Bipolar Disorder

Suicide is not a trivial matter – it upends families, robs partners of a loved one, prevents children from having a parent, and can destroy a parent’s most cherished being. It is not surprising that societies have repeatedly made it a goal to study and reduce suicide within their populations.

The suicide rate in the United States is trending upward, from about 10 per 100,000 in 2000 to about 15 per 100,000 in more recent reports. The increasing suicide rates have been accompanied by increasing distress among many strata of society. From a public health level, analysts are not just witnessing increasing suicide rates, but a shocking rise in all “deaths of despair,”¹ among which suicide can be considered the ultimate example.

On an individual level, many know someone who has died of suicide or suffered from a serious suicide attempt. From the public health level to the individual level, advocacy has called for various interventions in the field of psychiatry to remedy this tragic problem.

Psychiatrists have been firsthand witnesses to this increasing demand for suicide interventions. When in residency, the norm was to perform a suicide risk assessment at the time of admission to the hospital and again at the time of discharge. As the years passed, the new normal within psychiatric hospitals has shifted to asking about suicidality on a daily basis.

In what seems to us like an escalating arms race, the emerging standard of care at many facilities is now not only for daily suicide risk assessments by each psychiatrist, but also to require nurses to ask about suicidality during every 8-hour shift – in addition to documented inquiries about suicidality by other allied staff on the psychiatric unit. As a result, it is not uncommon for a patient hospitalized at an academic center to receive more than half a dozen suicide risk assessments in a day (first by the medical student, at least once – often more than once – by the resident, again by the attending psychiatrist, then the social worker and three nurses in 24 hours).

One of the concerns about such an approach is the lack of logic inherent to many risk assessment tools and symptom scales. Many of us are familiar with the Patient Health Questionnaire (PHQ-9) to assess depression.² The PHQ-9 asks to consider “over the last 2 weeks, how often have you ...” in relation to nine symptoms associated with depression. It has always defied reason to perform a PHQ-9 every day and expect the answers to change from “nearly every day” to “not at all,” considering only 1 day has passed since the last time the patient has answered the questions. Yet daily, or near daily, PHQ-9 scores are a frequently used tool of tracking symptom improvement in response to treatments, such as electroconvulsive therapy, performed multiple times a week.

One can argue that the patient’s perspective on how symptomatic he or she has been over the past 2 weeks may change rapidly with alleviation of a depressed mood. However, the PHQ-9 is both reported to be, and often regarded as, an objective score. If one wishes to utilize it as such, the defense of its use should not be that it is a subjective report with just as much utility as “Rate your depression on a scale of 0-27.”

Similarly, many suicide scales were intended to assess thoughts of suicide in the past month³ or have been re-tooled to address this particular concern by asking “since the last contact.”⁴ It is baffling to see a chart with many dozens of suicide risk assessments with at times widely differing answers, yet all measuring thoughts of suicide in the past month. Is one to expect the answer to “How many times have you had these thoughts [of suicide ideation]? (1) Less than once a week (2) Once a week ...” to change between 8 a.m. and noon? Furthermore, for the purpose of assessing acute risk of suicidality in the immediate future, to only consider symptoms since the last contact – or past 2 weeks, past month, etc. – is of unclear significance.
 

Provider liability

Another concern is the liability placed on providers. A common problem encountered in the inpatient setting is insurance companies refusing to reimburse a hospital stay for depressed patients denying suicidality.

Any provider in the position of caring for such a patient must ask: What is the likelihood of someone providing a false negative – a false denial of suicidality? Is the likelihood of a suicidal person denying suicidality different if asked 5 or 10 or more times in a day? There are innumerable instances where a patient at a very high risk of self-harm has denied suicidality, been discharged from the hospital, and suffered terrible consequences. Ethically, the psychiatrist aware of this risk is no more at ease discharging these patients, whether it is one suicide risk scale or a dozen that suggests a patient is at low risk.

Alternatively, it may feel untenable from a medicolegal perspective for a psychiatrist to discharge a patient denying suicidality when the chart includes over a dozen previously documented elevated suicide risk assessments in the past 72 hours. By placing the job of suicide risk assessment in the hands of providers of varying levels of training and responsibility, a situation is created in which the seasoned psychiatrist who would otherwise be comfortable discharging a patient feels unable to do so because every other note-writer in the record – from the triage nurse to the medical assistant to the sitter in the emergency department – has recorded the patient as high risk for suicide. When put in such a position, the thought often occurs that systems of care, rather than individual providers, are protected most by ever escalating requirements for suicide risk documentation. To make a clinical decision contrary to the body of suicide risk documentation puts the provider at risk of being scapegoated by the system of care, which can point to its illogical and ineffective, though profusely documented, suicide prevention protocols.
 

Limitations of risk assessments

Considering the ongoing rise in the use of suicide risk assessments, one would expect that the evidence for their efficacy was robust and well established. Yet a thorough review of suicide risk assessments funded by the MacArthur Foundation, which examined decades of research, came to disheartening conclusions: “predictive ability has not improved over the past 50 years”; “no risk factor category or subcategory is substantially stronger than any other”; and “predicting solely according to base rates may be comparable to prediction with current risk factors.”⁵

Those findings were consistent with the conclusions of many other studies, which have summarized the utility of suicide risk assessments as follows: “occurrence of suicide is too low to identify those individuals who are likely to die by suicide”;⁶ “suicide prediction models produce accurate overall classification models, but their accuracy of predicting a future event is near zero”;⁷ “risk stratification is too inaccurate to be clinically useful and might even be harmful”;⁸ “suicide risk prediction [lacks] any items or information that to a useful degree permit the identification of persons who will complete suicide”;⁹ “existing suicide prediction tools have little current clinical value”;¹⁰ “our current preoccupation with risk assessment has ... created a mythology with no evidence to support it.”¹¹ And that’s to cite just a few.

Sadly, we have known about the limitations of suicide risk assessments for many decades. In 1983 a large VA prospective study, which aimed to identify veterans who will die by suicide, examined 4,800 patients with a wide range of instruments and measures.¹² This study concluded that “discriminant analysis was clearly inadequate in correctly classifying the subjects. For an event as rare as suicide, our predictive tools and guides are simply not equal to the task.” The authors described the feelings of many in stating “courts and public opinion expect physicians to be able to pick out the particular persons who will later commit suicide. Although we may reconstruct causal chains and motives, we do not possess the tools to predict suicides.”

Yet, even several decades prior, in 1954, Dr. Albert Rosen performed an elegant statistical analysis and predicted that, considering the low base rate of suicide, suicide risk assessments are “of no practical value, for it would be impossible to treat the prodigious number of false positives.”¹³ It seems that we continue to be unable to accept Dr. Rosen’s premonition despite decades of confirmatory evidence.
 

“Quantity over quality”

Regardless of those sobering reports, the field of psychiatry is seemingly doubling down on efforts to predict and prevent suicide deaths, and the way it is doing so has very questionable validity.

One can reasonably argue that the periodic performance of a suicide risk assessment may have clinical utility in reminding us of modifiable risk factors such as intoxication, social isolation, and access to lethal means. One can also reasonably argue that these risk assessments may provide useful education to patients and their families on epidemiological risk factors such as gender, age, and marital status. But our pursuit of serial suicide risk assessments throughout the day is encouraging providers to focus on a particular risk factor that changes from moment to moment and has particularly low validity, that being self-reported suicidality.

Reported suicidality is one of the few risk factors that can change from shift to shift. But 80% of people who die by suicide had not previously expressed suicidality, and 98.3% of people who have endorsed suicidality do not die by suicide.¹⁴ While the former statistic may improve with increased assessment, the later will likely worsen.

Suicide is not a trivial matter. We admire those that study it and advocate for better interventions. We have compassion for those who have suffered the loss of a loved one to suicide. Our patients have died as a result of the human limitations surrounding suicide prevention. Recognizing the weight of suicide and making an effort to avoid minimizing its immense consequences drive our desire to be honest with ourselves, our patients and their families, and society. That includes the unfortunate truth regarding the current state of the evidence and our ability to enact change.

It is our concern that the rising fascination with repeated suicide risk assessment is misguided in its current form and serves the purpose of appeasing administrators more than reflecting a scientific understanding of the literature. More sadly, we are concerned that this “quantity-over-quality” approach is yet another barrier to practicing what may be one of the few interventions with any hope of meaningfully impacting a patient’s risk of suicide in the clinical setting – spending time connecting with our patients.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a member of the psychiatry faculty at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Badre and Dr. Compton have no conflicts of interest.

References

1. Joint Economic Committee. (2019). Long Term Trends in Deaths of Despair. SCP Report 4-19.

2. Kroenke K and Spitzer RL. The PHQ-9: A new depression diagnostic and severity measure. Psychiatr Ann. 2013;32(9):509-15. doi: 10.3928/0048-5713-20020901-06.

3. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Lifetime/Recent.

4. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Since Last Contact.

5. Franklin JC et al. Risk factors for suicidal thoughts and behaviors: A meta-analysis of 50 years of research. Psychol Bull. 2017 Feb;143(2):187-232. doi: 10.1037/bul0000084.

6. Beautrais AL. Further suicidal behavior among medically serious suicide attempters. Suicide Life Threat Behav. 2004 Spring;34(1):1-11. doi: 10.1521/suli.34.1.1.27772.

7. Belsher BE. Prediction models for suicide attempts and deaths: A systematic review and simulation. JAMA Psychiatry. 2019 Jun 1;76(6):642-651. doi: 10.1001/jamapsychiatry.2019.0174.

8. Carter G et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guideline for the management of deliberate self-harm. Aust N Z J Psychiatry. 2016 Oct;50(10):939-1000. doi: 10.1177/0004867416661039.

9. Fosse R et al. Predictors of suicide in the patient population admitted to a locked-door psychiatric acute ward. PLoS One. 2017 Mar 16;12(3):e0173958. doi: 10.1371/journal.pone.0173958.

10. Kessler RC et al. Suicide prediction models: A critical review of recent research with recommendations for the way forward. Mol Psychiatry. 2020 Jan;25(1):168-79. doi: 10.1038/s41380-019-0531-0.

11. Mulder R. Problems with suicide risk assessment. Aust N Z J Psychiatry. 2011 Aug;45(8):605-7. doi: 10.3109/00048674.2011.594786.

12. Pokorny AD. Prediction of suicide in psychiatric patients: Report of a prospective study. Arch Gen Psychiatry. 1983 Mar;40(3):249-57. doi: 10.1001/archpsyc.1983.01790030019002.

13. Rosen A. Detection of suicidal patients: An example of some limitations in the prediction of infrequent events. J Consult Psychol. 1954 Dec;18(6):397-403. doi: 10.1037/h0058579.

14. McHugh CM et al. (2019). Association between suicidal ideation and suicide: Meta-analyses of odds ratios, sensitivity, specificity and positive predictive value. BJPsych Open. 2019 Mar;5(2):e18. doi: 10.1192/bjo.2018.88.

Suicide is not a trivial matter – it upends families, robs partners of a loved one, prevents children from having a parent, and can destroy a parent’s most cherished being. It is not surprising that societies have repeatedly made it a goal to study and reduce suicide within their populations.

The suicide rate in the United States is trending upward, from about 10 per 100,000 in 2000 to about 15 per 100,000 in more recent reports. The increasing suicide rates have been accompanied by increasing distress among many strata of society. From a public health level, analysts are not just witnessing increasing suicide rates, but a shocking rise in all “deaths of despair,”¹ among which suicide can be considered the ultimate example.

On an individual level, many know someone who has died of suicide or suffered from a serious suicide attempt. From the public health level to the individual level, advocacy has called for various interventions in the field of psychiatry to remedy this tragic problem.

Psychiatrists have been firsthand witnesses to this increasing demand for suicide interventions. When in residency, the norm was to perform a suicide risk assessment at the time of admission to the hospital and again at the time of discharge. As the years passed, the new normal within psychiatric hospitals has shifted to asking about suicidality on a daily basis.

