantial impact on a child’s ability to function socially, emotionally, and academically.3
While it once was believed that children did not experience psychiatric illness, we now know that the majority of psychiatric illnesses present during childhood, adolescence, and young adulthood. The Centers for Disease Control and Prevention estimates that 50% of lifetime psychiatric illness has presented by the age of 15 years and 75% by the age of 24. Only one-quarter of all lifetime psychiatric illnesses emerge in full adulthood, or after the age of 24. Early diagnosis and treatment can make a significant difference in the overall impact of serious illnesses such as schizophrenia and bipolar disorder. We also can state with confidence that anxiety disorders are the most common psychiatric illnesses of youth, making up over 30% of all diagnoses, followed by disorders of behavior (19%), mood (14%), and then substance use (11%).4 Even compared with asthma (with a prevalence of approximately 11%), widely considered to be among the most common disease of childhood, psychiatric illnesses are the most common in youth.
The question then is whether these numbers are changing. The National Comorbidity Survey conducted in 2014 found that the incidence of major depressive episodes in adolescents had increased significantly between 2005 and 2014, from 9% to 11%.5 This is a survey of nearly 200,000 youth across the United States, interviewed by phone with a structured questionnaire assessing their (self-reported) DSM criteria for a major depressive episode, along with other illnesses. During this time frame, access to specialty mental health providers increased among adolescents, alongside their rate of use of psychiatric medications and inpatient hospitalization.
In Europe, where they have more robust epidemiological data, there also has been a public perception of an increase in depression in adolescents. Studies there have suggested that prevalence rates have not changed significantly, and that the problem actually may be a function of a growing population, greater public awareness, and higher rates of psychological distress.6
In the United States, it is difficult to place the prevalence rates in a meaningful context, given the shorter time frame during which we have been following these rates in young people. It is worth highlighting that although the rates at which young people are gaining access to mental health clinicians, being prescribed medications, and being admitted to psychiatric hospitals all have increased, there has not been an associated decrease in the rate of illness or in the severity of symptoms. It certainly is possible that the increase in use of services by youth is being driven by the increased prevalence of this diagnosis, or it may be that other factors, such as those detailed in international studies, are driving this increase in the incidence of depression.
What about the suicide rate?
Another statistic that addressed the question of whether there may be an epidemic of anxiety and depression in adolescents is the recent increase in the suicide rate. While the rate of completed suicide in 15- to 24-year-olds has been trending upward over the last decade, it is worth noting that this phenomenon appears to be occurring across age groups and is not isolated to adolescents. While adolescents may have a unique underlying set of issues driving the increase, it also may be that factors affecting the entire population (access to firearms, the epidemic of opioid addiction) may be at the core of this worrisome trend.
What about the role of stress?
It is worth noting that there is evidence of an increased rate of psychological distress in adolescents and young adults separate from any increase in the rate of psychiatric illness. Surveys of adolescents in high school and entering college demonstrate higher self-reported rates of severe stress and anxiety. One survey from the American Psychological Association from August 2018 found teenagers reporting higher levels of stress and related sadness and anxiety than the levels among the adults who were surveyed. So more young people are struggling with feelings of anxiety and sadness, without necessarily meeting criteria for a psychiatric illness. This suggests that levels of external stressors may have increased, or that the establishment of healthy coping skills has somehow been compromised in young people, or both.
What can you do as a clinician?
While the broader question of whether actual incidence rates of depression are on the rise will not be settled any time soon, when a patient of yours complains of high levels of stress, anxiety, or feelings of depression, it is very possible that the individual has a psychiatric diagnosis. A quick screening evaluation, using a questionnaire such as the Pediatric Symptom Checklist and/or a brief interview, can indicate if the patient may benefit from a referral.
In addition, all children, including those who have a psychiatric diagnosis, will benefit from a calm, patient, supportive adult who is interested in their distress. It would be very helpful if you are ready to talk about healthy coping skills, and how they are developed over time and only in the setting of actually struggling with some adversity. Help them frame their source of stress as a challenge rather than a threat. Help them identify their meaningful supports, particularly adults who know them well, and offer concrete and practical advice and motivation. And remind them about how self-care is essential to managing the normal stress of adolescence. Have handouts (or virtual ones) ready on good sleep hygiene, the value of exercise, and fact-based nutritional guidance. Offer strategies to manage screen time so that it is a recharging break and not a time sink. Support their identification of other strategies to decompress and manage stress: Are they recharged by time with friends? Exercise? Playing music? Listening to music? Playing video games? They should be building their personalized list, and it should include more active as well as passive strategies. Educate them about the risks of using drugs and alcohol “to relax,” or only having one way of unwinding. Educate your patients and parents about the special value of a mindfulness practice, whether meditation, yoga, or any activity in which they practice a nonjudgmental observation and acceptance of strong emotions.
Accurate prevalence rates can help us consider the statistical probability of a psychiatric diagnosis. By talking with your patients about stressful feelings, you can consider the individual need for a fuller psychiatric evaluation while also helping them reframe their approach to stress to one that is more empowering, adaptive, and healthy.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.
References
1. Mental Health: A Report of the Surgeon General, National Institutes of Mental Health (1999).
2. Prevalence of psychiatric disorders in childhood and adolescence, in “Mental Health Services: A Public Health Perspective,” 2nd ed. (Oxford, UK: Oxford University Press; 2004, pp. 111-28).
3. Public Health Rep. 2006 May-Jun;121(3):303-10.
4. J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):980-9.
5. Pediatrics. 2016 Dec;138(6):e20161878.
6. Depress Anxiety. 2014 Jun;31(6):506-16.
It seems that every week there are fresh headlines about a mental health crisis in children and adolescents, reporting exploding rates of severe anxiety and depression in youth. These reports raise the question of whether or not there has been a significant change in their incidence: Are more children developing depressive and anxiety disorders? Are they having greater difficulty accessing care? Are the disorders more severe than they were in the past? Or are young people failing to develop appropriate skills to manage anxiety, sadness, and other forms of distress that are a normal (if unpleasant) part of life? These are important questions, as they will help us to advocate for the proper services to address the public health challenge that underlies this “epidemic.”
What do the data show?
It is important to start by noting that epidemiologic data on child psychiatry in the United States are not as robust as we might like. It was only in 1999 that the Surgeon General’s Report on Mental Health articulated that there was a need for a more systematic approach to collecting epidemiologic data on psychiatric illness in children and adolescents. At that time, the consensus was that approximately one in five children would develop a psychiatric illness by the age of 18 and that approximately 5% of all children would experience a severe or persistent mental illness.1 In the 2 decades since then there have been expanded efforts to collect data, including the addition of an adolescent supplement to the National Comorbidity Survey sponsored by the National Institute of Mental Health, although our current estimates still are based on representative surveys of thousands of U.S. children and teenagers, often with questionnaires filled out by their parents. Thus, we may have overestimates of some behavioral disorders that are obvious and of concern to parents or underestimates of certain internalizing disorders such as depression that can remain unstated and contained in the mind of the adolescent. And even with accurate current estimates, our ability to make statements about trends or changes in rates of disease is limited by the very short period of time in which we have been studying these disease rates in U.S. youth, some changes in definitions, and the unknown impact of increasing recognition rather than true change in incidence.
What is unequivocally clear is that psychiatric illnesses usually present in youth and that these illnesses are among the most common illnesses of youth. Current estimates are that nearly one in four young people will have a psychiatric illness (by The Diagnostic and Statistical Manual of Mental Disorders [DSM], Fifth Edition criteria) by the time they turn 18,2 although only 10% of youth will experience an illness that meets the Substance Abuse and Mental Health Services Administration criteria for a serious emotional disturbance, or one that has a substantial impact on a child’s ability to function socially, emotionally, and academically.3
While it once was believed that children did not experience psychiatric illness, we now know that the majority of psychiatric illnesses present during childhood, adolescence, and young adulthood. The Centers for Disease Control and Prevention estimates that 50% of lifetime psychiatric illness has presented by the age of 15 years and 75% by the age of 24. Only one-quarter of all lifetime psychiatric illnesses emerge in full adulthood, or after the age of 24. Early diagnosis and treatment can make a significant difference in the overall impact of serious illnesses such as schizophrenia and bipolar disorder. We also can state with confidence that anxiety disorders are the most common psychiatric illnesses of youth, making up over 30% of all diagnoses, followed by disorders of behavior (19%), mood (14%), and then substance use (11%).4 Even compared with asthma (with a prevalence of approximately 11%), widely considered to be among the most common disease of childhood, psychiatric illnesses are the most common in youth.
