MDedge Psychiatry

Benefits of early LAI use

I want to thank Dr. Nasrallah for his editorial calling for more frequent and earlier use of long-acting injectable antipsychotics (LAIs) in schizophrenia (From the Editor, Current Psychiatry, May 2021, p. 9-12). I consider LAIs to be lifesaving interventions, so I’ve offered LAI administration via a drive-up service over the past year to ensure patients could continue to receive their treatment, even through the worst times of the COVID-19 pandemic.¹ LAIs can be beneficial for anyone living with schizophrenia, but are never more important than in first-episode psychosis (FEP), when repeated psychotic relapses have not yet ravaged the brain. Earlier aggressive treatment of FEP and subsequent relapses with LAIs can dramatically improve long-term outcomes for people with schizophrenia.

In addition to the neuroprotective biologic effects of early LAI usage, I’ve found that many of my FEP patients find great psychological comfort from incorporating LAIs into their treatment plan. The first psychotic break is generally when a person (and their family) feels the most afraid about the future and is in desperate need of hope that they can have a full life—with educational opportunities, sustained employment, meaningful relationships, and more. Just as society has seen the COVID-19 vaccines as a symbol of hope and the first step in overcoming the oppression of living in fear of an uncertain future, we need to help people experiencing FEP find hope in a needle.

Craig Chepke, MD, FAPA
Excel Psychiatric Associates
Huntersville, North Carolina

Reference

1. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30.

Dr. Nasrallah responds

Thank you, Dr. Chepke, for your letter confirming full support for using LAIs in schizophrenia. I like the phrase you coined: “hope in a needle.” The early use of LAIs in schizophrenia can provide the same type of hope that the vaccines against the life-threatening COVID-19 virus have generated in our society. Based on my direct observations, I also agree with you that the longer patients with schizophrenia remain on LAIs, the more engaged and happy they are with their progress and the quality of their lives. It is tragic that many patients never had the opportunity to return to their baseline with the early use of LAIs immediately following their first psychotic episode, instead of relapsing again and again due to their inability to adhere completely to their oral medications.

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: LAIs as the standard of care

Thank you, Dr. Nasrallah, for reiterating the importance of compliance with pharmacologic management of schizophrenia after FEP (From the Editor, Current Psychiatry, May 2021, p. 9-12). Long before LAIs, I appreciated the successes patients with schizophrenia experienced when they complied with treatment after the first episode. It was clear that success was forthcoming for patients who had an interested psychiatrist and a committed relationship with them.

As you point out in your editorial, the facts are powerful, well-known, undisputed, and yet not adopted in the United States, when in other countries LAIs are first-line care. Yes, LAIs are expensive, but not nearly as expensive as the disabilities caused by noncompliance are to society.

Why isn’t LAI use the standard of care here in the United States? In the United States, there is advocacy for treatment because there’s money in it. There is no good advocacy for preventive care because there’s no immediate money in it. We have another good example of this in the United States: private, for-profit prisons. They have a vested interest in keeping prisons full and building new ones. Patients with FEP are most often treated in the hospital, where a standard of care could easily be established that mandates LAIs as first-tier care. Why is that not so? Who is pushing for it? Who is resisting?

Your editorial inspired me to advocate more strongly. Do you have advice about how to effect policy change? I know administrators respond when we talk dollars and cents, not quality of care. What is the dollar cost of not using LAIs as the standard of care after FEP? Who cares? Who would listen to the numbers?

Edward A. Major, MD, LFAPA
Clinical Professor of Psychiatry
Upstate Medical Center
Syracuse, New York

Dr. Nasrallah responds

Dr. Major, thanks for your message. Establishing a standard of care for the use of LAIs (or any other therapy) is not that simple. It requires well-coordinated collaboration among several stakeholders (clinicians, researchers, payors, advocacy groups, and a national organization such as the American Psychiatric Association). The cost issue is certainly powerful, but the equation works in favor of LAIs because 1 psychiatric hospitalization due to a psychotic relapse costs up to 3 times the annual cost of an LAI medication that can prevent that rehospitalization. In addition, disability comprises the lion’s share of the large indirect costs of schizophrenia (disability payments, lifetime room and board, incarceration and legal costs, and loss of work and generation of taxes). LAIs can save both lives and expenditures, and a lot of suffering by patients and their families. I, too, long to see the emergence of a rational standard of care for schizophrenia using LAIs right after the initial psychotic episode. Oncology and cardiology have standards of care, so why not psychiatry?

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: Psychosis and epilepsy

I just read your editorial regarding the devastating consequences of psychotic relapses (From the Editor, Current Psychiatry, May 2021, p. 9-12). I was shocked to read of the extent of the damage caused by such relapses and the positive impact of LAIs, and I thank you for opening my eyes. 

I work in the spheres of psychiatry, epileptology, and whole genome sequencing, and have experienced a psychotic episode myself (in 2013, after temporal lobe resection and overdose). I now consider myself even more lucky to be out the other side! As Governor for South London and Maudsley NHS Foundation Trust (SLaM) and Trustee for Epilepsy Action, many of our patients have psychosis. Some patients with epilepsy even experience postictal psychosis. Just yesterday, we had a call at SLaM regarding patients from a secure unit, and a psychiatric nurse spoke about patients at risk to themselves and others because of their psychotic illness, and how crucial effective long-term care was.

Torie Robinson
CEO, Epilepsy Sparks

Dr. Nasrallah responds

Ms. Robinson, thank you for sharing your story. It is important to note that the neuro­biology of the psychosis that may occur with epilepsy may not be as neurodegenerative as the psychosis of schizophrenia. Many neurologic conditions can be associated with psychotic episodes, not only epilepsy. I am glad you overcame your post-temporal lobectomy psychotic episode and have had a very good outcome with high functioning.

Henry A. Nasrallah, MD
Editor-In-Chief

Disclosures
Dr. Chepke is a consultant to and speaker for Janssen Pharmaceuticals, Otsuka Pharmaceuticals, and Alkermes. The other authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

Benefits of early LAI use

I want to thank Dr. Nasrallah for his editorial calling for more frequent and earlier use of long-acting injectable antipsychotics (LAIs) in schizophrenia (From the Editor, Current Psychiatry, May 2021, p. 9-12). I consider LAIs to be lifesaving interventions, so I’ve offered LAI administration via a drive-up service over the past year to ensure patients could continue to receive their treatment, even through the worst times of the COVID-19 pandemic.¹ LAIs can be beneficial for anyone living with schizophrenia, but are never more important than in first-episode psychosis (FEP), when repeated psychotic relapses have not yet ravaged the brain. Earlier aggressive treatment of FEP and subsequent relapses with LAIs can dramatically improve long-term outcomes for people with schizophrenia.

In addition to the neuroprotective biologic effects of early LAI usage, I’ve found that many of my FEP patients find great psychological comfort from incorporating LAIs into their treatment plan. The first psychotic break is generally when a person (and their family) feels the most afraid about the future and is in desperate need of hope that they can have a full life—with educational opportunities, sustained employment, meaningful relationships, and more. Just as society has seen the COVID-19 vaccines as a symbol of hope and the first step in overcoming the oppression of living in fear of an uncertain future, we need to help people experiencing FEP find hope in a needle.

Craig Chepke, MD, FAPA
Excel Psychiatric Associates
Huntersville, North Carolina

Reference

1. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30.