In what seems to us like an escalating arms race, the emerging standard of care at many facilities is now not only for daily suicide risk assessments by each psychiatrist, but also to require nurses to ask about suicidality during every 8-hour shift – in addition to documented inquiries about suicidality by other allied staff on the psychiatric unit. As a result, it is not uncommon for a patient hospitalized at an academic center to receive more than half a dozen suicide risk assessments in a day (first by the medical student, at least once – often more than once – by the resident, again by the attending psychiatrist, then the social worker and three nurses in 24 hours).

One of the concerns about such an approach is the lack of logic inherent to many risk assessment tools and symptom scales. Many of us are familiar with the Patient Health Questionnaire (PHQ-9) to assess depression.² The PHQ-9 asks to consider “over the last 2 weeks, how often have you ...” in relation to nine symptoms associated with depression. It has always defied reason to perform a PHQ-9 every day and expect the answers to change from “nearly every day” to “not at all,” considering only 1 day has passed since the last time the patient has answered the questions. Yet daily, or near daily, PHQ-9 scores are a frequently used tool of tracking symptom improvement in response to treatments, such as electroconvulsive therapy, performed multiple times a week.

One can argue that the patient’s perspective on how symptomatic he or she has been over the past 2 weeks may change rapidly with alleviation of a depressed mood. However, the PHQ-9 is both reported to be, and often regarded as, an objective score. If one wishes to utilize it as such, the defense of its use should not be that it is a subjective report with just as much utility as “Rate your depression on a scale of 0-27.”

Similarly, many suicide scales were intended to assess thoughts of suicide in the past month³ or have been re-tooled to address this particular concern by asking “since the last contact.”⁴ It is baffling to see a chart with many dozens of suicide risk assessments with at times widely differing answers, yet all measuring thoughts of suicide in the past month. Is one to expect the answer to “How many times have you had these thoughts [of suicide ideation]? (1) Less than once a week (2) Once a week ...” to change between 8 a.m. and noon? Furthermore, for the purpose of assessing acute risk of suicidality in the immediate future, to only consider symptoms since the last contact – or past 2 weeks, past month, etc. – is of unclear significance.
 

Provider liability

Another concern is the liability placed on providers. A common problem encountered in the inpatient setting is insurance companies refusing to reimburse a hospital stay for depressed patients denying suicidality.

Any provider in the position of caring for such a patient must ask: What is the likelihood of someone providing a false negative – a false denial of suicidality? Is the likelihood of a suicidal person denying suicidality different if asked 5 or 10 or more times in a day? There are innumerable instances where a patient at a very high risk of self-harm has denied suicidality, been discharged from the hospital, and suffered terrible consequences. Ethically, the psychiatrist aware of this risk is no more at ease discharging these patients, whether it is one suicide risk scale or a dozen that suggests a patient is at low risk.

Alternatively, it may feel untenable from a medicolegal perspective for a psychiatrist to discharge a patient denying suicidality when the chart includes over a dozen previously documented elevated suicide risk assessments in the past 72 hours. By placing the job of suicide risk assessment in the hands of providers of varying levels of training and responsibility, a situation is created in which the seasoned psychiatrist who would otherwise be comfortable discharging a patient feels unable to do so because every other note-writer in the record – from the triage nurse to the medical assistant to the sitter in the emergency department – has recorded the patient as high risk for suicide. When put in such a position, the thought often occurs that systems of care, rather than individual providers, are protected most by ever escalating requirements for suicide risk documentation. To make a clinical decision contrary to the body of suicide risk documentation puts the provider at risk of being scapegoated by the system of care, which can point to its illogical and ineffective, though profusely documented, suicide prevention protocols.
 

Limitations of risk assessments

Considering the ongoing rise in the use of suicide risk assessments, one would expect that the evidence for their efficacy was robust and well established. Yet a thorough review of suicide risk assessments funded by the MacArthur Foundation, which examined decades of research, came to disheartening conclusions: “predictive ability has not improved over the past 50 years”; “no risk factor category or subcategory is substantially stronger than any other”; and “predicting solely according to base rates may be comparable to prediction with current risk factors.”⁵

Those findings were consistent with the conclusions of many other studies, which have summarized the utility of suicide risk assessments as follows: “occurrence of suicide is too low to identify those individuals who are likely to die by suicide”;⁶ “suicide prediction models produce accurate overall classification models, but their accuracy of predicting a future event is near zero”;⁷ “risk stratification is too inaccurate to be clinically useful and might even be harmful”;⁸ “suicide risk prediction [lacks] any items or information that to a useful degree permit the identification of persons who will complete suicide”;⁹ “existing suicide prediction tools have little current clinical value”;¹⁰ “our current preoccupation with risk assessment has ... created a mythology with no evidence to support it.”¹¹ And that’s to cite just a few.

Sadly, we have known about the limitations of suicide risk assessments for many decades. In 1983 a large VA prospective study, which aimed to identify veterans who will die by suicide, examined 4,800 patients with a wide range of instruments and measures.¹² This study concluded that “discriminant analysis was clearly inadequate in correctly classifying the subjects. For an event as rare as suicide, our predictive tools and guides are simply not equal to the task.” The authors described the feelings of many in stating “courts and public opinion expect physicians to be able to pick out the particular persons who will later commit suicide. Although we may reconstruct causal chains and motives, we do not possess the tools to predict suicides.”

Yet, even several decades prior, in 1954, Dr. Albert Rosen performed an elegant statistical analysis and predicted that, considering the low base rate of suicide, suicide risk assessments are “of no practical value, for it would be impossible to treat the prodigious number of false positives.”¹³ It seems that we continue to be unable to accept Dr. Rosen’s premonition despite decades of confirmatory evidence.
 

“Quantity over quality”

Regardless of those sobering reports, the field of psychiatry is seemingly doubling down on efforts to predict and prevent suicide deaths, and the way it is doing so has very questionable validity.

One can reasonably argue that the periodic performance of a suicide risk assessment may have clinical utility in reminding us of modifiable risk factors such as intoxication, social isolation, and access to lethal means. One can also reasonably argue that these risk assessments may provide useful education to patients and their families on epidemiological risk factors such as gender, age, and marital status. But our pursuit of serial suicide risk assessments throughout the day is encouraging providers to focus on a particular risk factor that changes from moment to moment and has particularly low validity, that being self-reported suicidality.

Reported suicidality is one of the few risk factors that can change from shift to shift. But 80% of people who die by suicide had not previously expressed suicidality, and 98.3% of people who have endorsed suicidality do not die by suicide.¹⁴ While the former statistic may improve with increased assessment, the later will likely worsen.

Suicide is not a trivial matter. We admire those that study it and advocate for better interventions. We have compassion for those who have suffered the loss of a loved one to suicide. Our patients have died as a result of the human limitations surrounding suicide prevention. Recognizing the weight of suicide and making an effort to avoid minimizing its immense consequences drive our desire to be honest with ourselves, our patients and their families, and society. That includes the unfortunate truth regarding the current state of the evidence and our ability to enact change.

It is our concern that the rising fascination with repeated suicide risk assessment is misguided in its current form and serves the purpose of appeasing administrators more than reflecting a scientific understanding of the literature. More sadly, we are concerned that this “quantity-over-quality” approach is yet another barrier to practicing what may be one of the few interventions with any hope of meaningfully impacting a patient’s risk of suicide in the clinical setting – spending time connecting with our patients.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a member of the psychiatry faculty at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Badre and Dr. Compton have no conflicts of interest.

References

1. Joint Economic Committee. (2019). Long Term Trends in Deaths of Despair. SCP Report 4-19.

2. Kroenke K and Spitzer RL. The PHQ-9: A new depression diagnostic and severity measure. Psychiatr Ann. 2013;32(9):509-15. doi: 10.3928/0048-5713-20020901-06.

3. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Lifetime/Recent.

4. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Since Last Contact.

5. Franklin JC et al. Risk factors for suicidal thoughts and behaviors: A meta-analysis of 50 years of research. Psychol Bull. 2017 Feb;143(2):187-232. doi: 10.1037/bul0000084.

6. Beautrais AL. Further suicidal behavior among medically serious suicide attempters. Suicide Life Threat Behav. 2004 Spring;34(1):1-11. doi: 10.1521/suli.34.1.1.27772.

7. Belsher BE. Prediction models for suicide attempts and deaths: A systematic review and simulation. JAMA Psychiatry. 2019 Jun 1;76(6):642-651. doi: 10.1001/jamapsychiatry.2019.0174.

8. Carter G et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guideline for the management of deliberate self-harm. Aust N Z J Psychiatry. 2016 Oct;50(10):939-1000. doi: 10.1177/0004867416661039.

9. Fosse R et al. Predictors of suicide in the patient population admitted to a locked-door psychiatric acute ward. PLoS One. 2017 Mar 16;12(3):e0173958. doi: 10.1371/journal.pone.0173958.

10. Kessler RC et al. Suicide prediction models: A critical review of recent research with recommendations for the way forward. Mol Psychiatry. 2020 Jan;25(1):168-79. doi: 10.1038/s41380-019-0531-0.

11. Mulder R. Problems with suicide risk assessment. Aust N Z J Psychiatry. 2011 Aug;45(8):605-7. doi: 10.3109/00048674.2011.594786.

12. Pokorny AD. Prediction of suicide in psychiatric patients: Report of a prospective study. Arch Gen Psychiatry. 1983 Mar;40(3):249-57. doi: 10.1001/archpsyc.1983.01790030019002.

13. Rosen A. Detection of suicidal patients: An example of some limitations in the prediction of infrequent events. J Consult Psychol. 1954 Dec;18(6):397-403. doi: 10.1037/h0058579.

14. McHugh CM et al. (2019). Association between suicidal ideation and suicide: Meta-analyses of odds ratios, sensitivity, specificity and positive predictive value. BJPsych Open. 2019 Mar;5(2):e18. doi: 10.1192/bjo.2018.88.

Suicide is not a trivial matter – it upends families, robs partners of a loved one, prevents children from having a parent, and can destroy a parent’s most cherished being. It is not surprising that societies have repeatedly made it a goal to study and reduce suicide within their populations.

The suicide rate in the United States is trending upward, from about 10 per 100,000 in 2000 to about 15 per 100,000 in more recent reports. The increasing suicide rates have been accompanied by increasing distress among many strata of society. From a public health level, analysts are not just witnessing increasing suicide rates, but a shocking rise in all “deaths of despair,”¹ among which suicide can be considered the ultimate example.

On an individual level, many know someone who has died of suicide or suffered from a serious suicide attempt. From the public health level to the individual level, advocacy has called for various interventions in the field of psychiatry to remedy this tragic problem.

Psychiatrists have been firsthand witnesses to this increasing demand for suicide interventions. When in residency, the norm was to perform a suicide risk assessment at the time of admission to the hospital and again at the time of discharge. As the years passed, the new normal within psychiatric hospitals has shifted to asking about suicidality on a daily basis.

In what seems to us like an escalating arms race, the emerging standard of care at many facilities is now not only for daily suicide risk assessments by each psychiatrist, but also to require nurses to ask about suicidality during every 8-hour shift – in addition to documented inquiries about suicidality by other allied staff on the psychiatric unit. As a result, it is not uncommon for a patient hospitalized at an academic center to receive more than half a dozen suicide risk assessments in a day (first by the medical student, at least once – often more than once – by the resident, again by the attending psychiatrist, then the social worker and three nurses in 24 hours).

One of the concerns about such an approach is the lack of logic inherent to many risk assessment tools and symptom scales. Many of us are familiar with the Patient Health Questionnaire (PHQ-9) to assess depression.² The PHQ-9 asks to consider “over the last 2 weeks, how often have you ...” in relation to nine symptoms associated with depression. It has always defied reason to perform a PHQ-9 every day and expect the answers to change from “nearly every day” to “not at all,” considering only 1 day has passed since the last time the patient has answered the questions. Yet daily, or near daily, PHQ-9 scores are a frequently used tool of tracking symptom improvement in response to treatments, such as electroconvulsive therapy, performed multiple times a week.