The question then is whether these numbers are changing. The National Comorbidity Survey conducted in 2014 found that the incidence of major depressive episodes in adolescents had increased significantly between 2005 and 2014, from 9% to 11%.5 This is a survey of nearly 200,000 youth across the United States, interviewed by phone with a structured questionnaire assessing their (self-reported) DSM criteria for a major depressive episode, along with other illnesses. During this time frame, access to specialty mental health providers increased among adolescents, alongside their rate of use of psychiatric medications and inpatient hospitalization.
In Europe, where they have more robust epidemiological data, there also has been a public perception of an increase in depression in adolescents. Studies there have suggested that prevalence rates have not changed significantly, and that the problem actually may be a function of a growing population, greater public awareness, and higher rates of psychological distress.6
In the United States, it is difficult to place the prevalence rates in a meaningful context, given the shorter time frame during which we have been following these rates in young people. It is worth highlighting that although the rates at which young people are gaining access to mental health clinicians, being prescribed medications, and being admitted to psychiatric hospitals all have increased, there has not been an associated decrease in the rate of illness or in the severity of symptoms. It certainly is possible that the increase in use of services by youth is being driven by the increased prevalence of this diagnosis, or it may be that other factors, such as those detailed in international studies, are driving this increase in the incidence of depression.
What about the suicide rate?
Another statistic that addressed the question of whether there may be an epidemic of anxiety and depression in adolescents is the recent increase in the suicide rate. While the rate of completed suicide in 15- to 24-year-olds has been trending upward over the last decade, it is worth noting that this phenomenon appears to be occurring across age groups and is not isolated to adolescents. While adolescents may have a unique underlying set of issues driving the increase, it also may be that factors affecting the entire population (access to firearms, the epidemic of opioid addiction) may be at the core of this worrisome trend.
What about the role of stress?
It is worth noting that there is evidence of an increased rate of psychological distress in adolescents and young adults separate from any increase in the rate of psychiatric illness. Surveys of adolescents in high school and entering college demonstrate higher self-reported rates of severe stress and anxiety. One survey from the American Psychological Association from August 2018 found teenagers reporting higher levels of stress and related sadness and anxiety than the levels among the adults who were surveyed. So more young people are struggling with feelings of anxiety and sadness, without necessarily meeting criteria for a psychiatric illness. This suggests that levels of external stressors may have increased, or that the establishment of healthy coping skills has somehow been compromised in young people, or both.
What can you do as a clinician?
While the broader question of whether actual incidence rates of depression are on the rise will not be settled any time soon, when a patient of yours complains of high levels of stress, anxiety, or feelings of depression, it is very possible that the individual has a psychiatric diagnosis. A quick screening evaluation, using a questionnaire such as the Pediatric Symptom Checklist and/or a brief interview, can indicate if the patient may benefit from a referral.
In addition, all children, including those who have a psychiatric diagnosis, will benefit from a calm, patient, supportive adult who is interested in their distress. It would be very helpful if you are ready to talk about healthy coping skills, and how they are developed over time and only in the setting of actually struggling with some adversity. Help them frame their source of stress as a challenge rather than a threat. Help them identify their meaningful supports, particularly adults who know them well, and offer concrete and practical advice and motivation. And remind them about how self-care is essential to managing the normal stress of adolescence. Have handouts (or virtual ones) ready on good sleep hygiene, the value of exercise, and fact-based nutritional guidance. Offer strategies to manage screen time so that it is a recharging break and not a time sink. Support their identification of other strategies to decompress and manage stress: Are they recharged by time with friends? Exercise? Playing music? Listening to music? Playing video games? They should be building their personalized list, and it should include more active as well as passive strategies. Educate them about the risks of using drugs and alcohol “to relax,” or only having one way of unwinding. Educate your patients and parents about the special value of a mindfulness practice, whether meditation, yoga, or any activity in which they practice a nonjudgmental observation and acceptance of strong emotions.
Accurate prevalence rates can help us consider the statistical probability of a psychiatric diagnosis. By talking with your patients about stressful feelings, you can consider the individual need for a fuller psychiatric evaluation while also helping them reframe their approach to stress to one that is more empowering, adaptive, and healthy.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.
References
1. Mental Health: A Report of the Surgeon General, National Institutes of Mental Health (1999).
2. Prevalence of psychiatric disorders in childhood and adolescence, in “Mental Health Services: A Public Health Perspective,” 2nd ed. (Oxford, UK: Oxford University Press; 2004, pp. 111-28).
3. Public Health Rep. 2006 May-Jun;121(3):303-10.
4. J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):980-9.
5. Pediatrics. 2016 Dec;138(6):e20161878.
6. Depress Anxiety. 2014 Jun;31(6):506-16.
It seems that every week there are fresh headlines about a mental health crisis in children and adolescents, reporting exploding rates of severe anxiety and depression in youth. These reports raise the question of whether or not there has been a significant change in their incidence: Are more children developing depressive and anxiety disorders? Are they having greater difficulty accessing care? Are the disorders more severe than they were in the past? Or are young people failing to develop appropriate skills to manage anxiety, sadness, and other forms of distress that are a normal (if unpleasant) part of life? These are important questions, as they will help us to advocate for the proper services to address the public health challenge that underlies this “epidemic.”
What do the data show?
It is important to start by noting that epidemiologic data on child psychiatry in the United States are not as robust as we might like. It was only in 1999 that the Surgeon General’s Report on Mental Health articulated that there was a need for a more systematic approach to collecting epidemiologic data on psychiatric illness in children and adolescents. At that time, the consensus was that approximately one in five children would develop a psychiatric illness by the age of 18 and that approximately 5% of all children would experience a severe or persistent mental illness.1 In the 2 decades since then there have been expanded efforts to collect data, including the addition of an adolescent supplement to the National Comorbidity Survey sponsored by the National Institute of Mental Health, although our current estimates still are based on representative surveys of thousands of U.S. children and teenagers, often with questionnaires filled out by their parents. Thus, we may have overestimates of some behavioral disorders that are obvious and of concern to parents or underestimates of certain internalizing disorders such as depression that can remain unstated and contained in the mind of the adolescent. And even with accurate current estimates, our ability to make statements about trends or changes in rates of disease is limited by the very short period of time in which we have been studying these disease rates in U.S. youth, some changes in definitions, and the unknown impact of increasing recognition rather than true change in incidence.
What is unequivocally clear is that psychiatric illnesses usually present in youth and that these illnesses are among the most common illnesses of youth. Current estimates are that nearly one in four young people will have a psychiatric illness (by The Diagnostic and Statistical Manual of Mental Disorders [DSM], Fifth Edition criteria) by the time they turn 18,2 although only 10% of youth will experience an illness that meets the Substance Abuse and Mental Health Services Administration criteria for a serious emotional disturbance, or one that has a substantial impact on a child’s ability to function socially, emotionally, and academically.3
While it once was believed that children did not experience psychiatric illness, we now know that the majority of psychiatric illnesses present during childhood, adolescence, and young adulthood. The Centers for Disease Control and Prevention estimates that 50% of lifetime psychiatric illness has presented by the age of 15 years and 75% by the age of 24. Only one-quarter of all lifetime psychiatric illnesses emerge in full adulthood, or after the age of 24. Early diagnosis and treatment can make a significant difference in the overall impact of serious illnesses such as schizophrenia and bipolar disorder. We also can state with confidence that anxiety disorders are the most common psychiatric illnesses of youth, making up over 30% of all diagnoses, followed by disorders of behavior (19%), mood (14%), and then substance use (11%).4 Even compared with asthma (with a prevalence of approximately 11%), widely considered to be among the most common disease of childhood, psychiatric illnesses are the most common in youth.
The question then is whether these numbers are changing. The National Comorbidity Survey conducted in 2014 found that the incidence of major depressive episodes in adolescents had increased significantly between 2005 and 2014, from 9% to 11%.5 This is a survey of nearly 200,000 youth across the United States, interviewed by phone with a structured questionnaire assessing their (self-reported) DSM criteria for a major depressive episode, along with other illnesses. During this time frame, access to specialty mental health providers increased among adolescents, alongside their rate of use of psychiatric medications and inpatient hospitalization.
In Europe, where they have more robust epidemiological data, there also has been a public perception of an increase in depression in adolescents. Studies there have suggested that prevalence rates have not changed significantly, and that the problem actually may be a function of a growing population, greater public awareness, and higher rates of psychological distress.6
In the United States, it is difficult to place the prevalence rates in a meaningful context, given the shorter time frame during which we have been following these rates in young people. It is worth highlighting that although the rates at which young people are gaining access to mental health clinicians, being prescribed medications, and being admitted to psychiatric hospitals all have increased, there has not been an associated decrease in the rate of illness or in the severity of symptoms. It certainly is possible that the increase in use of services by youth is being driven by the increased prevalence of this diagnosis, or it may be that other factors, such as those detailed in international studies, are driving this increase in the incidence of depression.