Dr. Nasrallah responds

Thank you, Dr. Chepke, for your letter confirming full support for using LAIs in schizophrenia. I like the phrase you coined: “hope in a needle.” The early use of LAIs in schizophrenia can provide the same type of hope that the vaccines against the life-threatening COVID-19 virus have generated in our society. Based on my direct observations, I also agree with you that the longer patients with schizophrenia remain on LAIs, the more engaged and happy they are with their progress and the quality of their lives. It is tragic that many patients never had the opportunity to return to their baseline with the early use of LAIs immediately following their first psychotic episode, instead of relapsing again and again due to their inability to adhere completely to their oral medications.

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: LAIs as the standard of care

Thank you, Dr. Nasrallah, for reiterating the importance of compliance with pharmacologic management of schizophrenia after FEP (From the Editor, Current Psychiatry, May 2021, p. 9-12). Long before LAIs, I appreciated the successes patients with schizophrenia experienced when they complied with treatment after the first episode. It was clear that success was forthcoming for patients who had an interested psychiatrist and a committed relationship with them.

As you point out in your editorial, the facts are powerful, well-known, undisputed, and yet not adopted in the United States, when in other countries LAIs are first-line care. Yes, LAIs are expensive, but not nearly as expensive as the disabilities caused by noncompliance are to society.

Why isn’t LAI use the standard of care here in the United States? In the United States, there is advocacy for treatment because there’s money in it. There is no good advocacy for preventive care because there’s no immediate money in it. We have another good example of this in the United States: private, for-profit prisons. They have a vested interest in keeping prisons full and building new ones. Patients with FEP are most often treated in the hospital, where a standard of care could easily be established that mandates LAIs as first-tier care. Why is that not so? Who is pushing for it? Who is resisting?

Your editorial inspired me to advocate more strongly. Do you have advice about how to effect policy change? I know administrators respond when we talk dollars and cents, not quality of care. What is the dollar cost of not using LAIs as the standard of care after FEP? Who cares? Who would listen to the numbers?

Edward A. Major, MD, LFAPA
Clinical Professor of Psychiatry
Upstate Medical Center
Syracuse, New York

Dr. Nasrallah responds

Dr. Major, thanks for your message. Establishing a standard of care for the use of LAIs (or any other therapy) is not that simple. It requires well-coordinated collaboration among several stakeholders (clinicians, researchers, payors, advocacy groups, and a national organization such as the American Psychiatric Association). The cost issue is certainly powerful, but the equation works in favor of LAIs because 1 psychiatric hospitalization due to a psychotic relapse costs up to 3 times the annual cost of an LAI medication that can prevent that rehospitalization. In addition, disability comprises the lion’s share of the large indirect costs of schizophrenia (disability payments, lifetime room and board, incarceration and legal costs, and loss of work and generation of taxes). LAIs can save both lives and expenditures, and a lot of suffering by patients and their families. I, too, long to see the emergence of a rational standard of care for schizophrenia using LAIs right after the initial psychotic episode. Oncology and cardiology have standards of care, so why not psychiatry?

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: Psychosis and epilepsy

I just read your editorial regarding the devastating consequences of psychotic relapses (From the Editor, Current Psychiatry, May 2021, p. 9-12). I was shocked to read of the extent of the damage caused by such relapses and the positive impact of LAIs, and I thank you for opening my eyes. 

I work in the spheres of psychiatry, epileptology, and whole genome sequencing, and have experienced a psychotic episode myself (in 2013, after temporal lobe resection and overdose). I now consider myself even more lucky to be out the other side! As Governor for South London and Maudsley NHS Foundation Trust (SLaM) and Trustee for Epilepsy Action, many of our patients have psychosis. Some patients with epilepsy even experience postictal psychosis. Just yesterday, we had a call at SLaM regarding patients from a secure unit, and a psychiatric nurse spoke about patients at risk to themselves and others because of their psychotic illness, and how crucial effective long-term care was.

Torie Robinson
CEO, Epilepsy Sparks

Dr. Nasrallah responds

Ms. Robinson, thank you for sharing your story. It is important to note that the neuro­biology of the psychosis that may occur with epilepsy may not be as neurodegenerative as the psychosis of schizophrenia. Many neurologic conditions can be associated with psychotic episodes, not only epilepsy. I am glad you overcame your post-temporal lobectomy psychotic episode and have had a very good outcome with high functioning.

Henry A. Nasrallah, MD
Editor-In-Chief

Disclosures
Dr. Chepke is a consultant to and speaker for Janssen Pharmaceuticals, Otsuka Pharmaceuticals, and Alkermes. The other authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

Benefits of early LAI use

I want to thank Dr. Nasrallah for his editorial calling for more frequent and earlier use of long-acting injectable antipsychotics (LAIs) in schizophrenia (From the Editor, Current Psychiatry, May 2021, p. 9-12). I consider LAIs to be lifesaving interventions, so I’ve offered LAI administration via a drive-up service over the past year to ensure patients could continue to receive their treatment, even through the worst times of the COVID-19 pandemic.¹ LAIs can be beneficial for anyone living with schizophrenia, but are never more important than in first-episode psychosis (FEP), when repeated psychotic relapses have not yet ravaged the brain. Earlier aggressive treatment of FEP and subsequent relapses with LAIs can dramatically improve long-term outcomes for people with schizophrenia.

In addition to the neuroprotective biologic effects of early LAI usage, I’ve found that many of my FEP patients find great psychological comfort from incorporating LAIs into their treatment plan. The first psychotic break is generally when a person (and their family) feels the most afraid about the future and is in desperate need of hope that they can have a full life—with educational opportunities, sustained employment, meaningful relationships, and more. Just as society has seen the COVID-19 vaccines as a symbol of hope and the first step in overcoming the oppression of living in fear of an uncertain future, we need to help people experiencing FEP find hope in a needle.

Craig Chepke, MD, FAPA
Excel Psychiatric Associates
Huntersville, North Carolina

Reference

1. Chepke C. Drive-up pharmacotherapy during the COVID-19 pandemic. Current Psychiatry. 2020;19(5):29-30.

Dr. Nasrallah responds

Thank you, Dr. Chepke, for your letter confirming full support for using LAIs in schizophrenia. I like the phrase you coined: “hope in a needle.” The early use of LAIs in schizophrenia can provide the same type of hope that the vaccines against the life-threatening COVID-19 virus have generated in our society. Based on my direct observations, I also agree with you that the longer patients with schizophrenia remain on LAIs, the more engaged and happy they are with their progress and the quality of their lives. It is tragic that many patients never had the opportunity to return to their baseline with the early use of LAIs immediately following their first psychotic episode, instead of relapsing again and again due to their inability to adhere completely to their oral medications.

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: LAIs as the standard of care

Thank you, Dr. Nasrallah, for reiterating the importance of compliance with pharmacologic management of schizophrenia after FEP (From the Editor, Current Psychiatry, May 2021, p. 9-12). Long before LAIs, I appreciated the successes patients with schizophrenia experienced when they complied with treatment after the first episode. It was clear that success was forthcoming for patients who had an interested psychiatrist and a committed relationship with them.

As you point out in your editorial, the facts are powerful, well-known, undisputed, and yet not adopted in the United States, when in other countries LAIs are first-line care. Yes, LAIs are expensive, but not nearly as expensive as the disabilities caused by noncompliance are to society.

Why isn’t LAI use the standard of care here in the United States? In the United States, there is advocacy for treatment because there’s money in it. There is no good advocacy for preventive care because there’s no immediate money in it. We have another good example of this in the United States: private, for-profit prisons. They have a vested interest in keeping prisons full and building new ones. Patients with FEP are most often treated in the hospital, where a standard of care could easily be established that mandates LAIs as first-tier care. Why is that not so? Who is pushing for it? Who is resisting?