One can argue that the patient’s perspective on how symptomatic he or she has been over the past 2 weeks may change rapidly with alleviation of a depressed mood. However, the PHQ-9 is both reported to be, and often regarded as, an objective score. If one wishes to utilize it as such, the defense of its use should not be that it is a subjective report with just as much utility as “Rate your depression on a scale of 0-27.”

Similarly, many suicide scales were intended to assess thoughts of suicide in the past month³ or have been re-tooled to address this particular concern by asking “since the last contact.”⁴ It is baffling to see a chart with many dozens of suicide risk assessments with at times widely differing answers, yet all measuring thoughts of suicide in the past month. Is one to expect the answer to “How many times have you had these thoughts [of suicide ideation]? (1) Less than once a week (2) Once a week ...” to change between 8 a.m. and noon? Furthermore, for the purpose of assessing acute risk of suicidality in the immediate future, to only consider symptoms since the last contact – or past 2 weeks, past month, etc. – is of unclear significance.
 

Provider liability

Another concern is the liability placed on providers. A common problem encountered in the inpatient setting is insurance companies refusing to reimburse a hospital stay for depressed patients denying suicidality.

Any provider in the position of caring for such a patient must ask: What is the likelihood of someone providing a false negative – a false denial of suicidality? Is the likelihood of a suicidal person denying suicidality different if asked 5 or 10 or more times in a day? There are innumerable instances where a patient at a very high risk of self-harm has denied suicidality, been discharged from the hospital, and suffered terrible consequences. Ethically, the psychiatrist aware of this risk is no more at ease discharging these patients, whether it is one suicide risk scale or a dozen that suggests a patient is at low risk.

Alternatively, it may feel untenable from a medicolegal perspective for a psychiatrist to discharge a patient denying suicidality when the chart includes over a dozen previously documented elevated suicide risk assessments in the past 72 hours. By placing the job of suicide risk assessment in the hands of providers of varying levels of training and responsibility, a situation is created in which the seasoned psychiatrist who would otherwise be comfortable discharging a patient feels unable to do so because every other note-writer in the record – from the triage nurse to the medical assistant to the sitter in the emergency department – has recorded the patient as high risk for suicide. When put in such a position, the thought often occurs that systems of care, rather than individual providers, are protected most by ever escalating requirements for suicide risk documentation. To make a clinical decision contrary to the body of suicide risk documentation puts the provider at risk of being scapegoated by the system of care, which can point to its illogical and ineffective, though profusely documented, suicide prevention protocols.
 

Limitations of risk assessments

Considering the ongoing rise in the use of suicide risk assessments, one would expect that the evidence for their efficacy was robust and well established. Yet a thorough review of suicide risk assessments funded by the MacArthur Foundation, which examined decades of research, came to disheartening conclusions: “predictive ability has not improved over the past 50 years”; “no risk factor category or subcategory is substantially stronger than any other”; and “predicting solely according to base rates may be comparable to prediction with current risk factors.”⁵

Those findings were consistent with the conclusions of many other studies, which have summarized the utility of suicide risk assessments as follows: “occurrence of suicide is too low to identify those individuals who are likely to die by suicide”;⁶ “suicide prediction models produce accurate overall classification models, but their accuracy of predicting a future event is near zero”;⁷ “risk stratification is too inaccurate to be clinically useful and might even be harmful”;⁸ “suicide risk prediction [lacks] any items or information that to a useful degree permit the identification of persons who will complete suicide”;⁹ “existing suicide prediction tools have little current clinical value”;¹⁰ “our current preoccupation with risk assessment has ... created a mythology with no evidence to support it.”¹¹ And that’s to cite just a few.

Sadly, we have known about the limitations of suicide risk assessments for many decades. In 1983 a large VA prospective study, which aimed to identify veterans who will die by suicide, examined 4,800 patients with a wide range of instruments and measures.¹² This study concluded that “discriminant analysis was clearly inadequate in correctly classifying the subjects. For an event as rare as suicide, our predictive tools and guides are simply not equal to the task.” The authors described the feelings of many in stating “courts and public opinion expect physicians to be able to pick out the particular persons who will later commit suicide. Although we may reconstruct causal chains and motives, we do not possess the tools to predict suicides.”

Yet, even several decades prior, in 1954, Dr. Albert Rosen performed an elegant statistical analysis and predicted that, considering the low base rate of suicide, suicide risk assessments are “of no practical value, for it would be impossible to treat the prodigious number of false positives.”¹³ It seems that we continue to be unable to accept Dr. Rosen’s premonition despite decades of confirmatory evidence.
 

“Quantity over quality”

Regardless of those sobering reports, the field of psychiatry is seemingly doubling down on efforts to predict and prevent suicide deaths, and the way it is doing so has very questionable validity.

One can reasonably argue that the periodic performance of a suicide risk assessment may have clinical utility in reminding us of modifiable risk factors such as intoxication, social isolation, and access to lethal means. One can also reasonably argue that these risk assessments may provide useful education to patients and their families on epidemiological risk factors such as gender, age, and marital status. But our pursuit of serial suicide risk assessments throughout the day is encouraging providers to focus on a particular risk factor that changes from moment to moment and has particularly low validity, that being self-reported suicidality.

Reported suicidality is one of the few risk factors that can change from shift to shift. But 80% of people who die by suicide had not previously expressed suicidality, and 98.3% of people who have endorsed suicidality do not die by suicide.¹⁴ While the former statistic may improve with increased assessment, the later will likely worsen.

Suicide is not a trivial matter. We admire those that study it and advocate for better interventions. We have compassion for those who have suffered the loss of a loved one to suicide. Our patients have died as a result of the human limitations surrounding suicide prevention. Recognizing the weight of suicide and making an effort to avoid minimizing its immense consequences drive our desire to be honest with ourselves, our patients and their families, and society. That includes the unfortunate truth regarding the current state of the evidence and our ability to enact change.

It is our concern that the rising fascination with repeated suicide risk assessment is misguided in its current form and serves the purpose of appeasing administrators more than reflecting a scientific understanding of the literature. More sadly, we are concerned that this “quantity-over-quality” approach is yet another barrier to practicing what may be one of the few interventions with any hope of meaningfully impacting a patient’s risk of suicide in the clinical setting – spending time connecting with our patients.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a member of the psychiatry faculty at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Badre and Dr. Compton have no conflicts of interest.

References

1. Joint Economic Committee. (2019). Long Term Trends in Deaths of Despair. SCP Report 4-19.

2. Kroenke K and Spitzer RL. The PHQ-9: A new depression diagnostic and severity measure. Psychiatr Ann. 2013;32(9):509-15. doi: 10.3928/0048-5713-20020901-06.

3. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Lifetime/Recent.

4. Columbia-Suicide Severity Rating Scale (C-SSRS) Full Since Last Contact.

5. Franklin JC et al. Risk factors for suicidal thoughts and behaviors: A meta-analysis of 50 years of research. Psychol Bull. 2017 Feb;143(2):187-232. doi: 10.1037/bul0000084.

6. Beautrais AL. Further suicidal behavior among medically serious suicide attempters. Suicide Life Threat Behav. 2004 Spring;34(1):1-11. doi: 10.1521/suli.34.1.1.27772.

7. Belsher BE. Prediction models for suicide attempts and deaths: A systematic review and simulation. JAMA Psychiatry. 2019 Jun 1;76(6):642-651. doi: 10.1001/jamapsychiatry.2019.0174.

8. Carter G et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guideline for the management of deliberate self-harm. Aust N Z J Psychiatry. 2016 Oct;50(10):939-1000. doi: 10.1177/0004867416661039.

9. Fosse R et al. Predictors of suicide in the patient population admitted to a locked-door psychiatric acute ward. PLoS One. 2017 Mar 16;12(3):e0173958. doi: 10.1371/journal.pone.0173958.

10. Kessler RC et al. Suicide prediction models: A critical review of recent research with recommendations for the way forward. Mol Psychiatry. 2020 Jan;25(1):168-79. doi: 10.1038/s41380-019-0531-0.

11. Mulder R. Problems with suicide risk assessment. Aust N Z J Psychiatry. 2011 Aug;45(8):605-7. doi: 10.3109/00048674.2011.594786.

12. Pokorny AD. Prediction of suicide in psychiatric patients: Report of a prospective study. Arch Gen Psychiatry. 1983 Mar;40(3):249-57. doi: 10.1001/archpsyc.1983.01790030019002.

13. Rosen A. Detection of suicidal patients: An example of some limitations in the prediction of infrequent events. J Consult Psychol. 1954 Dec;18(6):397-403. doi: 10.1037/h0058579.

14. McHugh CM et al. (2019). Association between suicidal ideation and suicide: Meta-analyses of odds ratios, sensitivity, specificity and positive predictive value. BJPsych Open. 2019 Mar;5(2):e18. doi: 10.1192/bjo.2018.88.

Eating disorders are a common comorbidity in bipolar disorder patients, especially those with type II, based on data from more than 2,000 individuals.

Previous research of bipolar disorder (BD) shows a high rate of comorbidities with other psychiatric disorders, including eating disorders (EDs), Valentin Flaudias, PhD, of Nantes (France) University and colleagues wrote.

Valentin Flaudias

“There is growing evidence that, compared with individuals with BD alone, individuals with both BD and EDs have a more severe clinical profile, including increased mood instability, alcohol use disorders, anxiety disorders, more depressive episodes, more rapid cycling, increased suicidality, and poorer response to medication,” but studies of BD type-specific ED prevalence have been inconsistent, they said.

In a study published in the Journal of Affective Disorders, the researchers reviewed data from 2,929 outpatients who underwent assessments for BD at 1 of 12 psychiatric centers in France. Of these, 1,505 met criteria for type I and 1,424 met criteria for type II. The post hoc analysis included identification of lifetime prevalence of ED. Diagnosis was based on the DSM-4-TR and the researchers considered three ED types: anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED). Subtypes of BD were type I and type II. DSM not otherwise specified diagnoses for BD and EDs were excluded. The mean age of the participants was 40.5 years, and 61% were women.

A total of 479 individuals met criteria for comorbid EDs (16.4%). ED prevalence was significantly higher in BD type II patients than in BD type I patients (20.6 % vs. 12.4 %, P < .001). The overall breakdown according to ED subtype was 30% for AN, 13% for BN, and 56% for BED. The researchers found no significant differences in patients with AN, BN, or BED according to BD subtype.

In a multivariate analysis, BD patients with ED were more likely than those without ED to be women (77% vs. 55%), especially those with AN (95% vs. 82%).

BD patients with ED also tended to be younger than those without ED (37 years vs. 41 years) and reported more frequent suicide attempts (50% vs. 35%). Younger age and more frequent suicide attempts were further significant among BD patients with AN, compared with those with BED, but BD patients with BED reported higher levels of childhood trauma.

BD patients with ED also reported higher levels of depressive symptoms than those without ED, although history of psychosis was less frequent among BD patients with AN and BED compared with BD patients without EDs.

Overall, “after controlling for other variables, the independent factors differentiating BD patients with versus without ED were primarily younger age, female gender, abnormal BMI, increased affective lability and higher comorbidity with anxiety disorders,” the researchers wrote. In addition, presence of EDs except for AN was associated with decreased current functioning.

The findings were limited by several factors including the cross-sectional design, lack of a control group of non-BD individuals, and the consideration of ED over a lifetime, and small number of BN cases, the researchers noted.

However, the results suggest a high prevalence of ED in BD patients and highlight the need to screen BD patients for ED and provide integrated care. More research is needed to explore the evolution of the two conditions as comorbidities and to examine subtypes and of both conditions and their interactions, they concluded.

The study was supported by the FondaMental Foundation, French National Institute for Health and Medical Research, Public Hospitals of Paris, and the French National Research Agency’s Investment for the Future program. The researchers had no financial conflicts to disclose.