What about the suicide rate?
Another statistic that addressed the question of whether there may be an epidemic of anxiety and depression in adolescents is the recent increase in the suicide rate. While the rate of completed suicide in 15- to 24-year-olds has been trending upward over the last decade, it is worth noting that this phenomenon appears to be occurring across age groups and is not isolated to adolescents. While adolescents may have a unique underlying set of issues driving the increase, it also may be that factors affecting the entire population (access to firearms, the epidemic of opioid addiction) may be at the core of this worrisome trend.
What about the role of stress?
It is worth noting that there is evidence of an increased rate of psychological distress in adolescents and young adults separate from any increase in the rate of psychiatric illness. Surveys of adolescents in high school and entering college demonstrate higher self-reported rates of severe stress and anxiety. One survey from the American Psychological Association from August 2018 found teenagers reporting higher levels of stress and related sadness and anxiety than the levels among the adults who were surveyed. So more young people are struggling with feelings of anxiety and sadness, without necessarily meeting criteria for a psychiatric illness. This suggests that levels of external stressors may have increased, or that the establishment of healthy coping skills has somehow been compromised in young people, or both.
What can you do as a clinician?
While the broader question of whether actual incidence rates of depression are on the rise will not be settled any time soon, when a patient of yours complains of high levels of stress, anxiety, or feelings of depression, it is very possible that the individual has a psychiatric diagnosis. A quick screening evaluation, using a questionnaire such as the Pediatric Symptom Checklist and/or a brief interview, can indicate if the patient may benefit from a referral.
In addition, all children, including those who have a psychiatric diagnosis, will benefit from a calm, patient, supportive adult who is interested in their distress. It would be very helpful if you are ready to talk about healthy coping skills, and how they are developed over time and only in the setting of actually struggling with some adversity. Help them frame their source of stress as a challenge rather than a threat. Help them identify their meaningful supports, particularly adults who know them well, and offer concrete and practical advice and motivation. And remind them about how self-care is essential to managing the normal stress of adolescence. Have handouts (or virtual ones) ready on good sleep hygiene, the value of exercise, and fact-based nutritional guidance. Offer strategies to manage screen time so that it is a recharging break and not a time sink. Support their identification of other strategies to decompress and manage stress: Are they recharged by time with friends? Exercise? Playing music? Listening to music? Playing video games? They should be building their personalized list, and it should include more active as well as passive strategies. Educate them about the risks of using drugs and alcohol “to relax,” or only having one way of unwinding. Educate your patients and parents about the special value of a mindfulness practice, whether meditation, yoga, or any activity in which they practice a nonjudgmental observation and acceptance of strong emotions.
Accurate prevalence rates can help us consider the statistical probability of a psychiatric diagnosis. By talking with your patients about stressful feelings, you can consider the individual need for a fuller psychiatric evaluation while also helping them reframe their approach to stress to one that is more empowering, adaptive, and healthy.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at pdnews@mdedge.com.
References
1. Mental Health: A Report of the Surgeon General, National Institutes of Mental Health (1999).
2. Prevalence of psychiatric disorders in childhood and adolescence, in “Mental Health Services: A Public Health Perspective,” 2nd ed. (Oxford, UK: Oxford University Press; 2004, pp. 111-28).
3. Public Health Rep. 2006 May-Jun;121(3):303-10.
4. J Am Acad Child Adolesc Psychiatry. 2010 Oct;49(10):980-9.
5. Pediatrics. 2016 Dec;138(6):e20161878.
6. Depress Anxiety. 2014 Jun;31(6):506-16.
Methylenetetrahydrofolate Reductase Screening in Treatment-Resistant Depression
Therapeutic response to antidepressant drugs is often partial. Multiple trials of medications may be prescribed before a patient achieves remission of symptoms. Further, no universally accepted definition for treatment-resistant depression (TRD) has been established. The most commonly proposed definition (and the definition used in this article) is the failure to achieve remission with 2 or more adequate antidepressant treatments.1
About 20% to 30% of patients with depression are treatment resistant. The overall Canada-wide prevalence of TRD in primary care was 21.7%.2 In the US, about 15.7 million adults have had at least 1 major depressive episode in the past year, and 10% to 15% of major depressive disorder (MDD) cases can be classified as treatment resistant.3,4 In a retrospective, longitudinal cohort analysis in a Medicaid population, 25.9% of pharmacologically treated adults with MDD met criteria for TRD.5 Similarly, TRD in this review was defined as starting a third treatment regimen after 2 adequate regimens of antidepressants.
Why is this important? Treatment resistance is often associated with high rates of disability and comorbidity. Given the significant prevalence and impact of TRD, research into better understanding and treating these patients is paramount. Pharmacogenetics has been proposed for tailoring therapy and theoretically circumventing treatment resistance to achieve better outcomes.
Methylenetetrahydrofolate reductase (MTHFR) is a gene that encodes an enzyme similarly called MTHFR. The enzyme converts 5,10-MTHF to 5-MTHF. 5-MTHF then donates a methyl group in the conversion of homocysteine to methionine. Decreased or absent expression of MTHFR leads to decreased levels of 5-MTHF, which then leads to high levels of homocysteine. This results in suboptimal production of monoamines, including serotonin, dopamine, and norepinephrine as well as subsequent abnormalities in neural and vascular pathways.6
Screening for MTHFR polymorphisms has been proposed in past years due to weak associations with conditions such as cardiac disease, poor pregnancy outcomes, and colorectal cancer.7 Recently, an increasing number of studies suggest screening for MTHFR polymorphisms in patients with depression. This proposal is based on demonstrated links between abnormal folate metabolism and high levels of homocysteine and an increased risk for MDD and reduced antidepressant effectiveness.
In a meta-analysis by Wu and colleagues of 26 published studies, including 4,992 depression cases and 17,082 controls, MTHFR C677T polymorphism was associated with an increased risk of depression especially in Asian populations. This relationship was not observed in the elderly.8 A more recent article reviewing 6 small studies from 2005 to 2016 suggested that the MTHFR A1298C polymorphism (via abnormal homocysteine metabolism and folate cycles) may play a role in identifying those at risk of developing MDD particularly women in white populations.9
As the proposed mechanism of treatment resistance associated with the MTHFR polymorphisms seems to be related to folate metabolism, L-methylfolate supplementation has been recommended. In a 60-day randomized trial of a selective serotonin reuptake inhibitor (SSRI) and L-methylfolate vs SSRI and placebo, patients prescribed an SSRI with L-methylfolate had a greater response rate (reduction of baseline symptoms by at least 50%) that was statistically significant (P = .04) vs patients taking the placebo.10
In primary care and specialty settings, screening patients with TRD for MTHFR polymorphisms has been proposed. LabCorp (Burlington, NC) and Quest Diagnostics (Secaucus, NJ) have a DNA assay that detects C677T and A1298C mutations in the MTHFR gene, using whole blood samples; however, the cost is high. In the DC/Maryland/Virginia region, test cost varies from $390 if the patient requests it from the lab to $325 if requested through an institution that has an account with LabCorp. Although there are little data regarding false positive and false negative rates, 1 source suggested an analytic sensitivity and specificity of 99% for the tests.11
Once obtained, positive screening results may assist in directing next steps in terms of adjunctive or next-line therapies. Given the high price of the test and positive responses with L-methylfolate supplementation thus far, the question remains: Why not supplement patients with TRD with folate and forego screening? For these 2 reasons: The treatment dosage in the studies referenced is 15 mg of L-methylfolate. This dosage is often unavailable over-the-counter and can cost as much as $75 for 90 capsules. Additionally, the high dosage of methylfolate may increase the risk of colon cancer in certain subpopulations, such as those with precancerous lesions.12Although the current data seem promising, further research is needed to explore the benefits of folate supplementation in larger study samples and perhaps other targeted treatment options for patients with TRD with MTHFR gene polymorphisms.
1. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
2. Rizvi SJ, Grima E, Tan M, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014;59(7):349-357.
3. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12(10):739-744.
4. Little A. Treatment-resistant depression. Am Fam Physician. 2009;80(2):167-172.
5. Olfson M, Amos TB, Benson C, McRae J, Marcus SC. Prospective service use and health care costs of Medicaid beneficiaries with treatment resistant depression. J Manag Care Spec Pharm. 2018;24(3):226-236.
6. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232.
7. Long S, Goldblatt J. MTHFR genetic testing: controversy and clinical implications. Aust Fam Physician. 2016;45(4):237-240.
8. Wu YL, Ding XX, Sun YH, et al. Association between MTHFR C677T polymorphism and depression: an updated meta-analysis of 26 studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:78-85.
9. Cho K, Amin ZM, An J, Rambaran KA, Johnson TB, Alzghari SK. Methylenetetrahydrogolate reductase A1298C polymorphism and major depressive disorder. Cureus. 2017;9(10):e1734.
10. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
11. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156.
12. Baggott JE, Oster RA, Tamura T. Meta-analysis of cancer risk in folic acid supplementation trials. Cancer Epidemiol. 2012;36(1):78-81.
Therapeutic response to antidepressant drugs is often partial. Multiple trials of medications may be prescribed before a patient achieves remission of symptoms. Further, no universally accepted definition for treatment-resistant depression (TRD) has been established. The most commonly proposed definition (and the definition used in this article) is the failure to achieve remission with 2 or more adequate antidepressant treatments.1
About 20% to 30% of patients with depression are treatment resistant. The overall Canada-wide prevalence of TRD in primary care was 21.7%.2 In the US, about 15.7 million adults have had at least 1 major depressive episode in the past year, and 10% to 15% of major depressive disorder (MDD) cases can be classified as treatment resistant.3,4 In a retrospective, longitudinal cohort analysis in a Medicaid population, 25.9% of pharmacologically treated adults with MDD met criteria for TRD.5 Similarly, TRD in this review was defined as starting a third treatment regimen after 2 adequate regimens of antidepressants.
Why is this important? Treatment resistance is often associated with high rates of disability and comorbidity. Given the significant prevalence and impact of TRD, research into better understanding and treating these patients is paramount. Pharmacogenetics has been proposed for tailoring therapy and theoretically circumventing treatment resistance to achieve better outcomes.
Methylenetetrahydrofolate reductase (MTHFR) is a gene that encodes an enzyme similarly called MTHFR. The enzyme converts 5,10-MTHF to 5-MTHF. 5-MTHF then donates a methyl group in the conversion of homocysteine to methionine. Decreased or absent expression of MTHFR leads to decreased levels of 5-MTHF, which then leads to high levels of homocysteine. This results in suboptimal production of monoamines, including serotonin, dopamine, and norepinephrine as well as subsequent abnormalities in neural and vascular pathways.6
Screening for MTHFR polymorphisms has been proposed in past years due to weak associations with conditions such as cardiac disease, poor pregnancy outcomes, and colorectal cancer.7 Recently, an increasing number of studies suggest screening for MTHFR polymorphisms in patients with depression. This proposal is based on demonstrated links between abnormal folate metabolism and high levels of homocysteine and an increased risk for MDD and reduced antidepressant effectiveness.
In a meta-analysis by Wu and colleagues of 26 published studies, including 4,992 depression cases and 17,082 controls, MTHFR C677T polymorphism was associated with an increased risk of depression especially in Asian populations. This relationship was not observed in the elderly.8 A more recent article reviewing 6 small studies from 2005 to 2016 suggested that the MTHFR A1298C polymorphism (via abnormal homocysteine metabolism and folate cycles) may play a role in identifying those at risk of developing MDD particularly women in white populations.9
As the proposed mechanism of treatment resistance associated with the MTHFR polymorphisms seems to be related to folate metabolism, L-methylfolate supplementation has been recommended. In a 60-day randomized trial of a selective serotonin reuptake inhibitor (SSRI) and L-methylfolate vs SSRI and placebo, patients prescribed an SSRI with L-methylfolate had a greater response rate (reduction of baseline symptoms by at least 50%) that was statistically significant (P = .04) vs patients taking the placebo.10
In primary care and specialty settings, screening patients with TRD for MTHFR polymorphisms has been proposed. LabCorp (Burlington, NC) and Quest Diagnostics (Secaucus, NJ) have a DNA assay that detects C677T and A1298C mutations in the MTHFR gene, using whole blood samples; however, the cost is high. In the DC/Maryland/Virginia region, test cost varies from $390 if the patient requests it from the lab to $325 if requested through an institution that has an account with LabCorp. Although there are little data regarding false positive and false negative rates, 1 source suggested an analytic sensitivity and specificity of 99% for the tests.11
Once obtained, positive screening results may assist in directing next steps in terms of adjunctive or next-line therapies. Given the high price of the test and positive responses with L-methylfolate supplementation thus far, the question remains: Why not supplement patients with TRD with folate and forego screening? For these 2 reasons: The treatment dosage in the studies referenced is 15 mg of L-methylfolate. This dosage is often unavailable over-the-counter and can cost as much as $75 for 90 capsules. Additionally, the high dosage of methylfolate may increase the risk of colon cancer in certain subpopulations, such as those with precancerous lesions.12Although the current data seem promising, further research is needed to explore the benefits of folate supplementation in larger study samples and perhaps other targeted treatment options for patients with TRD with MTHFR gene polymorphisms.
Therapeutic response to antidepressant drugs is often partial. Multiple trials of medications may be prescribed before a patient achieves remission of symptoms. Further, no universally accepted definition for treatment-resistant depression (TRD) has been established. The most commonly proposed definition (and the definition used in this article) is the failure to achieve remission with 2 or more adequate antidepressant treatments.1
About 20% to 30% of patients with depression are treatment resistant. The overall Canada-wide prevalence of TRD in primary care was 21.7%.2 In the US, about 15.7 million adults have had at least 1 major depressive episode in the past year, and 10% to 15% of major depressive disorder (MDD) cases can be classified as treatment resistant.3,4 In a retrospective, longitudinal cohort analysis in a Medicaid population, 25.9% of pharmacologically treated adults with MDD met criteria for TRD.5 Similarly, TRD in this review was defined as starting a third treatment regimen after 2 adequate regimens of antidepressants.
Why is this important? Treatment resistance is often associated with high rates of disability and comorbidity. Given the significant prevalence and impact of TRD, research into better understanding and treating these patients is paramount. Pharmacogenetics has been proposed for tailoring therapy and theoretically circumventing treatment resistance to achieve better outcomes.
Methylenetetrahydrofolate reductase (MTHFR) is a gene that encodes an enzyme similarly called MTHFR. The enzyme converts 5,10-MTHF to 5-MTHF. 5-MTHF then donates a methyl group in the conversion of homocysteine to methionine. Decreased or absent expression of MTHFR leads to decreased levels of 5-MTHF, which then leads to high levels of homocysteine. This results in suboptimal production of monoamines, including serotonin, dopamine, and norepinephrine as well as subsequent abnormalities in neural and vascular pathways.6
Screening for MTHFR polymorphisms has been proposed in past years due to weak associations with conditions such as cardiac disease, poor pregnancy outcomes, and colorectal cancer.7 Recently, an increasing number of studies suggest screening for MTHFR polymorphisms in patients with depression. This proposal is based on demonstrated links between abnormal folate metabolism and high levels of homocysteine and an increased risk for MDD and reduced antidepressant effectiveness.
In a meta-analysis by Wu and colleagues of 26 published studies, including 4,992 depression cases and 17,082 controls, MTHFR C677T polymorphism was associated with an increased risk of depression especially in Asian populations. This relationship was not observed in the elderly.8 A more recent article reviewing 6 small studies from 2005 to 2016 suggested that the MTHFR A1298C polymorphism (via abnormal homocysteine metabolism and folate cycles) may play a role in identifying those at risk of developing MDD particularly women in white populations.9
As the proposed mechanism of treatment resistance associated with the MTHFR polymorphisms seems to be related to folate metabolism, L-methylfolate supplementation has been recommended. In a 60-day randomized trial of a selective serotonin reuptake inhibitor (SSRI) and L-methylfolate vs SSRI and placebo, patients prescribed an SSRI with L-methylfolate had a greater response rate (reduction of baseline symptoms by at least 50%) that was statistically significant (P = .04) vs patients taking the placebo.10
In primary care and specialty settings, screening patients with TRD for MTHFR polymorphisms has been proposed. LabCorp (Burlington, NC) and Quest Diagnostics (Secaucus, NJ) have a DNA assay that detects C677T and A1298C mutations in the MTHFR gene, using whole blood samples; however, the cost is high. In the DC/Maryland/Virginia region, test cost varies from $390 if the patient requests it from the lab to $325 if requested through an institution that has an account with LabCorp. Although there are little data regarding false positive and false negative rates, 1 source suggested an analytic sensitivity and specificity of 99% for the tests.11
Once obtained, positive screening results may assist in directing next steps in terms of adjunctive or next-line therapies. Given the high price of the test and positive responses with L-methylfolate supplementation thus far, the question remains: Why not supplement patients with TRD with folate and forego screening? For these 2 reasons: The treatment dosage in the studies referenced is 15 mg of L-methylfolate. This dosage is often unavailable over-the-counter and can cost as much as $75 for 90 capsules. Additionally, the high dosage of methylfolate may increase the risk of colon cancer in certain subpopulations, such as those with precancerous lesions.12Although the current data seem promising, further research is needed to explore the benefits of folate supplementation in larger study samples and perhaps other targeted treatment options for patients with TRD with MTHFR gene polymorphisms.
1. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
2. Rizvi SJ, Grima E, Tan M, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014;59(7):349-357.
3. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12(10):739-744.
4. Little A. Treatment-resistant depression. Am Fam Physician. 2009;80(2):167-172.
5. Olfson M, Amos TB, Benson C, McRae J, Marcus SC. Prospective service use and health care costs of Medicaid beneficiaries with treatment resistant depression. J Manag Care Spec Pharm. 2018;24(3):226-236.
6. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232.
7. Long S, Goldblatt J. MTHFR genetic testing: controversy and clinical implications. Aust Fam Physician. 2016;45(4):237-240.
8. Wu YL, Ding XX, Sun YH, et al. Association between MTHFR C677T polymorphism and depression: an updated meta-analysis of 26 studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:78-85.
9. Cho K, Amin ZM, An J, Rambaran KA, Johnson TB, Alzghari SK. Methylenetetrahydrogolate reductase A1298C polymorphism and major depressive disorder. Cureus. 2017;9(10):e1734.
10. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
11. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156.
12. Baggott JE, Oster RA, Tamura T. Meta-analysis of cancer risk in folic acid supplementation trials. Cancer Epidemiol. 2012;36(1):78-81.
1. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord. 2014;156:1-7.
2. Rizvi SJ, Grima E, Tan M, et al. Treatment-resistant depression in primary care across Canada. Can J Psychiatry. 2014;59(7):349-357.
3. Stahl SM. Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent. CNS Spectr. 2007;12(10):739-744.
4. Little A. Treatment-resistant depression. Am Fam Physician. 2009;80(2):167-172.
5. Olfson M, Amos TB, Benson C, McRae J, Marcus SC. Prospective service use and health care costs of Medicaid beneficiaries with treatment resistant depression. J Manag Care Spec Pharm. 2018;24(3):226-236.
6. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000;69(2):228-232.
7. Long S, Goldblatt J. MTHFR genetic testing: controversy and clinical implications. Aust Fam Physician. 2016;45(4):237-240.
8. Wu YL, Ding XX, Sun YH, et al. Association between MTHFR C677T polymorphism and depression: an updated meta-analysis of 26 studies. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:78-85.
9. Cho K, Amin ZM, An J, Rambaran KA, Johnson TB, Alzghari SK. Methylenetetrahydrogolate reductase A1298C polymorphism and major depressive disorder. Cureus. 2017;9(10):e1734.
10. Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double blind, parallel-sequential trials. Am J Psychiatry. 2012;169(12):1267-1274.
11. Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013;15(2):153-156.
12. Baggott JE, Oster RA, Tamura T. Meta-analysis of cancer risk in folic acid supplementation trials. Cancer Epidemiol. 2012;36(1):78-81.
Depressive symptoms are associated with stroke risk
PHILADELPHIA – according to preliminary data from a prospective cohort study presented at the annual meeting of the American Academy of Neurology.
Prior research has found that depression may increase the likelihood of hypertension, cardiac morbidity and mortality, and stroke mortality. How depression affects the risk of incident stroke, however, “is underexplored, especially among Latinos and African Americans,” said study author Marialaura Simonetto, MD, of the University of Miami and associates.
To assess the relationship between depressive symptoms and risk of incident ischemic stroke, the researchers analyzed data from more than 1,100 participants in the MRI substudy of the Northern Manhattan Study. The cohort includes older adults who were clinically stroke free at baseline.
Researchers assessed depressive symptoms at baseline using the Center for Epidemiological Studies–Depression Scale (CES-D). Scores range from 0-60, and they considered CES-D scores of 16 or greater to be elevated.
The investigators used Cox proportional hazards models to estimate hazard ratios of incident ischemic stroke after adjusting for age, sex, race, ethnicity, years of education, smoking, physical activity, alcohol consumption, diabetes, and hypertension.
In all, 1,104 participants were included in the analysis. Participants had an average age of 70 years, 61% were women, and 69% were Hispanic. At baseline, 198 participants (18%) had elevated depressive symptoms.
During 14 years of follow-up, 101 participants had incident strokes, 87 of which were ischemic strokes. In adjusted models, participants with elevated depressive symptoms had a significantly greater risk of ischemic stroke (HR, 1.75; 95% confidence interval, 1.06-2.88). “Every 5-point increase in CES-D score conferred a 12% greater risk of ischemic stroke,” the researchers reported.
“Depression is common and often goes untreated,” Dr. Simonetto said in a news release. “If people with depression are at elevated risk of stroke, early detection and treatment will be even more important.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Simonetto reported no disclosures. Coauthors disclosed personal compensation and research support from pharmaceutical and medical device companies.
SOURCE: Simonetto M et al. AAN 2019, Abstract S1.003.
PHILADELPHIA – according to preliminary data from a prospective cohort study presented at the annual meeting of the American Academy of Neurology.
Prior research has found that depression may increase the likelihood of hypertension, cardiac morbidity and mortality, and stroke mortality. How depression affects the risk of incident stroke, however, “is underexplored, especially among Latinos and African Americans,” said study author Marialaura Simonetto, MD, of the University of Miami and associates.
To assess the relationship between depressive symptoms and risk of incident ischemic stroke, the researchers analyzed data from more than 1,100 participants in the MRI substudy of the Northern Manhattan Study. The cohort includes older adults who were clinically stroke free at baseline.
Researchers assessed depressive symptoms at baseline using the Center for Epidemiological Studies–Depression Scale (CES-D). Scores range from 0-60, and they considered CES-D scores of 16 or greater to be elevated.
The investigators used Cox proportional hazards models to estimate hazard ratios of incident ischemic stroke after adjusting for age, sex, race, ethnicity, years of education, smoking, physical activity, alcohol consumption, diabetes, and hypertension.
In all, 1,104 participants were included in the analysis. Participants had an average age of 70 years, 61% were women, and 69% were Hispanic. At baseline, 198 participants (18%) had elevated depressive symptoms.
During 14 years of follow-up, 101 participants had incident strokes, 87 of which were ischemic strokes. In adjusted models, participants with elevated depressive symptoms had a significantly greater risk of ischemic stroke (HR, 1.75; 95% confidence interval, 1.06-2.88). “Every 5-point increase in CES-D score conferred a 12% greater risk of ischemic stroke,” the researchers reported.
“Depression is common and often goes untreated,” Dr. Simonetto said in a news release. “If people with depression are at elevated risk of stroke, early detection and treatment will be even more important.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Simonetto reported no disclosures. Coauthors disclosed personal compensation and research support from pharmaceutical and medical device companies.
SOURCE: Simonetto M et al. AAN 2019, Abstract S1.003.
PHILADELPHIA – according to preliminary data from a prospective cohort study presented at the annual meeting of the American Academy of Neurology.
Prior research has found that depression may increase the likelihood of hypertension, cardiac morbidity and mortality, and stroke mortality. How depression affects the risk of incident stroke, however, “is underexplored, especially among Latinos and African Americans,” said study author Marialaura Simonetto, MD, of the University of Miami and associates.
To assess the relationship between depressive symptoms and risk of incident ischemic stroke, the researchers analyzed data from more than 1,100 participants in the MRI substudy of the Northern Manhattan Study. The cohort includes older adults who were clinically stroke free at baseline.
Researchers assessed depressive symptoms at baseline using the Center for Epidemiological Studies–Depression Scale (CES-D). Scores range from 0-60, and they considered CES-D scores of 16 or greater to be elevated.
The investigators used Cox proportional hazards models to estimate hazard ratios of incident ischemic stroke after adjusting for age, sex, race, ethnicity, years of education, smoking, physical activity, alcohol consumption, diabetes, and hypertension.
In all, 1,104 participants were included in the analysis. Participants had an average age of 70 years, 61% were women, and 69% were Hispanic. At baseline, 198 participants (18%) had elevated depressive symptoms.