Your editorial inspired me to advocate more strongly. Do you have advice about how to effect policy change? I know administrators respond when we talk dollars and cents, not quality of care. What is the dollar cost of not using LAIs as the standard of care after FEP? Who cares? Who would listen to the numbers?

Edward A. Major, MD, LFAPA
Clinical Professor of Psychiatry
Upstate Medical Center
Syracuse, New York

Dr. Nasrallah responds

Dr. Major, thanks for your message. Establishing a standard of care for the use of LAIs (or any other therapy) is not that simple. It requires well-coordinated collaboration among several stakeholders (clinicians, researchers, payors, advocacy groups, and a national organization such as the American Psychiatric Association). The cost issue is certainly powerful, but the equation works in favor of LAIs because 1 psychiatric hospitalization due to a psychotic relapse costs up to 3 times the annual cost of an LAI medication that can prevent that rehospitalization. In addition, disability comprises the lion’s share of the large indirect costs of schizophrenia (disability payments, lifetime room and board, incarceration and legal costs, and loss of work and generation of taxes). LAIs can save both lives and expenditures, and a lot of suffering by patients and their families. I, too, long to see the emergence of a rational standard of care for schizophrenia using LAIs right after the initial psychotic episode. Oncology and cardiology have standards of care, so why not psychiatry?

Henry A. Nasrallah, MD
Editor-In-Chief

Continue to: Psychosis and epilepsy

I just read your editorial regarding the devastating consequences of psychotic relapses (From the Editor, Current Psychiatry, May 2021, p. 9-12). I was shocked to read of the extent of the damage caused by such relapses and the positive impact of LAIs, and I thank you for opening my eyes. 

I work in the spheres of psychiatry, epileptology, and whole genome sequencing, and have experienced a psychotic episode myself (in 2013, after temporal lobe resection and overdose). I now consider myself even more lucky to be out the other side! As Governor for South London and Maudsley NHS Foundation Trust (SLaM) and Trustee for Epilepsy Action, many of our patients have psychosis. Some patients with epilepsy even experience postictal psychosis. Just yesterday, we had a call at SLaM regarding patients from a secure unit, and a psychiatric nurse spoke about patients at risk to themselves and others because of their psychotic illness, and how crucial effective long-term care was.

Torie Robinson
CEO, Epilepsy Sparks

Dr. Nasrallah responds

Ms. Robinson, thank you for sharing your story. It is important to note that the neuro­biology of the psychosis that may occur with epilepsy may not be as neurodegenerative as the psychosis of schizophrenia. Many neurologic conditions can be associated with psychotic episodes, not only epilepsy. I am glad you overcame your post-temporal lobectomy psychotic episode and have had a very good outcome with high functioning.

Henry A. Nasrallah, MD
Editor-In-Chief

Disclosures
Dr. Chepke is a consultant to and speaker for Janssen Pharmaceuticals, Otsuka Pharmaceuticals, and Alkermes. The other authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

Mr. B, age 32, was diagnosed with bipolar disorder 10 years ago after experiencing a manic episode that resulted in his first psychiatric hospitalization. He was prescribed quetiapine, 400 mg/d, and remained stable for the next several years. Unfortunately, Mr. B developed significant metabolic adverse effects, including diabetes and a 30-pound weight gain, so he was switched from quetiapine to lithium. Mr. B was unable to tolerate the sedation and cognitive effects of lithium, and the dose could not be titrated to within the therapeutic window. As a result, Mr. B experienced a moderate depressive episode. His current clinician would like to initiate lamotrigine at a starting dose of 25 mg/d. Mr. B has not had a manic episode since the index hospitalization, and this is his first depressive episode.

The term “mood stabilizer” has come to refer to medications that treat a depressive and/or manic episode without inducing the other. In conventional terms, it refers to non-antipsychotic medications such as lithium, divalproex, and lamotrigine. Except for lithium, mood stabilizers are also antiepileptic drugs (AEDs). The role of AEDs for treating psychiatric conditions was discovered after they were originally FDA-approved for treating seizures. Following this discovery, the recommended doses and therapeutic ranges for these agents when applied to psychiatric treatment fell into a gray area.

Every patient is different and requires an individualized treatment plan, but this often leaves the clinician wondering, “How high is too high for this mood stabilizer?” or “My patient is responding well, but could a higher dose be even more effective?” In the case of Mr. B, who has trialed 2 medications with poor tolerability, how high can the lamotrigine dose be titrated to achieve a therapeutic response without adverse effects? The literature on this topic does not provide an exact answer, but does shed some light on key considerations for such decisions.

Which mood stabilizers are recommended?

One of the most recently updated guidelines for the treatment of bipolar disorder was released in 2018 by the Canadian Network for Mood and Anxiety Treatments (CANMAT).¹ Lithium, divalproex, and lamotrigine were each recommended as a first-line option for treating bipolar disorder. For lithium and divalproex, the CANMAT guidelines recommend serum level monitoring for efficacy and tolerability; however, they do not recommend serum level monitoring for lamotrigine. Lithium and divalproex each have safety and tolerability concerns, particularly when selected for maintenance therapy, whereas lamotrigine is typically much better tolerated.¹ Divalproex and lithium can cause weight gain, gastrointestinal adverse effects (nausea, vomiting, diarrhea), and tremor. Additional tolerability concerns with lithium include renal toxicity, electrocardiogram abnormalities, hypothyroidism, cognitive impairment, and dermatologic reactions. Divalproex can produce greater levels of sedation and may impact reproductive function (oligomenorrhea or hyperandrogenism). One of the most common adverse effects of lamotrigine is a non-serious rash; however, slow dose titration is necessary to decrease the risk of a serious, life-threatening rash such as Stevens-Johnson syndrome.

Lithium

Lithium continues to be regarded as a gold-standard therapy for bipolar disorder. The exact serum levels corresponding to efficacy and tolerability vary. The Lithiumeter: Version 2.0 is a schematic that incorporates the various levels recommended by different clinical guidelines.² The recommended serum levels range from 0.6 to 1.0 mEq/L for mania and 0.4 to 0.8 mEq/L for depression.² One of the main issues with lithium dosing is balancing a therapeutic level with tolerability and toxicity. Toxicity may begin when lithium levels exceed 1.2 mEq/L, and levels >2.0 mEq/L can be lethal. Signs of acute toxicity include tremor, headache, arrhythmia, nausea, vomiting, diarrhea, polyuria, and polydipsia. Conversely, chronic lithium use may lead to chronic toxicity as patients age and their physical health changes. Signs of chronic toxicity include ataxia, confusion, renal dysfunction, and tremor. There is no “one size fits all” when it comes to lithium dosing. Individualized dosing is necessary to balance efficacy and tolerability.

Divalproex

Divalproex was initially studied for use as an AED, and its therapeutic levels as an AED are not the same as those indicated for bipolar disorder. Generally, patients with bipolar disorder require a divalproex serum level >50 µg/mL. Ranges closer to 100 µg/mL have been found to be most effective for treating acute mania.³ A loading dose of 20 to 30 mg/kg/d can be administered to help achieve mood stabilization. Again, efficacy must be balanced against toxicity. The maximum dose of divalproex is 60 mg/kg/d, which is rarely seen in psychiatric practice. Early studies of divalproex found adverse effects greatest in individuals with plasma levels >100 µg/mL. Reported adverse effects included alopecia, weight gain, tremor, and mental status changes.⁴

Lamotrigine

Unlike lithium and divalproex, lamotrigine therapeutic drug monitoring is not common. The accepted therapeutic reference range (TRR) for lamotrigine as an AED is 3,000 to 14,000 ng/mL. Unholzer et al⁵ evaluated the dose and TRR for individuals with bipolar disorder treated with lamotrigine. No statistically significant difference in lamotrigine serum levels was found in responders vs nonresponders.⁵ Most patients were prescribed ≤200 mg/d; however, some were prescribed higher doses. The maximum dose recommended when lamotrigine is used as an AED is 400 mg/d; however, this study furthered the evidence that lower doses tend to be effective in bipolar disorder.