Eating disorders are a common comorbidity in bipolar disorder patients, especially those with type II, based on data from more than 2,000 individuals.

Previous research of bipolar disorder (BD) shows a high rate of comorbidities with other psychiatric disorders, including eating disorders (EDs), Valentin Flaudias, PhD, of Nantes (France) University and colleagues wrote.

Valentin Flaudias

“There is growing evidence that, compared with individuals with BD alone, individuals with both BD and EDs have a more severe clinical profile, including increased mood instability, alcohol use disorders, anxiety disorders, more depressive episodes, more rapid cycling, increased suicidality, and poorer response to medication,” but studies of BD type-specific ED prevalence have been inconsistent, they said.

In a study published in the Journal of Affective Disorders, the researchers reviewed data from 2,929 outpatients who underwent assessments for BD at 1 of 12 psychiatric centers in France. Of these, 1,505 met criteria for type I and 1,424 met criteria for type II. The post hoc analysis included identification of lifetime prevalence of ED. Diagnosis was based on the DSM-4-TR and the researchers considered three ED types: anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED). Subtypes of BD were type I and type II. DSM not otherwise specified diagnoses for BD and EDs were excluded. The mean age of the participants was 40.5 years, and 61% were women.

A total of 479 individuals met criteria for comorbid EDs (16.4%). ED prevalence was significantly higher in BD type II patients than in BD type I patients (20.6 % vs. 12.4 %, P < .001). The overall breakdown according to ED subtype was 30% for AN, 13% for BN, and 56% for BED. The researchers found no significant differences in patients with AN, BN, or BED according to BD subtype.

In a multivariate analysis, BD patients with ED were more likely than those without ED to be women (77% vs. 55%), especially those with AN (95% vs. 82%).

BD patients with ED also tended to be younger than those without ED (37 years vs. 41 years) and reported more frequent suicide attempts (50% vs. 35%). Younger age and more frequent suicide attempts were further significant among BD patients with AN, compared with those with BED, but BD patients with BED reported higher levels of childhood trauma.

BD patients with ED also reported higher levels of depressive symptoms than those without ED, although history of psychosis was less frequent among BD patients with AN and BED compared with BD patients without EDs.

Overall, “after controlling for other variables, the independent factors differentiating BD patients with versus without ED were primarily younger age, female gender, abnormal BMI, increased affective lability and higher comorbidity with anxiety disorders,” the researchers wrote. In addition, presence of EDs except for AN was associated with decreased current functioning.

The findings were limited by several factors including the cross-sectional design, lack of a control group of non-BD individuals, and the consideration of ED over a lifetime, and small number of BN cases, the researchers noted.

However, the results suggest a high prevalence of ED in BD patients and highlight the need to screen BD patients for ED and provide integrated care. More research is needed to explore the evolution of the two conditions as comorbidities and to examine subtypes and of both conditions and their interactions, they concluded.

The study was supported by the FondaMental Foundation, French National Institute for Health and Medical Research, Public Hospitals of Paris, and the French National Research Agency’s Investment for the Future program. The researchers had no financial conflicts to disclose.

Eating disorders are a common comorbidity in bipolar disorder patients, especially those with type II, based on data from more than 2,000 individuals.

Previous research of bipolar disorder (BD) shows a high rate of comorbidities with other psychiatric disorders, including eating disorders (EDs), Valentin Flaudias, PhD, of Nantes (France) University and colleagues wrote.

Valentin Flaudias

“There is growing evidence that, compared with individuals with BD alone, individuals with both BD and EDs have a more severe clinical profile, including increased mood instability, alcohol use disorders, anxiety disorders, more depressive episodes, more rapid cycling, increased suicidality, and poorer response to medication,” but studies of BD type-specific ED prevalence have been inconsistent, they said.

In a study published in the Journal of Affective Disorders, the researchers reviewed data from 2,929 outpatients who underwent assessments for BD at 1 of 12 psychiatric centers in France. Of these, 1,505 met criteria for type I and 1,424 met criteria for type II. The post hoc analysis included identification of lifetime prevalence of ED. Diagnosis was based on the DSM-4-TR and the researchers considered three ED types: anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED). Subtypes of BD were type I and type II. DSM not otherwise specified diagnoses for BD and EDs were excluded. The mean age of the participants was 40.5 years, and 61% were women.

A total of 479 individuals met criteria for comorbid EDs (16.4%). ED prevalence was significantly higher in BD type II patients than in BD type I patients (20.6 % vs. 12.4 %, P < .001). The overall breakdown according to ED subtype was 30% for AN, 13% for BN, and 56% for BED. The researchers found no significant differences in patients with AN, BN, or BED according to BD subtype.

In a multivariate analysis, BD patients with ED were more likely than those without ED to be women (77% vs. 55%), especially those with AN (95% vs. 82%).

BD patients with ED also tended to be younger than those without ED (37 years vs. 41 years) and reported more frequent suicide attempts (50% vs. 35%). Younger age and more frequent suicide attempts were further significant among BD patients with AN, compared with those with BED, but BD patients with BED reported higher levels of childhood trauma.

BD patients with ED also reported higher levels of depressive symptoms than those without ED, although history of psychosis was less frequent among BD patients with AN and BED compared with BD patients without EDs.

Overall, “after controlling for other variables, the independent factors differentiating BD patients with versus without ED were primarily younger age, female gender, abnormal BMI, increased affective lability and higher comorbidity with anxiety disorders,” the researchers wrote. In addition, presence of EDs except for AN was associated with decreased current functioning.

The findings were limited by several factors including the cross-sectional design, lack of a control group of non-BD individuals, and the consideration of ED over a lifetime, and small number of BN cases, the researchers noted.

However, the results suggest a high prevalence of ED in BD patients and highlight the need to screen BD patients for ED and provide integrated care. More research is needed to explore the evolution of the two conditions as comorbidities and to examine subtypes and of both conditions and their interactions, they concluded.

The study was supported by the FondaMental Foundation, French National Institute for Health and Medical Research, Public Hospitals of Paris, and the French National Research Agency’s Investment for the Future program. The researchers had no financial conflicts to disclose.

A large brain imaging study of adults with six different psychiatric illnesses shows that heterogeneity in regional gray matter volume deviations is a general feature of psychiatric illness, but that these regionally heterogeneous areas are often embedded within common functional circuits and networks.

The findings suggest that “targeting brain circuits, rather than specific brain regions, may be a more effective way of developing new treatments,” study investigator Ashlea Segal said in an email.

The findings also suggest that it’s “unlikely that a single cause or mechanism of a given disorder exists, and that a ‘one-size-fits-all’ approach to treatment is likely only appropriate for a small subset of individuals. In fact, one size doesn’t fit all. It probably doesn’t even fit most,” said Ms. Segal, a PhD candidate with the Turner Institute for Brain and Mental Health’s Neural Systems and Behaviour Lab at Monash University in Melbourne.

“Focusing on brain alterations at an individual level allows us to develop more personally tailored treatments,” Ms. Segal added.

Regional heterogeneity, the authors write, “thus offers a plausible explanation for the well-described clinical heterogeneity observed in psychiatric disorders, while circuit- and network-level aggregation of deviations is a putative neural substrate for phenotypic similarities between patients assigned the same diagnosis.”

The study was published online in Nature Neuroscience
 

Beyond group averages

For decades, researchers have mapped brain areas showing reduced gray matter volume (GMV) in people diagnosed with a variety of mental illnesses, but these maps have only been generated at the level of group averages, Ms. Segal explained.

“This means that we understand how the brains of people with, say, schizophrenia, differ from those without schizophrenia on average, but we can’t really say much about individual people,” Ms. Segal said.

For their study, the researchers used new statistical techniques developed by Andre Marquand, PhD, who co-led the project, to characterize the heterogeneity of GMV differences in 1,294 individuals diagnosed with one of six psychiatric conditions and 1,465 matched controls. Dr. Marquand is affiliated with the Donders Institute for Brain, Cognition, and Behavior in Nijmegen, the Netherlands.

These techniques “allow us to benchmark the size of over 1,000 different brain regions in any given person relative to what we should expect to see in the general population. In this way, we can identify, for any person, brain regions showing unusually small or large volumes, given that person’s age and sex,” Ms. Segal told this news organization.

The clinical sample included 202 individuals with autism spectrum disorder, 153 with attention-deficit/hyperactivity disorder (ADHD), 228 with bipolar disorder, 161 with major depressive disorder, 167 with obsessive-compulsive disorder, and 383 individuals with schizophrenia.

Confirming earlier findings, those with psychiatric illness showed more GMV deviations than healthy controls, the researchers found.

However, at the individual level, deviations from population expectations for regional gray matter volumes were “highly heterogeneous,” affecting the same area in less than 7% of people with the same diagnosis, they note. “This result means that it is difficult to pinpoint treatment targets or causal mechanisms by focusing on group averages alone,” Alex Fornito, PhD, of Monash University, who led the research team, said in a statement.

“It may also explain why people with the same diagnosis show wide variability in their symptom profiles and treatment outcomes,” Dr. Fornito added.

Yet, despite considerable heterogeneity at the regional level across different diagnoses, these deviations were embedded within common functional circuits and networks in up to 56% of cases. 

The salience-ventral attention network, for example, which plays a central role in cognitive control, interoceptive awareness, and switching between internally and externally focused attention, was implicated across diagnoses, with other neural networks selectively involved in depression, bipolar disorder, schizophrenia, and ADHD.

The researchers say the approach they developed opens new opportunities for mapping brain changes in mental illness.

“The framework we have developed allows us to understand the diversity of brain changes in people with mental illness at different levels, from individual regions through to more widespread brain circuits and networks, offering a deeper insight into how the brain is affected in individual people,” Dr. Fornito said in a statement.

The study had no commercial funding. Ms. Segal, Dr. Fornito, and Dr. Marquand report no relevant financial relationships.

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

A large brain imaging study of adults with six different psychiatric illnesses shows that heterogeneity in regional gray matter volume deviations is a general feature of psychiatric illness, but that these regionally heterogeneous areas are often embedded within common functional circuits and networks.

The findings suggest that “targeting brain circuits, rather than specific brain regions, may be a more effective way of developing new treatments,” study investigator Ashlea Segal said in an email.

The findings also suggest that it’s “unlikely that a single cause or mechanism of a given disorder exists, and that a ‘one-size-fits-all’ approach to treatment is likely only appropriate for a small subset of individuals. In fact, one size doesn’t fit all. It probably doesn’t even fit most,” said Ms. Segal, a PhD candidate with the Turner Institute for Brain and Mental Health’s Neural Systems and Behaviour Lab at Monash University in Melbourne.

“Focusing on brain alterations at an individual level allows us to develop more personally tailored treatments,” Ms. Segal added.

Regional heterogeneity, the authors write, “thus offers a plausible explanation for the well-described clinical heterogeneity observed in psychiatric disorders, while circuit- and network-level aggregation of deviations is a putative neural substrate for phenotypic similarities between patients assigned the same diagnosis.”

The study was published online in Nature Neuroscience
 

Beyond group averages

For decades, researchers have mapped brain areas showing reduced gray matter volume (GMV) in people diagnosed with a variety of mental illnesses, but these maps have only been generated at the level of group averages, Ms. Segal explained.

“This means that we understand how the brains of people with, say, schizophrenia, differ from those without schizophrenia on average, but we can’t really say much about individual people,” Ms. Segal said.

For their study, the researchers used new statistical techniques developed by Andre Marquand, PhD, who co-led the project, to characterize the heterogeneity of GMV differences in 1,294 individuals diagnosed with one of six psychiatric conditions and 1,465 matched controls. Dr. Marquand is affiliated with the Donders Institute for Brain, Cognition, and Behavior in Nijmegen, the Netherlands.

These techniques “allow us to benchmark the size of over 1,000 different brain regions in any given person relative to what we should expect to see in the general population. In this way, we can identify, for any person, brain regions showing unusually small or large volumes, given that person’s age and sex,” Ms. Segal told this news organization.