During 14 years of follow-up, 101 participants had incident strokes, 87 of which were ischemic strokes. In adjusted models, participants with elevated depressive symptoms had a significantly greater risk of ischemic stroke (HR, 1.75; 95% confidence interval, 1.06-2.88). “Every 5-point increase in CES-D score conferred a 12% greater risk of ischemic stroke,” the researchers reported.
“Depression is common and often goes untreated,” Dr. Simonetto said in a news release. “If people with depression are at elevated risk of stroke, early detection and treatment will be even more important.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Simonetto reported no disclosures. Coauthors disclosed personal compensation and research support from pharmaceutical and medical device companies.
SOURCE: Simonetto M et al. AAN 2019, Abstract S1.003.
REPORTING FROM AAN 2019
An insidious onset of symptoms
CASE Tremors, increasing anxiety
Ms. S, age 56, has a history of depression and anxiety.
The authors’ observations
The incidence of serotonin syndrome has increased because of increasing use of serotonergic agents.1-3 Although the severity could range from benign to life-threatening, the potential lethality combined with difficulty of diagnosis makes this condition of continued interest. Stimulation of the 5-hydroxytryptamine (5-HT) receptor subtypes, specifically 5-HT1A and 5-HT2, are implicated in this syndrome.4,5
Serotonin syndrome is a clinical diagnosis with a triad of symptoms that includes mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.1,2 However, because of the varied presentation and similarity to other syndromes such as NMS, serotonin syndrome often is undiagnosed.5
TREATMENT Discontinue fluoxetine
Several months after the fluoxetine increase, Ms. S's physical symptoms emerge. Several weeks later, she notices significant hypertension of 162/102 mm Hg by checking her blood pressure at home. She had no history of hypertension before taking fluoxetine. She then tells her psychiatrist she has been experiencing confusion, shakiness, loss of balance, forgetfulness, joint pain, sweating, and fatigue, along with worsening anxiety. The treatment team makes a diagnosis of serotonin syndrome and recommends discontinuing fluoxetine and starting cyproheptadine, 4 mg initially, and then repeating the cyproheptadine dose in several hours if her symptoms do not resolve. Approximately, 2.5 months after the serotonin syndrome reaction, Ms. S receives hydroxyzine, 10 mg every 8 hours, as needed for anxiety.
The authors’ observations
The diagnosis of serotonin syndrome is most accurately made using Hunter Serotonin Toxicity Criteria (Table 16). Because Ms. S had an insidious onset of symptoms, and treatment was initiated before full evaluation, it is unknown if she met Hunter criteria. To meet these criteria, a patient must have ≥1 of the following6:
- spontaneous clonus
- inducible clonus plus agitation or diaphoresis
- ocular clonus plus agitation or diaphoresis
- tremor plus hyperreflexia
- hypertonia plus temperature >38°C plus ocular or inducible clonus.
The Sternbach diagnostic criteria for serotonin syndrome (Table 23) is another commonly used tool.3 These criteria include the addition or increase of a serotonin agent and absence of substances or metabolic derangements that could account for symptoms and at least 3 of the following 10 symptoms3:
- mental status changes (confusion, hypomania)
- agitation
- myoclonus
- hyperreflexia
- diaphoresis
- shivering
- tremor
- diarrhea
- incoordination
- fever.
Continue to: Ms. S met the Sternbach diagnostic criteria...
Ms. S met the Sternbach diagnostic criteria for serotonin syndrome.
Ms. S was taking a single serotonin agent and initially had mild symptoms. More commonly, a patient who presents with serotonin syndrome has been receiving ≥2 serotonergic agents or toxic levels of a single agent, and these agents usually include a psychotropic medication such as a monoamine oxidase inhibitor, tricyclic antidepressant, or SSRI, as well as a medication from a different class, such as dextromethorphan, linezolid, tramadol, methylene blue, and/or St. John’s wort.1,7-13 However, in this case, Ms. S also was taking bupropion, a known inhibitor of cytochrome P450 2D6. Bupropion might have increased Ms. S’s fluoxetine levels.
Ms. S was a healthy, middle-age patient who took no medications other than those listed, had no medical comorbidities, and had a straightforward psychiatric history, which makes the diagnosis of serotonin syndrome clearer. However, other potential differential diagnoses, such as NMS, delirium tremens, and anticholinergic toxicity, might cloud the clinical picture. When differentiating NMS and serotonin syndrome, it is helpful to note whether a patient shows tremor, diarrhea, and myoclonus present in the absence of muscular, “lead-pipe” rigidity, which suggests a diagnosis of serotonin syndrome.2,3,5
[polldaddy:10279173]
The authors’ observations
Treating serotonin syndrome includes supportive care, discontinuing offending agents, administering benzodiazepines, and using a serotonin antagonist as an antidote for patients with moderate-to-severe cases. Cyproheptadine is an antihistaminergic medication with non-specific 5-HT1A and 5-HT2 antagonism. It is FDA-approved for specific allergic reactions, urticaria, and anaphylaxis adjunctive therapy, but not for serotonin syndrome. Case series support the use of cyproheptadine for acute management of serotonin syndrome, with rapid symptom improvement.4,7,14-18 We observed a similar outcome with Ms. S. Her significant autonomic symptoms resolved rapidly, although she experienced some residual, mild symptoms that took weeks to resolve.
Continue to: Because serotonergic agents...
Because serotonergic agents are used frequently and readily by primary care clinicians as well as psychiatrists, the ability to properly diagnose this syndrome is vital, particularly because severe cases can rapidly deteriorate.1,9,16,17 This presentation of a single serotonergic agent causing significant symptoms that worsened over months is not typical, but important to recognize as a patient begins to experience autonomic instability. As was the case with Ms. S, it is important to remain vigilant when changing dosages or adding medications. Symptoms of serotonin syndrome might be vague and difficult to diagnose, especially if the clinician is not aware of the variability of presentation of this syndrome. Cyproheptadine can be used safely and rapidly and should be considered a treatment option for serotonin syndrome.
OUTCOME Hypertension resolves
After her first dose of cyproheptadine, Ms. S’s blood pressure drops to 146/86 mm Hg. Three hours later, she repeats the cyproheptadine dose and her blood pressure drops to 106/60 mm Hg. She reports that her anxiety has lessened, although she is still tremulous. Overall, she says she feels better. She experiences improvement of her condition with a pharmacologic regimen of bupropion, gabapentin, and hydroxyzine.
Several weeks later, her health returns to baseline, with complete resolution of hypertension.
Bottom Line
Although serotonin syndrome is most commonly associated with co-administered serotonergic medications, symptoms can emerge with a single, moderately dosed agent. Treatment includes withdrawing the offending agent, and administering a serotonin antagonist. Mild cases of serotonin syndrome usually resolve.
Related Resources
- Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.
- Iqbal MM, Basil MJ, Kaplan J, et al. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.
Drug Brand Names
Bupropion • Wellbutrin, Zyban
Cyproheptadine • Periactin
Dextromethorphan • Benylin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Neurontin
Hydroxyzine • Atarax
Linezolid • Zyvox
Tramadol • Ultram, Ryzolt
1. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome: presentation of 2 cases and review of literature. Medicine (Baltimore). 2000;79(4):201-209.
2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
3. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
4. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619.
5. Mills KC. Serotonin syndrome a clinical update. Crit Care Clin. 1997;13(4):763-783.
6. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635-642.
7. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care. 1999;15(5):325-327.
8. Kolecki P. Isolated venlafaxine-induced serotonin syndrome. J Emerg Med. 1996;15:491-493.
9. Pan J, Shen W. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother. 2003;37(2):209-211.
10. Hernández JL, Ramos FJ, Infante J, et al. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother. 2002;36(4):641-643.
11. Patel DD, Galarneau D. Serotonin syndrome with fluoxetine: two case reports. Ochsner J. 2016;16(4):554-557.
12. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54(7):988-992.
13. Zuschlag ZD, Warren MW, K Schultz S. Serotonin toxicity and urinary analgesics: a case report and systematic literature review of methylene blue-induced serotonin syndrome. Psychosomatics. 2018;59(6):539-546.
14. Kapur S, Zipursky RB, Jones C, et al. Cyproheptadine: a potent in vivo serotonin antagonist. Am J Psychiatry. 1997;154(6):884.
15. Baigel GD. Cyproheptadine and the treatment of an unconscious patient with the serotonin syndrome. Eur J Anaesthesiol. 2003;20(7):586-588.
16. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. 1994;331:1021-1022.