Continue to: CASE

It has been 3 months since Mr. B was initiated on lamotrigine, and he has since been titrated to his current, stable dose of 100 mg/d. Mr. B is no longer experiencing the sedation he had with lithium and has the energy to commit to an exercise routine. This has allowed him to lose 15 pounds so far and greatly improve control of his diabetes.

Dosage summary

Most available evidence supports dosing lithium and divalproex to effect, typically seen between 0.6 to 1.0 mEq/L and 50 to 125 µg/mL, respectively. Higher plasma levels tend to correspond to more adverse effects and toxicity. Lamotrigine does not have such a narrow therapeutic window. Lamotrigine for psychiatric treatment yields greatest efficacy at approximately 200 mg/d, but doses can be increased if warranted, which could be the case in Mr. B.

Table 1^1-5 outlines dosing strategies and therapeutic serum levels for lithium, divalproex, and lamotrigine. Table 2² lists signs and symptoms of lithium toxicity, and Table 3^1,2 describes strategies for managing adverse effects of lithium and divalproex.

Mr. B, age 32, was diagnosed with bipolar disorder 10 years ago after experiencing a manic episode that resulted in his first psychiatric hospitalization. He was prescribed quetiapine, 400 mg/d, and remained stable for the next several years. Unfortunately, Mr. B developed significant metabolic adverse effects, including diabetes and a 30-pound weight gain, so he was switched from quetiapine to lithium. Mr. B was unable to tolerate the sedation and cognitive effects of lithium, and the dose could not be titrated to within the therapeutic window. As a result, Mr. B experienced a moderate depressive episode. His current clinician would like to initiate lamotrigine at a starting dose of 25 mg/d. Mr. B has not had a manic episode since the index hospitalization, and this is his first depressive episode.

The term “mood stabilizer” has come to refer to medications that treat a depressive and/or manic episode without inducing the other. In conventional terms, it refers to non-antipsychotic medications such as lithium, divalproex, and lamotrigine. Except for lithium, mood stabilizers are also antiepileptic drugs (AEDs). The role of AEDs for treating psychiatric conditions was discovered after they were originally FDA-approved for treating seizures. Following this discovery, the recommended doses and therapeutic ranges for these agents when applied to psychiatric treatment fell into a gray area.

Every patient is different and requires an individualized treatment plan, but this often leaves the clinician wondering, “How high is too high for this mood stabilizer?” or “My patient is responding well, but could a higher dose be even more effective?” In the case of Mr. B, who has trialed 2 medications with poor tolerability, how high can the lamotrigine dose be titrated to achieve a therapeutic response without adverse effects? The literature on this topic does not provide an exact answer, but does shed some light on key considerations for such decisions.

Which mood stabilizers are recommended?

One of the most recently updated guidelines for the treatment of bipolar disorder was released in 2018 by the Canadian Network for Mood and Anxiety Treatments (CANMAT).¹ Lithium, divalproex, and lamotrigine were each recommended as a first-line option for treating bipolar disorder. For lithium and divalproex, the CANMAT guidelines recommend serum level monitoring for efficacy and tolerability; however, they do not recommend serum level monitoring for lamotrigine. Lithium and divalproex each have safety and tolerability concerns, particularly when selected for maintenance therapy, whereas lamotrigine is typically much better tolerated.¹ Divalproex and lithium can cause weight gain, gastrointestinal adverse effects (nausea, vomiting, diarrhea), and tremor. Additional tolerability concerns with lithium include renal toxicity, electrocardiogram abnormalities, hypothyroidism, cognitive impairment, and dermatologic reactions. Divalproex can produce greater levels of sedation and may impact reproductive function (oligomenorrhea or hyperandrogenism). One of the most common adverse effects of lamotrigine is a non-serious rash; however, slow dose titration is necessary to decrease the risk of a serious, life-threatening rash such as Stevens-Johnson syndrome.

Lithium

Lithium continues to be regarded as a gold-standard therapy for bipolar disorder. The exact serum levels corresponding to efficacy and tolerability vary. The Lithiumeter: Version 2.0 is a schematic that incorporates the various levels recommended by different clinical guidelines.² The recommended serum levels range from 0.6 to 1.0 mEq/L for mania and 0.4 to 0.8 mEq/L for depression.² One of the main issues with lithium dosing is balancing a therapeutic level with tolerability and toxicity. Toxicity may begin when lithium levels exceed 1.2 mEq/L, and levels >2.0 mEq/L can be lethal. Signs of acute toxicity include tremor, headache, arrhythmia, nausea, vomiting, diarrhea, polyuria, and polydipsia. Conversely, chronic lithium use may lead to chronic toxicity as patients age and their physical health changes. Signs of chronic toxicity include ataxia, confusion, renal dysfunction, and tremor. There is no “one size fits all” when it comes to lithium dosing. Individualized dosing is necessary to balance efficacy and tolerability.

Divalproex

Divalproex was initially studied for use as an AED, and its therapeutic levels as an AED are not the same as those indicated for bipolar disorder. Generally, patients with bipolar disorder require a divalproex serum level >50 µg/mL. Ranges closer to 100 µg/mL have been found to be most effective for treating acute mania.³ A loading dose of 20 to 30 mg/kg/d can be administered to help achieve mood stabilization. Again, efficacy must be balanced against toxicity. The maximum dose of divalproex is 60 mg/kg/d, which is rarely seen in psychiatric practice. Early studies of divalproex found adverse effects greatest in individuals with plasma levels >100 µg/mL. Reported adverse effects included alopecia, weight gain, tremor, and mental status changes.⁴

Lamotrigine

Unlike lithium and divalproex, lamotrigine therapeutic drug monitoring is not common. The accepted therapeutic reference range (TRR) for lamotrigine as an AED is 3,000 to 14,000 ng/mL. Unholzer et al⁵ evaluated the dose and TRR for individuals with bipolar disorder treated with lamotrigine. No statistically significant difference in lamotrigine serum levels was found in responders vs nonresponders.⁵ Most patients were prescribed ≤200 mg/d; however, some were prescribed higher doses. The maximum dose recommended when lamotrigine is used as an AED is 400 mg/d; however, this study furthered the evidence that lower doses tend to be effective in bipolar disorder.

Continue to: CASE

It has been 3 months since Mr. B was initiated on lamotrigine, and he has since been titrated to his current, stable dose of 100 mg/d. Mr. B is no longer experiencing the sedation he had with lithium and has the energy to commit to an exercise routine. This has allowed him to lose 15 pounds so far and greatly improve control of his diabetes.

Dosage summary

Most available evidence supports dosing lithium and divalproex to effect, typically seen between 0.6 to 1.0 mEq/L and 50 to 125 µg/mL, respectively. Higher plasma levels tend to correspond to more adverse effects and toxicity. Lamotrigine does not have such a narrow therapeutic window. Lamotrigine for psychiatric treatment yields greatest efficacy at approximately 200 mg/d, but doses can be increased if warranted, which could be the case in Mr. B.

Table 1^1-5 outlines dosing strategies and therapeutic serum levels for lithium, divalproex, and lamotrigine. Table 2² lists signs and symptoms of lithium toxicity, and Table 3^1,2 describes strategies for managing adverse effects of lithium and divalproex.