The clinical sample included 202 individuals with autism spectrum disorder, 153 with attention-deficit/hyperactivity disorder (ADHD), 228 with bipolar disorder, 161 with major depressive disorder, 167 with obsessive-compulsive disorder, and 383 individuals with schizophrenia.

Confirming earlier findings, those with psychiatric illness showed more GMV deviations than healthy controls, the researchers found.

However, at the individual level, deviations from population expectations for regional gray matter volumes were “highly heterogeneous,” affecting the same area in less than 7% of people with the same diagnosis, they note. “This result means that it is difficult to pinpoint treatment targets or causal mechanisms by focusing on group averages alone,” Alex Fornito, PhD, of Monash University, who led the research team, said in a statement.

“It may also explain why people with the same diagnosis show wide variability in their symptom profiles and treatment outcomes,” Dr. Fornito added.

Yet, despite considerable heterogeneity at the regional level across different diagnoses, these deviations were embedded within common functional circuits and networks in up to 56% of cases. 

The salience-ventral attention network, for example, which plays a central role in cognitive control, interoceptive awareness, and switching between internally and externally focused attention, was implicated across diagnoses, with other neural networks selectively involved in depression, bipolar disorder, schizophrenia, and ADHD.

The researchers say the approach they developed opens new opportunities for mapping brain changes in mental illness.

“The framework we have developed allows us to understand the diversity of brain changes in people with mental illness at different levels, from individual regions through to more widespread brain circuits and networks, offering a deeper insight into how the brain is affected in individual people,” Dr. Fornito said in a statement.

The study had no commercial funding. Ms. Segal, Dr. Fornito, and Dr. Marquand report no relevant financial relationships.

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

A large brain imaging study of adults with six different psychiatric illnesses shows that heterogeneity in regional gray matter volume deviations is a general feature of psychiatric illness, but that these regionally heterogeneous areas are often embedded within common functional circuits and networks.

The findings suggest that “targeting brain circuits, rather than specific brain regions, may be a more effective way of developing new treatments,” study investigator Ashlea Segal said in an email.

The findings also suggest that it’s “unlikely that a single cause or mechanism of a given disorder exists, and that a ‘one-size-fits-all’ approach to treatment is likely only appropriate for a small subset of individuals. In fact, one size doesn’t fit all. It probably doesn’t even fit most,” said Ms. Segal, a PhD candidate with the Turner Institute for Brain and Mental Health’s Neural Systems and Behaviour Lab at Monash University in Melbourne.

“Focusing on brain alterations at an individual level allows us to develop more personally tailored treatments,” Ms. Segal added.

Regional heterogeneity, the authors write, “thus offers a plausible explanation for the well-described clinical heterogeneity observed in psychiatric disorders, while circuit- and network-level aggregation of deviations is a putative neural substrate for phenotypic similarities between patients assigned the same diagnosis.”

The study was published online in Nature Neuroscience
 

Beyond group averages

For decades, researchers have mapped brain areas showing reduced gray matter volume (GMV) in people diagnosed with a variety of mental illnesses, but these maps have only been generated at the level of group averages, Ms. Segal explained.

“This means that we understand how the brains of people with, say, schizophrenia, differ from those without schizophrenia on average, but we can’t really say much about individual people,” Ms. Segal said.

For their study, the researchers used new statistical techniques developed by Andre Marquand, PhD, who co-led the project, to characterize the heterogeneity of GMV differences in 1,294 individuals diagnosed with one of six psychiatric conditions and 1,465 matched controls. Dr. Marquand is affiliated with the Donders Institute for Brain, Cognition, and Behavior in Nijmegen, the Netherlands.

These techniques “allow us to benchmark the size of over 1,000 different brain regions in any given person relative to what we should expect to see in the general population. In this way, we can identify, for any person, brain regions showing unusually small or large volumes, given that person’s age and sex,” Ms. Segal told this news organization.

The clinical sample included 202 individuals with autism spectrum disorder, 153 with attention-deficit/hyperactivity disorder (ADHD), 228 with bipolar disorder, 161 with major depressive disorder, 167 with obsessive-compulsive disorder, and 383 individuals with schizophrenia.

Confirming earlier findings, those with psychiatric illness showed more GMV deviations than healthy controls, the researchers found.

However, at the individual level, deviations from population expectations for regional gray matter volumes were “highly heterogeneous,” affecting the same area in less than 7% of people with the same diagnosis, they note. “This result means that it is difficult to pinpoint treatment targets or causal mechanisms by focusing on group averages alone,” Alex Fornito, PhD, of Monash University, who led the research team, said in a statement.

“It may also explain why people with the same diagnosis show wide variability in their symptom profiles and treatment outcomes,” Dr. Fornito added.

Yet, despite considerable heterogeneity at the regional level across different diagnoses, these deviations were embedded within common functional circuits and networks in up to 56% of cases. 

The salience-ventral attention network, for example, which plays a central role in cognitive control, interoceptive awareness, and switching between internally and externally focused attention, was implicated across diagnoses, with other neural networks selectively involved in depression, bipolar disorder, schizophrenia, and ADHD.

The researchers say the approach they developed opens new opportunities for mapping brain changes in mental illness.

“The framework we have developed allows us to understand the diversity of brain changes in people with mental illness at different levels, from individual regions through to more widespread brain circuits and networks, offering a deeper insight into how the brain is affected in individual people,” Dr. Fornito said in a statement.

The study had no commercial funding. Ms. Segal, Dr. Fornito, and Dr. Marquand report no relevant financial relationships.

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

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

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

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

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

The first randomized controlled trial testing the safety and efficacy of long-term antidepressant maintenance therapy after remission of a depressive episode in adults with bipolar I disorder has yielded mixed results.

Continuing antidepressant therapy for 52 weeks, as opposed to stopping it at 8 weeks, was not more beneficial with regard to the primary outcome of occurrence of any mood episode.

However, a prespecified sensitivity analysis of the primary outcome and of the secondary analyses suggests that continuing antidepressant therapy for 52 weeks may prolong the time to a depressive relapse.

“Because the primary outcome is negative and the prespecified sensitivity analysis is positive and the secondary outcomes are positive, some clinicians will pick the position that they work and some that they don’t work,” lead investigator Lakshmi Yatham, MBBS, with University of British Columbia, Vancouver, told this news organization.

University of British Columbia

Controversial issue

Adjunctive antidepressant therapy – alongside mood stabilizers and/or second-generation antipsychotic medications – are often used to treat acute depressive episodes in patients with bipolar I disorder.

Currently, the Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) advise discontinuing antidepressant treatment 8 weeks after remission of depression.

Yet, the duration of antidepressant therapy for bipolar depression is “highly controversial,” due to a lack of evidence and concerns that antidepressants may induce mania, mixed states, or rapid cycling between mania and depression, Dr. Yatham said.

Dr. Yatham and colleagues assessed the safety and efficacy of continuing adjunctive antidepressant treatment (escitalopram or bupropion XL) for 52 weeks after remission, compared with discontinuing antidepressant therapy at 8 weeks after remission.

The final analysis included 177 patients (mean age 41 years, 48% men) with bipolar I disorder who had remission of depression; 90 patients continued treatment with an antidepressant for 52 weeks and 87 were switched to placebo at 8 weeks. All were taking a mood stabilizer or a second-generation antipsychotic or both.

The primary outcome, assessed in a time-to-event analysis, was any mood episode, as defined by scores on scales measuring symptoms of hypomania or mania, depression, suicidality, and mood-episode severity; additional treatment or hospitalization for mood symptoms; or attempted or completed suicide.

At 52 weeks, 28 patients (31%) in the 52-week group had experienced any mood episode (primary outcome), compared with 40 patients (46%) in the 8-week group.

The primary outcome did not reach statistical significance (hazard ratio, 0.68; 95% confidence interval, 0.43-1.10; P = .12).

The researchers note that the decision by the study team to include relapses that occurred during the first 6 weeks of the study may have affected the primary outcome.

“During the first 6 weeks, both groups were getting the same treatment, and we thought there shouldn’t be any difference in relapse, but sadly, there were more relapses in the 52-week group even though the treatments were identical,” Dr. Yatham said.

However, in a sensitivity analysis of the primary outcome after week 6, when treatment between the two groups differed, patients continuing antidepressant treatment were 40% less likely to experience a relapse of any mood event (HR, 0.60) and 59% less likely to experience a depressive episode (HR, 0.41) relative to the placebo group.

“From the point where the two groups began receiving different treatments, we see a significant benefit for patients who continued treatment with antidepressants,” Dr. Yatham said in a news release.

“Treating depression in bipolar disorder is challenging. Reducing the risk of relapse is important because it can provide patients with a great deal of stability that ultimately lets them get back to the activities they enjoy and can greatly improve their quality of life,” he added.

Although fewer patients in the 52-week group than 8-week group had a depressive episode within 52 weeks (17% vs. 40%; HR, 0.43), more had a manic or hypomanic event (12% vs. 6%; HR, 2.28).

The estimated probability of remaining free of a depressive episode at 52 weeks was 72% in the 52-week group versus 53% in the 8-week group. The estimated probability of remaining free of a manic episode at 52 weeks was 81% and 92%, respectively.

The incidence of adverse events was similar in the two groups, with a low rate of discontinuation due to adverse events and no serious adverse events. Clinically significant weight gain (≥ 7% increase in body weight) was observed in 14% of patients in the 52-week group and 7% of patients in the 8-week group.

Limitations of the trial include the fact that it was stopped early, before the planned sample size was reached, owing to slow recruitment and funding issues.

Other limitations include a lack of ethnic diversity (only 12% were White and < 1% Black) and overrepresentation of patients from India, which may limit generalizability. 

In addition, the findings may not be applicable to treatment with antidepressants other than escitalopram and buproprion XL. Finally, the study population was also enriched for patients who responded to these antidepressants.
 

Need for an individualized approach

Commenting on the study, Roger McIntyre, MD, professor of psychiatry in pharmacology, University of Toronto, noted the study was not easy to conduct, and the investigators should be credited for conducting a maintenance study in bipolar depression.

“Although the study reports, as it should, that there is no evidence of maintenance effect, the secondary analysis, which was not adjusted for multiplicity, does suggest that there is a benefit,” said Dr. McIntyre, who was not associated with this research.

“However, the authors are also correct in stating that one cannot draw a conclusion because it was not the primary question and was not adjusted for multiplicity,” he added.

“If anything,” said Dr. McIntyre, “what these results do support is the notion that antidepressants are unlikely to destabilize all patients. Instead, the risk of destabilization seems to be largely limited to some persons, and there is a suggestion, based on the secondary outcome of this study, that maintenance antidepressant benefits can be seen in some people. But again that’s a testable hypothesis.”

Also weighing in on the research, Madhukar H. Trivedi, MD, professor of psychiatry and director, Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, said the study is “interesting,” adding that it was “unfortunate that the researchers had to curtail recruitment and reduce the size of the trial.”

University of Texas Southwestern Medical Center

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

Ancestry was a significant predictor of response to lithium by adults with bipolar disorder (BPD), based on data from 172 individuals.

Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.

Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.

In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.

Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.

The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).

The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.

Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.

“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.

Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.

The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.

However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.

The study was supported by PRISMA U.T., Colciencias, Invitación 990 del 3 de Agosto de 2017, Código 111577757629, Contrato 781 de 2017; Convocatoria Programática Ciencias de la Salud 2014-2015 CODI-UdeA, and Convocatoria N.727-2015 Doctorados Nacionales, Colciencias, 2015. The researchers had no financial conflicts to disclose.

Ancestry was a significant predictor of response to lithium by adults with bipolar disorder (BPD), based on data from 172 individuals.

Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.

Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.

In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.

Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.

The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).

The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.

Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.

“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.

Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.

The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.

However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.