17. McDaniel WW. Serotonin syndrome: early management with cyproheptadine. Ann Pharmacother. 2001;35(7-8):870-873.
18. Kolecki P. Venlafaxine induced serotonin syndrome occurring after abstinence from phenelzine for more than two weeks. J Toxicol Clin Toxicol. 1997;35(2):211-212.
CASE Tremors, increasing anxiety
Ms. S, age 56, has a history of depression and anxiety.
The authors’ observations
The incidence of serotonin syndrome has increased because of increasing use of serotonergic agents.1-3 Although the severity could range from benign to life-threatening, the potential lethality combined with difficulty of diagnosis makes this condition of continued interest. Stimulation of the 5-hydroxytryptamine (5-HT) receptor subtypes, specifically 5-HT1A and 5-HT2, are implicated in this syndrome.4,5
Serotonin syndrome is a clinical diagnosis with a triad of symptoms that includes mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.1,2 However, because of the varied presentation and similarity to other syndromes such as NMS, serotonin syndrome often is undiagnosed.5
TREATMENT Discontinue fluoxetine
Several months after the fluoxetine increase, Ms. S's physical symptoms emerge. Several weeks later, she notices significant hypertension of 162/102 mm Hg by checking her blood pressure at home. She had no history of hypertension before taking fluoxetine. She then tells her psychiatrist she has been experiencing confusion, shakiness, loss of balance, forgetfulness, joint pain, sweating, and fatigue, along with worsening anxiety. The treatment team makes a diagnosis of serotonin syndrome and recommends discontinuing fluoxetine and starting cyproheptadine, 4 mg initially, and then repeating the cyproheptadine dose in several hours if her symptoms do not resolve. Approximately, 2.5 months after the serotonin syndrome reaction, Ms. S receives hydroxyzine, 10 mg every 8 hours, as needed for anxiety.
The authors’ observations
The diagnosis of serotonin syndrome is most accurately made using Hunter Serotonin Toxicity Criteria (Table 16). Because Ms. S had an insidious onset of symptoms, and treatment was initiated before full evaluation, it is unknown if she met Hunter criteria. To meet these criteria, a patient must have ≥1 of the following6:
- spontaneous clonus
- inducible clonus plus agitation or diaphoresis
- ocular clonus plus agitation or diaphoresis
- tremor plus hyperreflexia
- hypertonia plus temperature >38°C plus ocular or inducible clonus.
The Sternbach diagnostic criteria for serotonin syndrome (Table 23) is another commonly used tool.3 These criteria include the addition or increase of a serotonin agent and absence of substances or metabolic derangements that could account for symptoms and at least 3 of the following 10 symptoms3:
- mental status changes (confusion, hypomania)
- agitation
- myoclonus
- hyperreflexia
- diaphoresis
- shivering
- tremor
- diarrhea
- incoordination
- fever.
Continue to: Ms. S met the Sternbach diagnostic criteria...
Ms. S met the Sternbach diagnostic criteria for serotonin syndrome.
Ms. S was taking a single serotonin agent and initially had mild symptoms. More commonly, a patient who presents with serotonin syndrome has been receiving ≥2 serotonergic agents or toxic levels of a single agent, and these agents usually include a psychotropic medication such as a monoamine oxidase inhibitor, tricyclic antidepressant, or SSRI, as well as a medication from a different class, such as dextromethorphan, linezolid, tramadol, methylene blue, and/or St. John’s wort.1,7-13 However, in this case, Ms. S also was taking bupropion, a known inhibitor of cytochrome P450 2D6. Bupropion might have increased Ms. S’s fluoxetine levels.
Ms. S was a healthy, middle-age patient who took no medications other than those listed, had no medical comorbidities, and had a straightforward psychiatric history, which makes the diagnosis of serotonin syndrome clearer. However, other potential differential diagnoses, such as NMS, delirium tremens, and anticholinergic toxicity, might cloud the clinical picture. When differentiating NMS and serotonin syndrome, it is helpful to note whether a patient shows tremor, diarrhea, and myoclonus present in the absence of muscular, “lead-pipe” rigidity, which suggests a diagnosis of serotonin syndrome.2,3,5
[polldaddy:10279173]
The authors’ observations
Treating serotonin syndrome includes supportive care, discontinuing offending agents, administering benzodiazepines, and using a serotonin antagonist as an antidote for patients with moderate-to-severe cases. Cyproheptadine is an antihistaminergic medication with non-specific 5-HT1A and 5-HT2 antagonism. It is FDA-approved for specific allergic reactions, urticaria, and anaphylaxis adjunctive therapy, but not for serotonin syndrome. Case series support the use of cyproheptadine for acute management of serotonin syndrome, with rapid symptom improvement.4,7,14-18 We observed a similar outcome with Ms. S. Her significant autonomic symptoms resolved rapidly, although she experienced some residual, mild symptoms that took weeks to resolve.
Continue to: Because serotonergic agents...
Because serotonergic agents are used frequently and readily by primary care clinicians as well as psychiatrists, the ability to properly diagnose this syndrome is vital, particularly because severe cases can rapidly deteriorate.1,9,16,17 This presentation of a single serotonergic agent causing significant symptoms that worsened over months is not typical, but important to recognize as a patient begins to experience autonomic instability. As was the case with Ms. S, it is important to remain vigilant when changing dosages or adding medications. Symptoms of serotonin syndrome might be vague and difficult to diagnose, especially if the clinician is not aware of the variability of presentation of this syndrome. Cyproheptadine can be used safely and rapidly and should be considered a treatment option for serotonin syndrome.
OUTCOME Hypertension resolves
After her first dose of cyproheptadine, Ms. S’s blood pressure drops to 146/86 mm Hg. Three hours later, she repeats the cyproheptadine dose and her blood pressure drops to 106/60 mm Hg. She reports that her anxiety has lessened, although she is still tremulous. Overall, she says she feels better. She experiences improvement of her condition with a pharmacologic regimen of bupropion, gabapentin, and hydroxyzine.
Several weeks later, her health returns to baseline, with complete resolution of hypertension.
Bottom Line
Although serotonin syndrome is most commonly associated with co-administered serotonergic medications, symptoms can emerge with a single, moderately dosed agent. Treatment includes withdrawing the offending agent, and administering a serotonin antagonist. Mild cases of serotonin syndrome usually resolve.
Related Resources
- Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.
- Iqbal MM, Basil MJ, Kaplan J, et al. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.
Drug Brand Names
Bupropion • Wellbutrin, Zyban
Cyproheptadine • Periactin
Dextromethorphan • Benylin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Neurontin
Hydroxyzine • Atarax
Linezolid • Zyvox
Tramadol • Ultram, Ryzolt
CASE Tremors, increasing anxiety
Ms. S, age 56, has a history of depression and anxiety.
The authors’ observations
The incidence of serotonin syndrome has increased because of increasing use of serotonergic agents.1-3 Although the severity could range from benign to life-threatening, the potential lethality combined with difficulty of diagnosis makes this condition of continued interest. Stimulation of the 5-hydroxytryptamine (5-HT) receptor subtypes, specifically 5-HT1A and 5-HT2, are implicated in this syndrome.4,5
Serotonin syndrome is a clinical diagnosis with a triad of symptoms that includes mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.1,2 However, because of the varied presentation and similarity to other syndromes such as NMS, serotonin syndrome often is undiagnosed.5
TREATMENT Discontinue fluoxetine
Several months after the fluoxetine increase, Ms. S's physical symptoms emerge. Several weeks later, she notices significant hypertension of 162/102 mm Hg by checking her blood pressure at home. She had no history of hypertension before taking fluoxetine. She then tells her psychiatrist she has been experiencing confusion, shakiness, loss of balance, forgetfulness, joint pain, sweating, and fatigue, along with worsening anxiety. The treatment team makes a diagnosis of serotonin syndrome and recommends discontinuing fluoxetine and starting cyproheptadine, 4 mg initially, and then repeating the cyproheptadine dose in several hours if her symptoms do not resolve. Approximately, 2.5 months after the serotonin syndrome reaction, Ms. S receives hydroxyzine, 10 mg every 8 hours, as needed for anxiety.
The authors’ observations
The diagnosis of serotonin syndrome is most accurately made using Hunter Serotonin Toxicity Criteria (Table 16). Because Ms. S had an insidious onset of symptoms, and treatment was initiated before full evaluation, it is unknown if she met Hunter criteria. To meet these criteria, a patient must have ≥1 of the following6:
- spontaneous clonus
- inducible clonus plus agitation or diaphoresis
- ocular clonus plus agitation or diaphoresis
- tremor plus hyperreflexia
- hypertonia plus temperature >38°C plus ocular or inducible clonus.