Mr. B, age 32, was diagnosed with bipolar disorder 10 years ago after experiencing a manic episode that resulted in his first psychiatric hospitalization. He was prescribed quetiapine, 400 mg/d, and remained stable for the next several years. Unfortunately, Mr. B developed significant metabolic adverse effects, including diabetes and a 30-pound weight gain, so he was switched from quetiapine to lithium. Mr. B was unable to tolerate the sedation and cognitive effects of lithium, and the dose could not be titrated to within the therapeutic window. As a result, Mr. B experienced a moderate depressive episode. His current clinician would like to initiate lamotrigine at a starting dose of 25 mg/d. Mr. B has not had a manic episode since the index hospitalization, and this is his first depressive episode.

The term “mood stabilizer” has come to refer to medications that treat a depressive and/or manic episode without inducing the other. In conventional terms, it refers to non-antipsychotic medications such as lithium, divalproex, and lamotrigine. Except for lithium, mood stabilizers are also antiepileptic drugs (AEDs). The role of AEDs for treating psychiatric conditions was discovered after they were originally FDA-approved for treating seizures. Following this discovery, the recommended doses and therapeutic ranges for these agents when applied to psychiatric treatment fell into a gray area.

Every patient is different and requires an individualized treatment plan, but this often leaves the clinician wondering, “How high is too high for this mood stabilizer?” or “My patient is responding well, but could a higher dose be even more effective?” In the case of Mr. B, who has trialed 2 medications with poor tolerability, how high can the lamotrigine dose be titrated to achieve a therapeutic response without adverse effects? The literature on this topic does not provide an exact answer, but does shed some light on key considerations for such decisions.

Which mood stabilizers are recommended?

One of the most recently updated guidelines for the treatment of bipolar disorder was released in 2018 by the Canadian Network for Mood and Anxiety Treatments (CANMAT).¹ Lithium, divalproex, and lamotrigine were each recommended as a first-line option for treating bipolar disorder. For lithium and divalproex, the CANMAT guidelines recommend serum level monitoring for efficacy and tolerability; however, they do not recommend serum level monitoring for lamotrigine. Lithium and divalproex each have safety and tolerability concerns, particularly when selected for maintenance therapy, whereas lamotrigine is typically much better tolerated.¹ Divalproex and lithium can cause weight gain, gastrointestinal adverse effects (nausea, vomiting, diarrhea), and tremor. Additional tolerability concerns with lithium include renal toxicity, electrocardiogram abnormalities, hypothyroidism, cognitive impairment, and dermatologic reactions. Divalproex can produce greater levels of sedation and may impact reproductive function (oligomenorrhea or hyperandrogenism). One of the most common adverse effects of lamotrigine is a non-serious rash; however, slow dose titration is necessary to decrease the risk of a serious, life-threatening rash such as Stevens-Johnson syndrome.

Lithium

Lithium continues to be regarded as a gold-standard therapy for bipolar disorder. The exact serum levels corresponding to efficacy and tolerability vary. The Lithiumeter: Version 2.0 is a schematic that incorporates the various levels recommended by different clinical guidelines.² The recommended serum levels range from 0.6 to 1.0 mEq/L for mania and 0.4 to 0.8 mEq/L for depression.² One of the main issues with lithium dosing is balancing a therapeutic level with tolerability and toxicity. Toxicity may begin when lithium levels exceed 1.2 mEq/L, and levels >2.0 mEq/L can be lethal. Signs of acute toxicity include tremor, headache, arrhythmia, nausea, vomiting, diarrhea, polyuria, and polydipsia. Conversely, chronic lithium use may lead to chronic toxicity as patients age and their physical health changes. Signs of chronic toxicity include ataxia, confusion, renal dysfunction, and tremor. There is no “one size fits all” when it comes to lithium dosing. Individualized dosing is necessary to balance efficacy and tolerability.

Divalproex

Divalproex was initially studied for use as an AED, and its therapeutic levels as an AED are not the same as those indicated for bipolar disorder. Generally, patients with bipolar disorder require a divalproex serum level >50 µg/mL. Ranges closer to 100 µg/mL have been found to be most effective for treating acute mania.³ A loading dose of 20 to 30 mg/kg/d can be administered to help achieve mood stabilization. Again, efficacy must be balanced against toxicity. The maximum dose of divalproex is 60 mg/kg/d, which is rarely seen in psychiatric practice. Early studies of divalproex found adverse effects greatest in individuals with plasma levels >100 µg/mL. Reported adverse effects included alopecia, weight gain, tremor, and mental status changes.⁴

Lamotrigine

Unlike lithium and divalproex, lamotrigine therapeutic drug monitoring is not common. The accepted therapeutic reference range (TRR) for lamotrigine as an AED is 3,000 to 14,000 ng/mL. Unholzer et al⁵ evaluated the dose and TRR for individuals with bipolar disorder treated with lamotrigine. No statistically significant difference in lamotrigine serum levels was found in responders vs nonresponders.⁵ Most patients were prescribed ≤200 mg/d; however, some were prescribed higher doses. The maximum dose recommended when lamotrigine is used as an AED is 400 mg/d; however, this study furthered the evidence that lower doses tend to be effective in bipolar disorder.

Continue to: CASE

It has been 3 months since Mr. B was initiated on lamotrigine, and he has since been titrated to his current, stable dose of 100 mg/d. Mr. B is no longer experiencing the sedation he had with lithium and has the energy to commit to an exercise routine. This has allowed him to lose 15 pounds so far and greatly improve control of his diabetes.

Dosage summary

Most available evidence supports dosing lithium and divalproex to effect, typically seen between 0.6 to 1.0 mEq/L and 50 to 125 µg/mL, respectively. Higher plasma levels tend to correspond to more adverse effects and toxicity. Lamotrigine does not have such a narrow therapeutic window. Lamotrigine for psychiatric treatment yields greatest efficacy at approximately 200 mg/d, but doses can be increased if warranted, which could be the case in Mr. B.

Table 1^1-5 outlines dosing strategies and therapeutic serum levels for lithium, divalproex, and lamotrigine. Table 2² lists signs and symptoms of lithium toxicity, and Table 3^1,2 describes strategies for managing adverse effects of lithium and divalproex.

The impact of the COVID-19 pandemic on the well-being of youth has been significant. Its possible effects range from boredom, depression, anxiety, and suicidal ideation to potential increased rates of internet gaming disorder (IGD), which may have worsened during a nationwide shutdown and extended period of limited social interactions. Presently, there is a paucity of research on the impact of internet gaming on children and adolescents’ mental health and well-being during COVID-19. This article aims to bring awareness to the possible rising impact of the COVID-19 pandemic on IGD and mental health in youth.