The study was supported by PRISMA U.T., Colciencias, Invitación 990 del 3 de Agosto de 2017, Código 111577757629, Contrato 781 de 2017; Convocatoria Programática Ciencias de la Salud 2014-2015 CODI-UdeA, and Convocatoria N.727-2015 Doctorados Nacionales, Colciencias, 2015. The researchers had no financial conflicts to disclose.

Ancestry was a significant predictor of response to lithium by adults with bipolar disorder (BPD), based on data from 172 individuals.

Lithium remains the first-line treatment for BPD, but clinical improvement occurs in less than one-third of patients, and factors that might affect response, especially genetic factors, have not been well studied, wrote Ana M. Díaz-Zuluaga, MD, of University of Antioquia, Medellín, Colombia, and colleagues.

Previous genetic research identified four linked single nucleotide polymorphisms (SNPs) in a single locus on chromosome 21 that were associated with lithium response, but the study was limited to individuals with European and Asian ancestry, the researchers said.

In a study published in the Journal of Affective Disorders, the researchers identified 172 adults aged 18 and older with a diagnosis of BPD I or II based on the DSM-IV-TR criteria. Participants had been taking lithium continuously for at least 6 months. Lithium response was defined using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with BD, also known as the Alda scale. Total Alda scale scores of 7 or higher indicated a responder phenotype; scores less than 7 were considered nonresponders.

Ancestry was determined using DNA samples and the software Structure Version 2.2, and participants were classified as Amerindian, African, or European.

The overall response rate to lithium was 15.11% (26 of 172 patients). In a univariate analysis, no significant differences emerged between responders and nonresponders in demographics or clinical characteristics. However, patients responsive to lithium were significantly less likely of African ancestry, compared with nonresponders (0.1 vs. 0.2, P = .005) and more likely of European ancestry (0.5 vs. 0.3, P = .024), and had fewer depressive episodes (2 vs. 3.9, P = .002). The difference in responders vs. nonresponders of Amerindian ancestry was not statistically significant (0.4 vs. 0.5, P = .204).

The researchers then used machine learning based on Advanced Recursive Partitioning Approaches (ARPAs) to create classification trees with and without ancestry components for predicting response to lithium. “Variable importance analysis shows that the most important predictor is the probability of Amerindian ancestry component, followed by the Amerindian and European ancestral components individual variances, and then by the African and European ancestry components,” the researchers wrote.

Without the ancestry component, the sensitivity and specificity for predicting a treatment response to lithium were 50% and 94.5% respectively, with an area under the curve of 72.2%.

“However, when ancestral components are included in the model, the sensitivity and specificity are 93 % and 84 %, respectively,” with an AUC of 89.2%, the researchers said.

Clinical predictors of treatment response included disease duration, number of depressive episodes, total number of affective episodes, and number of manic episodes.

The findings were limited by several factors including the cross-sectional design and potential impact of other psychotropic drugs, the researchers noted. A replication of the study in an independent dataset is needed to validate the findings, they said.

However, the study is the first known to explore the effect of ancestry on bipolar patients’ response to lithium, and suggests that ancestry components have potential predictive value in the clinical setting that could support a more personalized approach to treatment, the researchers said.

The study was supported by PRISMA U.T., Colciencias, Invitación 990 del 3 de Agosto de 2017, Código 111577757629, Contrato 781 de 2017; Convocatoria Programática Ciencias de la Salud 2014-2015 CODI-UdeA, and Convocatoria N.727-2015 Doctorados Nacionales, Colciencias, 2015. The researchers had no financial conflicts to disclose.

Bipolar disorder (BD) is linked to a sixfold increased risk of early death from external causes and a twofold increased risk of dying prematurely from somatic disease than the general population, a new study shows.

In addition, patients with BD are three times more likely to die prematurely of all causes, compared with the general population, with alcohol-related diseases contributing to more premature deaths than cardiovascular disease (CVD), diabetes, and cancer.

The study results emphasize the need for personalized approaches to risk prediction and prevention of premature cause-specific mortality over the life-course of individuals with BD, lead investigator Tapio Paljärvi, PhD, an epidemiologist at Niuvanniemi Hospital in Kuopio, Finland, told this news organization.

The findings were published online in BMJ Mental Health.
 

Alcohol a major contributor to early death

A number of studies have established that those with BD have twice the risk of dying prematurely, compared with those without the disorder.

To learn more about the factors contributing to early death in this patient population, the investigators analyzed data from nationwide Finnish medical and insurance registries. They identified and tracked the health of 47,000 patients, aged 15-64 years, with BD between 2004 and 2018.

The average age at the beginning of the monitoring period was 38 years, and 57% of the cohort were women.

To determine the excess deaths directly attributable to BD, the researchers compared the ratio of deaths observed over the monitoring period in those with BD to the number expected to die in the general population, also known as the standard mortality ratio.

Of the group with BD, 3,300 died during the monitoring period. The average age at death was 50, and almost two-thirds (65%, or 2,137) of those who died were men.

Investigators grouped excess deaths in BD patients into two categories – somatic and external.

Of those with BD who died from somatic or disease-related causes, alcohol caused the highest rate of death (29%). The second-leading cause was heart disease and stroke (27%), followed by cancer (22%), respiratory diseases (4%), and diabetes (2%).

Among the 595 patients with BD who died because of alcohol consumption, liver disease was the leading cause of death (48%). The second cause was accidental alcohol poisoning (28%), followed by alcohol dependence (10%).

The leading cause of death from external causes in BD patients was suicide (58%, or 740), nearly half of which (48%) were from an overdose with prescribed psychotropic medications.

Overall, 64%, or 2,104, of the deaths in BD patients from any cause were considered excess deaths, that is, the number of deaths above those expected for those without BD of comparable age and sex.

Most of the excess deaths from somatic illness were either from alcohol-related causes (40%) – a rate three times higher than that of the general population – CVD (26%), or cancer (10%).
 

High suicide rate

When the team examined excess deaths from external causes, they found that 61% (651) were attributable to suicide, a rate eight times higher than that of the general population.

“In terms of absolute numbers, somatic causes of death represented the majority of all deaths in BD, as also reported in previous research,” Dr. Paljärvi said.

“However, this finding reflects the fact that in many high-income countries most of the deaths are due to somatic causes; with CVD, cancers, and diseases of the nervous system as the leading causes of death in the older age groups,” he added.

Dr. Paljärvi advised that clinicians treating patients with BD balance therapeutic response with potentially serious long-term medication side effects, to prevent premature deaths.

A stronger emphasis on identifying and treating comorbid substance abuse is also warranted, he noted.

Dr. Paljärvi noted that the underlying causes of the excess somatic mortality in people with BD are not fully understood, but may result from the “complex interaction between various established risk factors, including tobacco use, alcohol abuse, physical inactivity, unhealthy diet, obesity, hypertension, etc.”

Regarding the generalizability of the findings, he said many previous studies have been based only on inpatient data and noted that the current study included individuals from various sources including inpatient and outpatient registries as well as social insurance registries.

“While the reported excess all-cause mortality rates are strikingly similar across populations globally, there is a paucity of more detailed cause-specific analyses of excess mortality in BD,” said Dr. Paljärvi, adding that these findings should be replicated in other countries, including the United States.
 

Chronic inflammation

Commenting on the findings, Benjamin Goldstein, MD, PhD, professor of psychiatry and pharmacology at the University of Toronto, noted that there are clear disparities in access to, and quality of care among, patients with BD and other serious mental illnesses.

“Taking heart disease as an example, disparities exist at virtually every point of contact, ranging from the point of preventive care to the time it takes to be assessed in the ER, to the likelihood of receiving cardiac catheterization, to the quality of postdischarge care,” said Dr. Goldstein.

He also noted that CVD occurs in patients with BD, on average, 10-15 years earlier than the general population. However, he added, “there is important evidence that when people with BD receive the same standard of care as those without BD their cardiovascular outcomes are similar.”

Dr. Goldstein also noted that inflammation, which is a driver of cardiovascular risk, is elevated among patients with BD, particularly during mania and depression.

“Given that the average person with BD has some degree of mood symptoms about 40% of the time, chronically elevated inflammation likely contributes in part to the excess risk of heart disease in bipolar disorder,” he said.

Dr. Goldstein’s team’s research focuses on microvessels. “We have found that microvessel function in both the heart and the brain, determined by MRI, is reduced among teens with BD,” he said.

His team has also found that endothelial function in fingertip microvessels, an indicator of future heart disease risk, varies according to mood states.

“Collectively, these findings suggest the microvascular problems may explain, in part, the extra risk of heart disease beyond traditional risk factors in BD,” he added.

The study was funded by a Wellcome Trust Senior Clinical Research Fellowship and by the Oxford Health Biomedical Research Centre. Dr. Paljärvi and Dr. Goldstein report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Bipolar disorder (BD) is linked to a sixfold increased risk of early death from external causes and a twofold increased risk of dying prematurely from somatic disease than the general population, a new study shows.

In addition, patients with BD are three times more likely to die prematurely of all causes, compared with the general population, with alcohol-related diseases contributing to more premature deaths than cardiovascular disease (CVD), diabetes, and cancer.

The study results emphasize the need for personalized approaches to risk prediction and prevention of premature cause-specific mortality over the life-course of individuals with BD, lead investigator Tapio Paljärvi, PhD, an epidemiologist at Niuvanniemi Hospital in Kuopio, Finland, told this news organization.

The findings were published online in BMJ Mental Health.
 

Alcohol a major contributor to early death

A number of studies have established that those with BD have twice the risk of dying prematurely, compared with those without the disorder.

To learn more about the factors contributing to early death in this patient population, the investigators analyzed data from nationwide Finnish medical and insurance registries. They identified and tracked the health of 47,000 patients, aged 15-64 years, with BD between 2004 and 2018.

The average age at the beginning of the monitoring period was 38 years, and 57% of the cohort were women.

To determine the excess deaths directly attributable to BD, the researchers compared the ratio of deaths observed over the monitoring period in those with BD to the number expected to die in the general population, also known as the standard mortality ratio.

Of the group with BD, 3,300 died during the monitoring period. The average age at death was 50, and almost two-thirds (65%, or 2,137) of those who died were men.

Investigators grouped excess deaths in BD patients into two categories – somatic and external.

Of those with BD who died from somatic or disease-related causes, alcohol caused the highest rate of death (29%). The second-leading cause was heart disease and stroke (27%), followed by cancer (22%), respiratory diseases (4%), and diabetes (2%).

Among the 595 patients with BD who died because of alcohol consumption, liver disease was the leading cause of death (48%). The second cause was accidental alcohol poisoning (28%), followed by alcohol dependence (10%).

The leading cause of death from external causes in BD patients was suicide (58%, or 740), nearly half of which (48%) were from an overdose with prescribed psychotropic medications.

Overall, 64%, or 2,104, of the deaths in BD patients from any cause were considered excess deaths, that is, the number of deaths above those expected for those without BD of comparable age and sex.

Most of the excess deaths from somatic illness were either from alcohol-related causes (40%) – a rate three times higher than that of the general population – CVD (26%), or cancer (10%).
 

High suicide rate

When the team examined excess deaths from external causes, they found that 61% (651) were attributable to suicide, a rate eight times higher than that of the general population.

“In terms of absolute numbers, somatic causes of death represented the majority of all deaths in BD, as also reported in previous research,” Dr. Paljärvi said.

“However, this finding reflects the fact that in many high-income countries most of the deaths are due to somatic causes; with CVD, cancers, and diseases of the nervous system as the leading causes of death in the older age groups,” he added.

Dr. Paljärvi advised that clinicians treating patients with BD balance therapeutic response with potentially serious long-term medication side effects, to prevent premature deaths.

A stronger emphasis on identifying and treating comorbid substance abuse is also warranted, he noted.

Dr. Paljärvi noted that the underlying causes of the excess somatic mortality in people with BD are not fully understood, but may result from the “complex interaction between various established risk factors, including tobacco use, alcohol abuse, physical inactivity, unhealthy diet, obesity, hypertension, etc.”