The Sternbach diagnostic criteria for serotonin syndrome (Table 23) is another commonly used tool.3 These criteria include the addition or increase of a serotonin agent and absence of substances or metabolic derangements that could account for symptoms and at least 3 of the following 10 symptoms3:
- mental status changes (confusion, hypomania)
- agitation
- myoclonus
- hyperreflexia
- diaphoresis
- shivering
- tremor
- diarrhea
- incoordination
- fever.
Continue to: Ms. S met the Sternbach diagnostic criteria...
Ms. S met the Sternbach diagnostic criteria for serotonin syndrome.
Ms. S was taking a single serotonin agent and initially had mild symptoms. More commonly, a patient who presents with serotonin syndrome has been receiving ≥2 serotonergic agents or toxic levels of a single agent, and these agents usually include a psychotropic medication such as a monoamine oxidase inhibitor, tricyclic antidepressant, or SSRI, as well as a medication from a different class, such as dextromethorphan, linezolid, tramadol, methylene blue, and/or St. John’s wort.1,7-13 However, in this case, Ms. S also was taking bupropion, a known inhibitor of cytochrome P450 2D6. Bupropion might have increased Ms. S’s fluoxetine levels.
Ms. S was a healthy, middle-age patient who took no medications other than those listed, had no medical comorbidities, and had a straightforward psychiatric history, which makes the diagnosis of serotonin syndrome clearer. However, other potential differential diagnoses, such as NMS, delirium tremens, and anticholinergic toxicity, might cloud the clinical picture. When differentiating NMS and serotonin syndrome, it is helpful to note whether a patient shows tremor, diarrhea, and myoclonus present in the absence of muscular, “lead-pipe” rigidity, which suggests a diagnosis of serotonin syndrome.2,3,5
[polldaddy:10279173]
The authors’ observations
Treating serotonin syndrome includes supportive care, discontinuing offending agents, administering benzodiazepines, and using a serotonin antagonist as an antidote for patients with moderate-to-severe cases. Cyproheptadine is an antihistaminergic medication with non-specific 5-HT1A and 5-HT2 antagonism. It is FDA-approved for specific allergic reactions, urticaria, and anaphylaxis adjunctive therapy, but not for serotonin syndrome. Case series support the use of cyproheptadine for acute management of serotonin syndrome, with rapid symptom improvement.4,7,14-18 We observed a similar outcome with Ms. S. Her significant autonomic symptoms resolved rapidly, although she experienced some residual, mild symptoms that took weeks to resolve.
Continue to: Because serotonergic agents...
Because serotonergic agents are used frequently and readily by primary care clinicians as well as psychiatrists, the ability to properly diagnose this syndrome is vital, particularly because severe cases can rapidly deteriorate.1,9,16,17 This presentation of a single serotonergic agent causing significant symptoms that worsened over months is not typical, but important to recognize as a patient begins to experience autonomic instability. As was the case with Ms. S, it is important to remain vigilant when changing dosages or adding medications. Symptoms of serotonin syndrome might be vague and difficult to diagnose, especially if the clinician is not aware of the variability of presentation of this syndrome. Cyproheptadine can be used safely and rapidly and should be considered a treatment option for serotonin syndrome.
OUTCOME Hypertension resolves
After her first dose of cyproheptadine, Ms. S’s blood pressure drops to 146/86 mm Hg. Three hours later, she repeats the cyproheptadine dose and her blood pressure drops to 106/60 mm Hg. She reports that her anxiety has lessened, although she is still tremulous. Overall, she says she feels better. She experiences improvement of her condition with a pharmacologic regimen of bupropion, gabapentin, and hydroxyzine.
Several weeks later, her health returns to baseline, with complete resolution of hypertension.
Bottom Line
Although serotonin syndrome is most commonly associated with co-administered serotonergic medications, symptoms can emerge with a single, moderately dosed agent. Treatment includes withdrawing the offending agent, and administering a serotonin antagonist. Mild cases of serotonin syndrome usually resolve.
Related Resources
- Turner AH, Kim JJ, McCarron RM. Differentiating serotonin syndrome and neuroleptic malignant syndrome. Current Psychiatry. 2019;18(2):30-36.
- Iqbal MM, Basil MJ, Kaplan J, et al. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.
Drug Brand Names
Bupropion • Wellbutrin, Zyban
Cyproheptadine • Periactin
Dextromethorphan • Benylin
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Neurontin
Hydroxyzine • Atarax
Linezolid • Zyvox
Tramadol • Ultram, Ryzolt
1. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome: presentation of 2 cases and review of literature. Medicine (Baltimore). 2000;79(4):201-209.
2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
3. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
4. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619.
5. Mills KC. Serotonin syndrome a clinical update. Crit Care Clin. 1997;13(4):763-783.
6. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635-642.
7. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care. 1999;15(5):325-327.
8. Kolecki P. Isolated venlafaxine-induced serotonin syndrome. J Emerg Med. 1996;15:491-493.
9. Pan J, Shen W. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother. 2003;37(2):209-211.
10. Hernández JL, Ramos FJ, Infante J, et al. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother. 2002;36(4):641-643.
11. Patel DD, Galarneau D. Serotonin syndrome with fluoxetine: two case reports. Ochsner J. 2016;16(4):554-557.
12. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54(7):988-992.
13. Zuschlag ZD, Warren MW, K Schultz S. Serotonin toxicity and urinary analgesics: a case report and systematic literature review of methylene blue-induced serotonin syndrome. Psychosomatics. 2018;59(6):539-546.
14. Kapur S, Zipursky RB, Jones C, et al. Cyproheptadine: a potent in vivo serotonin antagonist. Am J Psychiatry. 1997;154(6):884.
15. Baigel GD. Cyproheptadine and the treatment of an unconscious patient with the serotonin syndrome. Eur J Anaesthesiol. 2003;20(7):586-588.
16. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. 1994;331:1021-1022.
17. McDaniel WW. Serotonin syndrome: early management with cyproheptadine. Ann Pharmacother. 2001;35(7-8):870-873.
18. Kolecki P. Venlafaxine induced serotonin syndrome occurring after abstinence from phenelzine for more than two weeks. J Toxicol Clin Toxicol. 1997;35(2):211-212.
1. Mason PJ, Morris VA, Balcezak TJ. Serotonin syndrome: presentation of 2 cases and review of literature. Medicine (Baltimore). 2000;79(4):201-209.
2. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112-1120.
3. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991;148(6):705-713.
4. Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with cyproheptadine. J Emerg Med. 1998;16(4):615-619.
5. Mills KC. Serotonin syndrome a clinical update. Crit Care Clin. 1997;13(4):763-783.
6. Dunkley EJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003;96:635-642.
7. Horowitz BZ, Mullins ME. Cyproheptadine for serotonin syndrome in an accidental pediatric sertraline ingestion. Pediatr Emerg Care. 1999;15(5):325-327.
8. Kolecki P. Isolated venlafaxine-induced serotonin syndrome. J Emerg Med. 1996;15:491-493.
9. Pan J, Shen W. Serotonin syndrome induced by low-dose venlafaxine. Ann Pharmacother. 2003;37(2):209-211.
10. Hernández JL, Ramos FJ, Infante J, et al. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother. 2002;36(4):641-643.
11. Patel DD, Galarneau D. Serotonin syndrome with fluoxetine: two case reports. Ochsner J. 2016;16(4):554-557.
12. Frank C. Recognition and treatment of serotonin syndrome. Can Fam Physician. 2008;54(7):988-992.
13. Zuschlag ZD, Warren MW, K Schultz S. Serotonin toxicity and urinary analgesics: a case report and systematic literature review of methylene blue-induced serotonin syndrome. Psychosomatics. 2018;59(6):539-546.
14. Kapur S, Zipursky RB, Jones C, et al. Cyproheptadine: a potent in vivo serotonin antagonist. Am J Psychiatry. 1997;154(6):884.
15. Baigel GD. Cyproheptadine and the treatment of an unconscious patient with the serotonin syndrome. Eur J Anaesthesiol. 2003;20(7):586-588.
16. Lappin RI, Auchincloss EL. Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med. 1994;331:1021-1022.
17. McDaniel WW. Serotonin syndrome: early management with cyproheptadine. Ann Pharmacother. 2001;35(7-8):870-873.
18. Kolecki P. Venlafaxine induced serotonin syndrome occurring after abstinence from phenelzine for more than two weeks. J Toxicol Clin Toxicol. 1997;35(2):211-212.