Gaming offers benefits—and risks

The gaming industry has grown immensely over the past several years. While many businesses were impacted negatively during the pandemic, the gaming industry grew. It was estimated to be worth $159.3 billion in 2020, an increase of 9.3% from 2019.¹

Stay-at-home orders and quarantine protocols during the COVID-19 pandemic have significantly disrupted normal activities, resulting in increased time for digital entertainment, including online gaming and related activities. Internet gaming offers some benefits for children and adolescents, including socialization and connection with peers, which was especially important for avoiding isolation during the pandemic. Empirical evidence of the positive effects of internet gaming can be seen in studies of youth undergoing chemotherapy, those receiving psychotherapy for anxiety or depression, and those having emotional and behavioral problems.² Internet gaming also provides participants with a platform to communicate with the outside world while maintaining social distancing, and might reduce anxiety, and in some cases, depression.³

Despite these benefits, for some youth, excessive internet gaming can have adverse effects. Due to its addictive properties, internet gaming can be dangerous for vulnerable individuals and lead to unhealthy habits, such as disturbed sleep patterns and increased anxiety.⁴ In a cross-sectional study conducted in China, Yu et al⁵ examined the association between IGD and suicidal ideation. They concluded that IGD was positively associated with insomnia and then depression, which in turn contributed to suicide ideation.⁵ A study based on a survey conducted in Iran from May to August 2020 in individuals age 13 to 18 years found that depression, anxiety, and stress were significant mediators in the association between IGD and self-reported quality of life.²

Internet gaming disorder is included in DSM-5 as a “condition for further study” and in ICD-11.⁶ Before the COVID-19 pandemic, a study of 1,178 American youth age 8 to 18 years revealed that 8.5% of gamers met the criteria for IGD.⁷ In a meta-analysis that included 16 studies, the pooled prevalence of IGD among adolescents was 4.6%.⁸ Some countries, including China and South Korea, have developed treatment plans for IGD,⁶ but in the United States treatment guidelines have not been established due to insufficient evidence.⁹

The COVID-19 pandemic has likely led to an increased number of children and adolescents with IGD and its adverse effects on their mental health and well-being. It remains to be seen whether these youth will improve as the pandemic resolves and they resume normal activities, or if impairments will persist.

In conclusion, while internet gaming during the COVID-19 pandemic has provided benefits for many children and adolescents, the negative impact for those who develop IGD may be significant. We should be prepared to detect and address the needs of these youth and their families. Additional research is needed on the post-pandemic prevalence of IGD, its impact on youth mental health, and treatment strategies.

The impact of the COVID-19 pandemic on the well-being of youth has been significant. Its possible effects range from boredom, depression, anxiety, and suicidal ideation to potential increased rates of internet gaming disorder (IGD), which may have worsened during a nationwide shutdown and extended period of limited social interactions. Presently, there is a paucity of research on the impact of internet gaming on children and adolescents’ mental health and well-being during COVID-19. This article aims to bring awareness to the possible rising impact of the COVID-19 pandemic on IGD and mental health in youth.

Gaming offers benefits—and risks

The gaming industry has grown immensely over the past several years. While many businesses were impacted negatively during the pandemic, the gaming industry grew. It was estimated to be worth $159.3 billion in 2020, an increase of 9.3% from 2019.¹

Stay-at-home orders and quarantine protocols during the COVID-19 pandemic have significantly disrupted normal activities, resulting in increased time for digital entertainment, including online gaming and related activities. Internet gaming offers some benefits for children and adolescents, including socialization and connection with peers, which was especially important for avoiding isolation during the pandemic. Empirical evidence of the positive effects of internet gaming can be seen in studies of youth undergoing chemotherapy, those receiving psychotherapy for anxiety or depression, and those having emotional and behavioral problems.² Internet gaming also provides participants with a platform to communicate with the outside world while maintaining social distancing, and might reduce anxiety, and in some cases, depression.³

Despite these benefits, for some youth, excessive internet gaming can have adverse effects. Due to its addictive properties, internet gaming can be dangerous for vulnerable individuals and lead to unhealthy habits, such as disturbed sleep patterns and increased anxiety.⁴ In a cross-sectional study conducted in China, Yu et al⁵ examined the association between IGD and suicidal ideation. They concluded that IGD was positively associated with insomnia and then depression, which in turn contributed to suicide ideation.⁵ A study based on a survey conducted in Iran from May to August 2020 in individuals age 13 to 18 years found that depression, anxiety, and stress were significant mediators in the association between IGD and self-reported quality of life.²

Internet gaming disorder is included in DSM-5 as a “condition for further study” and in ICD-11.⁶ Before the COVID-19 pandemic, a study of 1,178 American youth age 8 to 18 years revealed that 8.5% of gamers met the criteria for IGD.⁷ In a meta-analysis that included 16 studies, the pooled prevalence of IGD among adolescents was 4.6%.⁸ Some countries, including China and South Korea, have developed treatment plans for IGD,⁶ but in the United States treatment guidelines have not been established due to insufficient evidence.⁹

The COVID-19 pandemic has likely led to an increased number of children and adolescents with IGD and its adverse effects on their mental health and well-being. It remains to be seen whether these youth will improve as the pandemic resolves and they resume normal activities, or if impairments will persist.

In conclusion, while internet gaming during the COVID-19 pandemic has provided benefits for many children and adolescents, the negative impact for those who develop IGD may be significant. We should be prepared to detect and address the needs of these youth and their families. Additional research is needed on the post-pandemic prevalence of IGD, its impact on youth mental health, and treatment strategies.

The impact of the COVID-19 pandemic on the well-being of youth has been significant. Its possible effects range from boredom, depression, anxiety, and suicidal ideation to potential increased rates of internet gaming disorder (IGD), which may have worsened during a nationwide shutdown and extended period of limited social interactions. Presently, there is a paucity of research on the impact of internet gaming on children and adolescents’ mental health and well-being during COVID-19. This article aims to bring awareness to the possible rising impact of the COVID-19 pandemic on IGD and mental health in youth.

Gaming offers benefits—and risks

The gaming industry has grown immensely over the past several years. While many businesses were impacted negatively during the pandemic, the gaming industry grew. It was estimated to be worth $159.3 billion in 2020, an increase of 9.3% from 2019.¹

Stay-at-home orders and quarantine protocols during the COVID-19 pandemic have significantly disrupted normal activities, resulting in increased time for digital entertainment, including online gaming and related activities. Internet gaming offers some benefits for children and adolescents, including socialization and connection with peers, which was especially important for avoiding isolation during the pandemic. Empirical evidence of the positive effects of internet gaming can be seen in studies of youth undergoing chemotherapy, those receiving psychotherapy for anxiety or depression, and those having emotional and behavioral problems.² Internet gaming also provides participants with a platform to communicate with the outside world while maintaining social distancing, and might reduce anxiety, and in some cases, depression.³

Despite these benefits, for some youth, excessive internet gaming can have adverse effects. Due to its addictive properties, internet gaming can be dangerous for vulnerable individuals and lead to unhealthy habits, such as disturbed sleep patterns and increased anxiety.⁴ In a cross-sectional study conducted in China, Yu et al⁵ examined the association between IGD and suicidal ideation. They concluded that IGD was positively associated with insomnia and then depression, which in turn contributed to suicide ideation.⁵ A study based on a survey conducted in Iran from May to August 2020 in individuals age 13 to 18 years found that depression, anxiety, and stress were significant mediators in the association between IGD and self-reported quality of life.²

Internet gaming disorder is included in DSM-5 as a “condition for further study” and in ICD-11.⁶ Before the COVID-19 pandemic, a study of 1,178 American youth age 8 to 18 years revealed that 8.5% of gamers met the criteria for IGD.⁷ In a meta-analysis that included 16 studies, the pooled prevalence of IGD among adolescents was 4.6%.⁸ Some countries, including China and South Korea, have developed treatment plans for IGD,⁶ but in the United States treatment guidelines have not been established due to insufficient evidence.⁹

The COVID-19 pandemic has likely led to an increased number of children and adolescents with IGD and its adverse effects on their mental health and well-being. It remains to be seen whether these youth will improve as the pandemic resolves and they resume normal activities, or if impairments will persist.

In conclusion, while internet gaming during the COVID-19 pandemic has provided benefits for many children and adolescents, the negative impact for those who develop IGD may be significant. We should be prepared to detect and address the needs of these youth and their families. Additional research is needed on the post-pandemic prevalence of IGD, its impact on youth mental health, and treatment strategies.