Regarding the generalizability of the findings, he said many previous studies have been based only on inpatient data and noted that the current study included individuals from various sources including inpatient and outpatient registries as well as social insurance registries.

“While the reported excess all-cause mortality rates are strikingly similar across populations globally, there is a paucity of more detailed cause-specific analyses of excess mortality in BD,” said Dr. Paljärvi, adding that these findings should be replicated in other countries, including the United States.
 

Chronic inflammation

Commenting on the findings, Benjamin Goldstein, MD, PhD, professor of psychiatry and pharmacology at the University of Toronto, noted that there are clear disparities in access to, and quality of care among, patients with BD and other serious mental illnesses.

“Taking heart disease as an example, disparities exist at virtually every point of contact, ranging from the point of preventive care to the time it takes to be assessed in the ER, to the likelihood of receiving cardiac catheterization, to the quality of postdischarge care,” said Dr. Goldstein.

He also noted that CVD occurs in patients with BD, on average, 10-15 years earlier than the general population. However, he added, “there is important evidence that when people with BD receive the same standard of care as those without BD their cardiovascular outcomes are similar.”

Dr. Goldstein also noted that inflammation, which is a driver of cardiovascular risk, is elevated among patients with BD, particularly during mania and depression.

“Given that the average person with BD has some degree of mood symptoms about 40% of the time, chronically elevated inflammation likely contributes in part to the excess risk of heart disease in bipolar disorder,” he said.

Dr. Goldstein’s team’s research focuses on microvessels. “We have found that microvessel function in both the heart and the brain, determined by MRI, is reduced among teens with BD,” he said.

His team has also found that endothelial function in fingertip microvessels, an indicator of future heart disease risk, varies according to mood states.

“Collectively, these findings suggest the microvascular problems may explain, in part, the extra risk of heart disease beyond traditional risk factors in BD,” he added.

The study was funded by a Wellcome Trust Senior Clinical Research Fellowship and by the Oxford Health Biomedical Research Centre. Dr. Paljärvi and Dr. Goldstein report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Bipolar disorder (BD) is linked to a sixfold increased risk of early death from external causes and a twofold increased risk of dying prematurely from somatic disease than the general population, a new study shows.

In addition, patients with BD are three times more likely to die prematurely of all causes, compared with the general population, with alcohol-related diseases contributing to more premature deaths than cardiovascular disease (CVD), diabetes, and cancer.

The study results emphasize the need for personalized approaches to risk prediction and prevention of premature cause-specific mortality over the life-course of individuals with BD, lead investigator Tapio Paljärvi, PhD, an epidemiologist at Niuvanniemi Hospital in Kuopio, Finland, told this news organization.

The findings were published online in BMJ Mental Health.
 

Alcohol a major contributor to early death

A number of studies have established that those with BD have twice the risk of dying prematurely, compared with those without the disorder.

To learn more about the factors contributing to early death in this patient population, the investigators analyzed data from nationwide Finnish medical and insurance registries. They identified and tracked the health of 47,000 patients, aged 15-64 years, with BD between 2004 and 2018.

The average age at the beginning of the monitoring period was 38 years, and 57% of the cohort were women.

To determine the excess deaths directly attributable to BD, the researchers compared the ratio of deaths observed over the monitoring period in those with BD to the number expected to die in the general population, also known as the standard mortality ratio.

Of the group with BD, 3,300 died during the monitoring period. The average age at death was 50, and almost two-thirds (65%, or 2,137) of those who died were men.

Investigators grouped excess deaths in BD patients into two categories – somatic and external.

Of those with BD who died from somatic or disease-related causes, alcohol caused the highest rate of death (29%). The second-leading cause was heart disease and stroke (27%), followed by cancer (22%), respiratory diseases (4%), and diabetes (2%).

Among the 595 patients with BD who died because of alcohol consumption, liver disease was the leading cause of death (48%). The second cause was accidental alcohol poisoning (28%), followed by alcohol dependence (10%).

The leading cause of death from external causes in BD patients was suicide (58%, or 740), nearly half of which (48%) were from an overdose with prescribed psychotropic medications.

Overall, 64%, or 2,104, of the deaths in BD patients from any cause were considered excess deaths, that is, the number of deaths above those expected for those without BD of comparable age and sex.

Most of the excess deaths from somatic illness were either from alcohol-related causes (40%) – a rate three times higher than that of the general population – CVD (26%), or cancer (10%).
 

High suicide rate

When the team examined excess deaths from external causes, they found that 61% (651) were attributable to suicide, a rate eight times higher than that of the general population.

“In terms of absolute numbers, somatic causes of death represented the majority of all deaths in BD, as also reported in previous research,” Dr. Paljärvi said.

“However, this finding reflects the fact that in many high-income countries most of the deaths are due to somatic causes; with CVD, cancers, and diseases of the nervous system as the leading causes of death in the older age groups,” he added.

Dr. Paljärvi advised that clinicians treating patients with BD balance therapeutic response with potentially serious long-term medication side effects, to prevent premature deaths.

A stronger emphasis on identifying and treating comorbid substance abuse is also warranted, he noted.

Dr. Paljärvi noted that the underlying causes of the excess somatic mortality in people with BD are not fully understood, but may result from the “complex interaction between various established risk factors, including tobacco use, alcohol abuse, physical inactivity, unhealthy diet, obesity, hypertension, etc.”

Regarding the generalizability of the findings, he said many previous studies have been based only on inpatient data and noted that the current study included individuals from various sources including inpatient and outpatient registries as well as social insurance registries.

“While the reported excess all-cause mortality rates are strikingly similar across populations globally, there is a paucity of more detailed cause-specific analyses of excess mortality in BD,” said Dr. Paljärvi, adding that these findings should be replicated in other countries, including the United States.
 

Chronic inflammation

Commenting on the findings, Benjamin Goldstein, MD, PhD, professor of psychiatry and pharmacology at the University of Toronto, noted that there are clear disparities in access to, and quality of care among, patients with BD and other serious mental illnesses.

“Taking heart disease as an example, disparities exist at virtually every point of contact, ranging from the point of preventive care to the time it takes to be assessed in the ER, to the likelihood of receiving cardiac catheterization, to the quality of postdischarge care,” said Dr. Goldstein.

He also noted that CVD occurs in patients with BD, on average, 10-15 years earlier than the general population. However, he added, “there is important evidence that when people with BD receive the same standard of care as those without BD their cardiovascular outcomes are similar.”

Dr. Goldstein also noted that inflammation, which is a driver of cardiovascular risk, is elevated among patients with BD, particularly during mania and depression.

“Given that the average person with BD has some degree of mood symptoms about 40% of the time, chronically elevated inflammation likely contributes in part to the excess risk of heart disease in bipolar disorder,” he said.

Dr. Goldstein’s team’s research focuses on microvessels. “We have found that microvessel function in both the heart and the brain, determined by MRI, is reduced among teens with BD,” he said.

His team has also found that endothelial function in fingertip microvessels, an indicator of future heart disease risk, varies according to mood states.

“Collectively, these findings suggest the microvascular problems may explain, in part, the extra risk of heart disease beyond traditional risk factors in BD,” he added.

The study was funded by a Wellcome Trust Senior Clinical Research Fellowship and by the Oxford Health Biomedical Research Centre. Dr. Paljärvi and Dr. Goldstein report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

Bipolar disorder (BD) is a psychotic mood disorder. Like schizophrenia, it has been shown to be associated with significant degeneration and structural brain abnormalities with multiple relapses.^1,2

Just as I have always advocated preventing recurrences in schizophrenia by using long-acting injectable (LAI) antipsychotic formulations immediately after the first episode to prevent psychotic relapses and progressive brain damage,³ I strongly recommend using LAIs right after hospital discharge from the first manic episode. It is the most rational management approach for bipolar mania given the grave consequences of multiple episodes, which are so common in this psychotic mood disorder due to poor medication adherence.

In contrast to the depressive episodes of BD I, where patients have insight into their depression and seek psychiatric treatment, during a manic episode patients often have no insight (anosognosia) that they suffer from a serious brain disorder, and refuse treatment.⁴ In addition, young patients with BD I frequently discontinue their oral mood stabilizer or second-generation antipsychotic (which are approved for mania) because they miss the blissful euphoria and the buoyant physical and mental energy of their manic episodes. They are completely oblivious to (and uninformed about) the grave neurobiological damage of further manic episodes, which can condemn them to clinical, functional, and cognitive deterioration. These patients are also likely to become treatment-resistant, which has been labeled as “the malignant transformation of bipolar disorder.”⁵

The evidence for progressive brain tissue loss, clinical deterioration, functional decline, and treatment resistance is abundant.⁶ I was the lead investigator of the first study to report ventricular dilatation (which is a proxy for cortical atrophy) in bipolar mania,⁷ a discovery that was subsequently replicated by 2 dozen researchers. This was followed by numerous neuroimaging studies reporting a loss of volume across multiple brain regions, including the frontal lobe, temporal lobe, cerebellum, thalamus, hippocampus, and basal ganglia. BD is heterogeneous⁸ with 4 stages (Table 1⁹), and patients experience progressively worse brain structure and function with each stage.

Many patients with bipolar mania end up with poor clinical and functional outcomes, even when they respond well to initial treatment with lithium, anticonvulsant mood stabilizers, or second-generation antipsychotics. With their intentional nonadherence to oral medications leading to multiple recurrent relapses, these patients are at serious risk for neuroprogression and brain atrophic changes driven by multiple factors: inflammatory cytokines, increased cortical steroids, decreased neurotrophins, deceased neurogenesis, increased oxidative stress, and mitochondrial energy dysfunction. The consequences include progressive shortening of the interval between episodes with every relapse and loss of responsiveness to pharmacotherapy as the illness progresses.^6,10 Predictors of a downhill progression include genetic vulnerability, perinatal complication during fetal life, childhood trauma (physical, sexual, emotional, or neglect), substance use, stress, psychiatric/medial comorbidities, and especially the number of episodes.^9,11

Biomarkers have been reported in both the early and late stages of BD (Table 2¹²) as well as in postmortem studies (Table 3^8,13). They reflect the progressive neurodegenerative nature of recurrent BD I episodes as the disorder moves to the advanced stages. I summarize these stages in Table 1⁹ and Table 2¹² for the benefit of psychiatric clinicians who do not have access to the neuroscience journals where such findings are usually published.

BD I is also believed to be associated with accelerated aging^14,15 and an increased risk for dementia¹⁶ or cognitive deterioration.¹⁷ There is also an emerging hypothesis that neuroprogression and treatment resistance in BD is frequently associated with insulin resistance,¹⁸ peripheral inflammation,¹⁹ and blood-brain barrier permeability dysfunction.²⁰

The bottom line is that like patients with schizophrenia, where relapses lead to devastating consequences,²¹ those with BD are at a similar high risk for neuroprogression, which includes atrophy in several brain regions, treatment resistance, and functional disability. This underscores the urgency for implementing LAI therapy early in the illness, when the first manic episode (Stage 2) emerges after the prodrome (Stage 1). This is the best strategy to preserve brain health in persons with BD²² and to allow them to remain functional with their many intellectual gifts, such as eloquence, poetry, artistic talents, humor, and social skills. It is unfortunate that the combination of patients’ and clinicians’ reluctance to use an LAI early in the illness dooms many patients with BD to a potentially avoidable malignant outcome.

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

Primary care providers (PCPs) are addressing an increasing number of mental health visits, requiring collaborative and innovative approaches to providing psychiatric care.

This growth in the number of patients needing behavioral health–related care is likely driven by multiple factors, including a shortage of mental health care providers, an increasing incidence of psychiatric illness, and destigmatization of mental health in general, suggested Swetha P. Iruku, MD, MPH, associate professor of family medicine and community health at the University of Pennsylvania and Penn Medicine family physician in Philadelphia.