CASE Aggressive behaviors, psychosis

Ms. N, age 58, has a long history of bipolar disorder with psychotic features. She presents to our emergency department (ED) after an acute fall and frequent violent behaviors at her nursing home, where she had resided since being diagnosed with an unspecified neurocognitive disorder. For several weeks before her fall, she was physically aggressive, throwing objects at nursing home staff, and was unable to have her behavior redirected.

While in the ED, Ms. N rambles and appears to be responding to internal stimuli. Suddenly, she stops responding and begins to stare.

HISTORY Severe, chronic psychosis and hospitalization

Ms. N is well-known at our inpatient psychiatry and electroconvulsive therapy (ECT) services. During the last 10 years, she has had worsening manic, psychotic, and catatonic (both excited and stuporous subtype) episodes. Three years ago, she had experienced a period of severe, chronic psychosis and excited catatonia that required extended inpatient treatment. While hospitalized, Ms. N had marginal responses to clozapine and benzodiazepines, but improved dramatically with ECT. After Ms. N left the hospital, she went to live with her boyfriend. She remained stable on monthly maintenance ECT treatments (bifrontal) before she was lost to follow-up 14 months prior to the current presentation. Ms. N’s family reports that she needed a cardiac clearance before continuing ECT treatment; however, she was hospitalized at another hospital with pneumonia and subsequent complications that interrupted the maintenance ECT treatments.

Approximately 3 months after medical issues requiring hospitalization began, Ms. N received a diagnosis of neurocognitive disorder due to difficulty with activities of daily living and cognitive decline. She was transferred to a nursing home by the outside hospital. When Ms. N’s symptoms of psychosis returned and she required inpatient psychiatric care, she was transferred to a nearby facility that did not have ECT available or knowledge of her history of catatonia resistant to pharmacologic management. Ms. N had a documented history of catatonia that spanned 10 years. During the last 4 years, Ms. N often required ECT treatment. Her current medication regimen prescribed by an outpatient psychiatrist includes clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily, both for bipolar disorder.

EVALUATION An unusual mix of symptoms

In the ED, Ms. N undergoes a CT of the head, which is found to be nonacute. Laboratory results show that her white blood cell count is 14.3 K/µL, which is mildly elevated. Results from a urinalysis and electrocardiogram (ECG) are unremarkable.

After Ms. N punches a radiology technician, she is administered IV lorazepam, 2 mg once, for her agitation. Twenty minutes after receiving IV lorazepam, she is calm and cooperative. However, approximately 4 hours later, Ms. N is yelling, tearful, and expressing delusions of grandeur—she believes she is God.

After she is admitted to the medical floor, Ms. N is seen by our consultation and liaison psychiatry service. She exhibits several signs of catatonia, including grasp reflex, gegenhalten (oppositional paratonia), waxy flexibility, and echolalia. Ms. N also has an episode of urinary incontinence. At some parts of the day, she is alert and oriented to self and location; at other times, she is somnolent and disoriented. The treatment team continues Ms. N’s previous medication regimen of clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily. Unfortunately, at times Ms. N spits out and hides her administered oral medications, which leads to the decision to discontinue clozapine. Once medically cleared, Ms. N is transferred to the psychiatric floor.

[polldaddy:10869949]

Continue to: TREATMENT

TREATMENT Bifrontal ECT initiated

On hospital Day 3 Ms. N is administered a trial of IM lorazepam, titrated up to 6 mg/d (maximum tolerated dose) while the treatment team initiates the legal process to conduct ECT because she is unable to give consent. Once Ms. N begins tolerating oral medications, amantadine, 100 mg twice daily, is added to treat her catatonia. As in prior hospitalizations, Ms. N is unresponsive to pharmacotherapy alone for her catatonic symptoms. On hospital Day 8, forced ECT is granted, which is 5 days after the process of filing paperwork was started. Bifrontal ECT is utilized with the following settings: frequency 70 Hz, pulse width 1.5 ms, 100% energy dose, 504 mC. Ms. N does not experience a significant improvement until she receives 10 ECT treatments as part of a 3-times-per-week acute series protocol. The Bush-Francis Catatonia Rating Scale (BFCRS) and the KANNER scale are used to monitor her progress. Her initial BFCRS score is 17 and initial KANNER scale, part 2 score is 26.

Ms. N spends a total of 61 days in the hospital, which is significantly longer than her previous hospital admissions on our psychiatric unit; these previous admissions were for treatment of both stuporous and excited subtypes of catatonia. This increased length of stay coincides with a significantly longer duration of untreated catatonia. Knowledge of her history of both the stuporous and excited subtypes of catatonia would have allowed for faster diagnosis and treatment.¹

The authors’ observations

Originally conceptualized as a separate syndrome by Karl Kahlbaum, catatonia was considered only as a specifier for neuropsychiatric conditions (primarily schizophrenia) as recently as DSM-IV-TR.² DSM-5 describes catatonia as a marked psychomotor disturbance and acknowledges its connection to schizophrenia by keeping it in the same chapter.³ DSM-5 includes separate diagnoses for catatonia, catatonia due to a general medical condition, and unspecified catatonia (for catatonia without a known underlying disorder).³ A recent meta-analysis found the prevalence of catatonia is higher in patients with medical/neurologic illness, bipolar disorder, and autism than in those with schizophrenia.⁴

Table 1³ highlights the DSM-5 criteria for catatonia. DSM-5 requires 3 of 12 symptoms to be present, although symptoms may fluctuate with time.³ If a clinician is not specifically looking for catatonia, it can be a difficult syndrome to diagnose. Does rigidity indicate catatonia, or excessive dopamine blockade from an antipsychotic? How can seemingly contradictory symptoms be part of the same syndrome? Many clinicians associate catatonia with the stuporous subtype (immobility, posturing, catalepsy), which is more prevalent, but the excited subtype, which may involve severe agitation, autonomic dysfunction, and impaired consciousness, can be lethal.² The diversity in presentation of catatonia is not unlike the challenging variety of symptoms of heart attacks.

A retrospective study of all adults admitted to a hospital found that only 41% of patients who met criteria for catatonia received this diagnosis.⁵ Further complicating the diagnosis, delirium and catatonia can co-exist; one study found this was the case in 1 of 3 critically ill patients.⁶ DSM-5 criteria for catatonia due to another medical condition exclude the diagnosis if delirium is present, but this study and others suggest this needs to be reconsidered.³   

Continue to: A standardized evaluation is key

A standardized evaluation is key

Just as a patient who presents with chest pain requires a standardized evaluation, including a pertinent history, laboratory workup, and ECG, psychiatrists may also use standardized diagnostic instruments to aid in the diagnosis of catatonia. One study of hospitalized patients with schizophrenia found that using a standardized diagnostic procedure for catatonia resulted in a 7-fold increase in the diagnosis.⁷ The BFCRS is the most common standardized instrument for catatonia, likely due to its high inter-rater reliability.⁸ Other scales include the KANNER scale and Northoff Catatonia Scale, which emphasize different aspects of the disease or for certain clinical populations (eg, the KANNER scale adjusts for patients who are nonverbal at baseline). One study suggested that BFCRS has lower reliability for less-severe illness.⁹ These differences emphasize that psychiatry does not have a thorough understanding of the intricacies of catatonia. However, using validated screening tools can lead to more consistent diagnoses and continue important research on this often-misunderstood illness.