The Centers for Disease Control and Prevention noted that “the COVID-19 pandemic has been associated with mental health challenges related to the morbidity and mortality caused by the disease and to mitigation activities, including the impact of physical distancing and stay-at-home orders,” in a Morbidity and Mortality Weekly Report.

From June 24 to 30, 2020, U.S. adults reported considerably elevated adverse mental health conditions associated with COVID-19, and symptoms of anxiety disorder and depressive disorder climbed during the months of April through June of the same year, compared with the same period in 2019, they wrote.

Even before the pandemic got underway, multiple studies of national data published this year suggested mental issues were on the rise in the United States. For example, the proportion of adult patient visits to primary care providers that addressed mental health concerns rose from 10.7% to 15.9% from 2006 to 2018, according to research published in Health Affairs. Plus, the number and proportion of pediatric acute care hospitalizations because of mental health diagnoses increased significantly between 2009 and 2019, according to a paper published in JAMA.

“I truly believe that we can’t, as primary care physicians, take care of someone’s physical health without also taking care of their mental health,” Dr. Iruku said in an interview. “It’s all intertwined.”

To rise to this challenge, PCPs first need a collaborative mindset, she suggested, as well as familiarity with available resources, both locally and virtually.

This article examines strategies for managing mental illness in primary care, outlines clinical resources, and reviews related educational opportunities.

In addition, clinical pearls are shared by Dr. Iruku and five other clinicians who provide or have provided mental health care to primary care patients or work in close collaboration with a primary care practice, including a clinical psychologist, a nurse practitioner licensed in psychiatric health, a pediatrician, and a licensed clinical social worker.
 

Build a network

Most of the providers interviewed cited the importance of collaboration in mental health care, particularly for complex cases.

“I would recommend [that primary care providers get] to know the psychiatric providers [in their area],” said Jessica Viton, DNP, FNP, PMHNP, who delivers mental health care through a community-based primary care practice in Colorado which she requested remain anonymous.

Dr. Iruku suggested making an in-person connection first, if possible.

“So much of what we do is ‘see one, do one, teach one,’ so learn a little bit, then go off and trial,” she said. “[It can be valuable] having someone in your back pocket that you can contact in the case of an emergency, or in a situation where you just don’t know how to tackle it.”
 

Screen for depression and anxiety

William J. Sieber, PhD, a clinical psychologist, director of integrated behavioral health, and professor in the department of family medicine and public health and the department of psychiatry at the University of California, San Diego, said primary care providers should screen all adult patients for depression and anxiety with the Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder Assessment (GAD-7), respectively.

To save time, he suggested a cascading approach.

“In primary care, everybody’s in a hurry,” Dr. Sieber said. “[With the cascading approach,] the first two items [from each questionnaire] are given, and if a person endorses either of those items … then they are asked to complete the other items.”

Jennifer Mullally, MD, a pediatrician at Sanford Health in Fargo, N.D., uses this cascading approach to depression and anxiety screening with all her patients aged 13-18. For younger kids, she screens only those who present with signs or symptoms of mental health issues, or if the parent shares a concern.

This approach differs slightly from U.S. Preventive Services Task Force recommendations, which suggest screening for anxiety in patients aged 8-18 years and depression in patients aged 12-18 years.
 

Use other screening tools only as needed

Dr. Sieber, the research director for the division of family medicine at UC San Diego, collaborates regularly with primary care providers via hallway consultations, by sharing cases, and through providing oversight of psychiatric care at 13 primary care practices within the UC San Diego network. He recommended against routine screening beyond depression and anxiety in the primary care setting.

“There are a lot of screening tools,” Dr. Sieber said. “It depends on what you’re presented with. The challenge in primary care is you’re going to see all kinds of things. It’s not like running a depression clinic.”

Other than the PHQ-9 and GAD-7, he suggested primary care providers establish familiarity with screening tools for posttraumatic stress disorder and attention-deficit/hyperactivity disorder, noting again that these should be used only when one of the conditions is already suspected.

Dr. Mullally follows a similar approach with her pediatric population. In addition to the GAD-7, she investigates whether a patient has anxiety with the Screen for Child Anxiety Related Disorders (SCARED). For depression, she couples the PHQ-9 with the Columbia Suicide Severity Rating Scale.

While additional screening tools like these are readily available online, Dr. Viton suggested that they should be employed only if the provider is trained to interpret and respond to those findings, and only if they know which tool to use, and when.

For example, she has recently observed PCPs diagnosing adults with ADHD using a three-question test, when in fact a full-length, standardized instrument should be administered by a provider with necessary training.

She also pointed out that bipolar disorder continues to be underdiagnosed, possibly because of providers detecting depression using a questionnaire like the PHQ-9, while failing to inquire about manic episodes.
 

Leverage online resources

If depression is confirmed, Dr. Iruku often directs the patient to the Mayo Clinic Depression Medication Choice Decision Aid. This website steers patients through medication options based on their answers to a questionnaire. Choices are listed alongside possible adverse effects.

For clinician use, Dr. Iruku recommended The Waco Guide to Psychopharmacology in Primary Care, which aids clinical decision-making for mental illness and substance abuse. The app processes case details to suggest first-, second-, and third-line pharmacotherapies, as well as modifications based on patient needs.

Even with tools like these, however, a referral may be needed.

“[Primary care providers] may not be the best fit for what the patient is looking for, from a mental health or behavioral standpoint,” Dr. Sieber said.

In this case, he encourages patients to visit Psychology Today, a “quite popular portal” that helps patients locate a suitable provider based on location, insurance, driving radius, and mental health concern. This usually generates 10-20 options, Dr. Sieber said, although results can vary.

“It may be discouraging, because maybe only three [providers] pop up based on your criteria, and the closest one is miles away,” he said.
 

Consider virtual support

If no local psychiatric help is available, Dr. Sieber suggested virtual support, highlighting that “it’s much easier now than it was 3 or 4 years ago” to connect patients with external mental health care.

But this strategy should be reserved for cases of actual need instead of pure convenience, cautioned Dr. Viton, who noted that virtual visits may fail to capture the nuance of an in-person meeting, as body language, mode of dress, and other clues can provide insights into mental health status.

“Occasionally, I think you do have to have an in-person visit, especially when you’re developing a rapport with someone,” Dr. Viton said.

Claire McArdle, a licensed clinical social worker in Fort Collins, Colo., noted that virtual care from an outside provider may also impede the collaboration needed to effectively address mental illness.

In her 11 years in primary care at Associates in Family Medicine, Ms. McArdle had countless interactions with colleagues seeking support when managing a complex case. “I’m coaching providers, front desk staff, and nursing staff on how to interact with patients [with] behavioral health needs,” she said, citing the multitude of nonmedical factors that need to be considered, such as family relationships and patient preferences.

These unscheduled conversations with colleagues throughout the day are impossible to have when sharing a case with an unknown, remote peer.

Ms. McArdle speaks from experience. She recently resigned from Associates in Family Medicine to start her own private therapy practice after her former employer was acquired by VillageMD, a national provider that terminated employment of most other social workers in the practice and began outsourcing mental health care to Mindoula Health, a virtual provider.

Dr. Sieber offered a similar perspective on in-person collaboration as the psychiatric specialist at his center. He routinely offers on-site support for both providers and patients, serving as “another set of eyes and ears” when there is a concern about patient safety or directly managing care when a patient is hospitalized for mental illness.

While virtual solutions may fall short of in-person management, they can offer care at a scale and cost impossible through traditional practice.

This could even be free. Zero-cost, automated software now allows individuals who are uninsured or unable to afford care at least one avenue to manage their mental health concerns.

For example, Bliss is a free, 8-session, interactive online therapy program for depression that was created by the Centre for Interactive Mental Health Solutions. The program offers a tool for monitoring mood and quizzes to test understanding of personal mental health management, among other features.

More advanced programs are emerging as artificial intelligence (AI) enables dialogues between humans and machines. This is the case with Woebot, an app that asks the user about their mood throughout the day, and responds with evidence-based strategies for managing concerns, all for free at press time.
 

Keep learning

A range of educational options and professional resources are available for primary care providers who would like to improve their knowledge of mental health care. These include formal fellowships in primary care psychiatry/behavioral health integration, free mental health webinars, and various other opportunities.

Eric Eschweiler, DNP, APRN, FNP-C, PHN, completed the University of California, Irvine, Train New Trainers (TNT) Primary Care Psychiatry (PCP) Fellowship in 2016, when he was working as a solo nurse practitioner.

“I was drowning in practice,” said Dr. Eschweiler, director of nursing and public health outreach services at Riverside-San Bernardino County Indian Health, Grand Terrace, Calif., in an interview. “I was a solo NP. There was no physician on site. We were seeing a lot of [individuals with] schizoaffective [disorder] in downtown San Bernardino, the homeless, unhoused – a lot of substance use. I felt I needed to have the skills to be able to treat them effectively. That’s what the fellowship did.”

The skills Dr. Eschweiler learned from participating in his fellowship allowed him to manage more cases of mental illness without need for referral. When a referral was needed for a complex or severe case, he had the confidence to bridge care and collaborate more effectively with psychiatric specialists.

“It was awesome, because we were able to communicate using the same language,” Dr. Eschweiler said of these collaborations. “It’s [about] talking that same language, starting those initial treatments, and then moving forward with specialty care, and vice versa. [Psychiatric specialists] would send me patients that needed medical care because of the types of medications they were taking. And I was then very well aware of those side effects and other issues that might come up from those treatments. So it’s a two-way street.”

Dr. Eschweiler was so impressed by his fellowship that he has since ushered multiple providers through the program since transitioning to an administrative role as director of nursing.

In Fargo, where psychiatric care is sparse and wait times for referral can be months long, Dr. Mullally, like Dr. Eschweiler, knew that she needed more training in mental health.

“I don’t feel like we get enough training in residency,” Dr. Mullally said. “So you do need to look at your options for further CME.”

Out of several CME courses she has taken to further her understanding of pediatric psychiatry, Dr. Mullally recommended The Reach Institute above all others, as their courses involve in-depth discussions and valuable handouts, particularly for medication selection.

“I think that a lot of the other CMEs tend to involve a lot more PowerPoint presentations,” Dr. Mullally said. “And you don’t necessarily leave with a lot of good documents. I still use my Reach handouts. I have them sitting right next to me. I use them every single day.”

Providers interested in The Reach Institute, however, should be prepared to invest both time and money, she added, citing a 2-3 day commitment, and calling it “not cheap.” To overcome these barriers, she suggested that providers get their institution to support their attendance.

For a lighter commitment, Dr. Iruku recommended the American Academy of Family Physicians CME portal, as this offers 13 online, accredited courses covering a range of topics, from adolescent health to substance abuse disorders.

Dr. Sieber suggested that primary care providers join the Collaborative Family Healthcare Association, which aims to integrate physical and behavioral health in routine practice. CFHA, of which he is a member, offers a “bevy of different resources” for interested providers, including a conference in Phoenix this October.

The interviewees disclosed no conflicts of interest.

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

The investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein, MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.
 

‘Excessively present’

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers noted.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction – considered a precursor of CVD – can be assessed in youth,” said Dr. Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, Toronto, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth aged 13-20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP), were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.
 

Positive affect beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs. 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs. 35%; P = .03; V = 0.21), higher body mass index (BMI, 24.4 ± 4.6 vs. 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs. 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F_3,202 = 4.47; P = .005; n_p²  = 0.06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed versus the HC group (P = .04; d = 0.4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI, compared with the other BD groups and the HC group.

RHI was associated with higher mania scores (beta, 0.26; P = .006), but there was no similar significant association with depression mood scores (beta, 0.01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to healthy youth,” Dr. Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators noted. For example, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers concluded that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.
 

Observable changes in youth

In a comment, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Dr. Fiedorowicz, who is also a professor in the department of psychiatry and senior research chair in adult psychiatry at the Brain and Mind Research Institute, University of Ottawa, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Dr. Goldstein and coauthors declare no relevant financial relationships. Dr. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

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