Dangers of untreated catatonia

Rapid treatment of catatonia is necessary to prevent mortality. A study of patients in Kentucky’s state psychiatric hospitals found that untreated catatonia with resultant death from pulmonary embolism was the leading cause of preventable death.¹⁰ A 17-year retrospective study of patients with schizophrenia admitted to 1 hospital found that those with catatonia were >4 times as likely to die during hospitalization than those without catatonia.¹¹ The significant morbidity and mortality from untreated catatonia are typically attributed to the consequences of poorly controlled movements, immobility, autonomic instability, and poor/no oral intake. Reduced oral intake can result in malnutrition, dehydration, arrhythmias, and increased risk of infections. Furthermore, chronic catatonic episodes are more difficult to treat.¹² In addition to the aggressive management of neuropsychiatric symptoms, it is vital to evaluate relevant medical etiologies that may be contributing to the syndrome (Table 2¹³). Tracking vital signs and laboratory values, such as creatine kinase, electrolytes, and complete blood count, is required to ensure the medical condition does not become life-threatening.

Treatment options

Studies and expert opinion suggest that benzodiazepines (specifically lorazepam, because it is the most studied agent) are the first-line treatment for catatonia. A lorazepam challenge test—providing 1 or 2 mg of IV lorazepam—is considered diagnostic and therapeutic given the high rate of response within 10 minutes.¹⁴ Patients with limited response to lorazepam or who are medically compromised should undergo ECT. Electroconvulsive therapy is considered the gold-standard treatment for catatonia; estimated response rates range from 59% to 100%, even in patients who fail to respond to pharmacotherapy.¹⁵ Although highly effective, ECT is often hindered by the time required to initiate treatment, stigma, lack of access, and other logistical challenges. 

Table 3^14-18 highlights the advantages and disadvantages of treatment options for catatonia. Some researchers have suggested a zolpidem challenge test could augment lorazepam because some patients respond only to zolpidem.¹⁴ The efficacy of these medications along with some evidence of anti-N-methyl-d-aspartate medications, such as amantadine and memantine, suggest that there is an underactivation of gamma-aminobutyric acid (GABA) and overactivation of glutamate in the brain,¹⁶ with some researchers noting the similarity between catatonia and the fear response.¹⁷ Consequently, excessive dopamine D2 antagonism or withdrawal of dopamine agonists can either bring on or worsen the symptoms of catatonia, with researchers identifying an overlap between neuroleptic malignant syndrome and catatonia.¹⁸ Although some studies suggest that second-generation antipsychotics (SGAs), particularly lower-potency agents such as olanzapine, may help treat catatonia, other studies suggest using caution when initiating in patients without an underlying psychotic illness. The treating clinician may want to consider switching a patient receiving a high-potency antipsychotic to one with a lower potency, lowering the dose of high-potency agent, or discontinuing the medication altogether.

Ms. N was ultimately diagnosed with bipolar disorder, current episode mixed, with psychotic and catatonic features. Ms. N had symptoms of mania including grandiosity, periods of lack of sleep, delusions as well as depressive symptoms of tearfulness and low mood. The treatment team had considered that Ms. N had delirious mania because she had fluctuating sensorium, which included varying degrees of orientation and ability to answer questioning. However, the literature supporting the differentiation between delirious mania and excited catatonia is unclear, and both conditions may respond to ECT.¹⁸ A diagnosis of catatonia allowed the team to use rating scales to track Ms. N’s progress by monitoring for specific signs, such as grasp reflex and waxy flexibility.

Continue to: OUTCOME

OUTCOME Return to baseline

Before discharge, Ms. N’s BFCRS score decreases from the initial score of 17 to 0, and her KANNER scale score decreases from the initial score of 26 to 4, which correlates with vast improvement in clinical presentation. Once Ms. N completes the acute ECT treatment, she returns to her baseline level of functioning, and is discharged to live with her boyfriend. She is advised to continue weekly ECT for the first several months to ensure clinical stability. This regimen is later transitioned to biweekly and then monthly. Electroconvulsive therapy protocols from previous research were utilized in Ms. N’s case, but ultimately the lowest number of ECT treatments needed to maintain stability is determined clinically over many years.¹⁹ Ms. N is discharged on aripiprazole, 15 mg/d; bupropion ER, 300 mg/d (added after depressive symptoms emerge while catatonia symptoms improve midway through her lengthy hospitalization); and memantine, 10 mg/d. Ideally, clozapine would have been continued; however, due to her history of nonadherence and frequent restarting of the medication at a low dose, clozapine was discontinued and aripiprazole initiated.

More than 1 year later, Ms. N remains stable and continues to receive monthly ECT maintenance treatments.

Bottom Line

Catatonia should always be considered in a patient who presents with acute neuropsychiatric symptoms. Rapid diagnosis with standardized screening instruments and aggressive treatment are vital to prevent morbidity and mortality.

Related Resource

• Freudenreich O, Francis A, Fricchione GL. Chapter 9. Psychosis, mania, and catatonia. In: Levenson, James L, ed. The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. 3rd ed. American Psychiatric Association Publishing; 2019.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Baclofen • Ozobax
Bupropion ER • Wellbutrin XL
Clonazepam • Klonopin
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Metoclopramide • Reglan
Memantine • Namenda
Topiramate • Topamax
Zolpidem • Ambien

CASE Aggressive behaviors, psychosis

Ms. N, age 58, has a long history of bipolar disorder with psychotic features. She presents to our emergency department (ED) after an acute fall and frequent violent behaviors at her nursing home, where she had resided since being diagnosed with an unspecified neurocognitive disorder. For several weeks before her fall, she was physically aggressive, throwing objects at nursing home staff, and was unable to have her behavior redirected.

While in the ED, Ms. N rambles and appears to be responding to internal stimuli. Suddenly, she stops responding and begins to stare.

HISTORY Severe, chronic psychosis and hospitalization

Ms. N is well-known at our inpatient psychiatry and electroconvulsive therapy (ECT) services. During the last 10 years, she has had worsening manic, psychotic, and catatonic (both excited and stuporous subtype) episodes. Three years ago, she had experienced a period of severe, chronic psychosis and excited catatonia that required extended inpatient treatment. While hospitalized, Ms. N had marginal responses to clozapine and benzodiazepines, but improved dramatically with ECT. After Ms. N left the hospital, she went to live with her boyfriend. She remained stable on monthly maintenance ECT treatments (bifrontal) before she was lost to follow-up 14 months prior to the current presentation. Ms. N’s family reports that she needed a cardiac clearance before continuing ECT treatment; however, she was hospitalized at another hospital with pneumonia and subsequent complications that interrupted the maintenance ECT treatments.

Approximately 3 months after medical issues requiring hospitalization began, Ms. N received a diagnosis of neurocognitive disorder due to difficulty with activities of daily living and cognitive decline. She was transferred to a nursing home by the outside hospital. When Ms. N’s symptoms of psychosis returned and she required inpatient psychiatric care, she was transferred to a nearby facility that did not have ECT available or knowledge of her history of catatonia resistant to pharmacologic management. Ms. N had a documented history of catatonia that spanned 10 years. During the last 4 years, Ms. N often required ECT treatment. Her current medication regimen prescribed by an outpatient psychiatrist includes clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily, both for bipolar disorder.

EVALUATION An unusual mix of symptoms

In the ED, Ms. N undergoes a CT of the head, which is found to be nonacute. Laboratory results show that her white blood cell count is 14.3 K/µL, which is mildly elevated. Results from a urinalysis and electrocardiogram (ECG) are unremarkable.

After Ms. N punches a radiology technician, she is administered IV lorazepam, 2 mg once, for her agitation. Twenty minutes after receiving IV lorazepam, she is calm and cooperative. However, approximately 4 hours later, Ms. N is yelling, tearful, and expressing delusions of grandeur—she believes she is God.

After she is admitted to the medical floor, Ms. N is seen by our consultation and liaison psychiatry service. She exhibits several signs of catatonia, including grasp reflex, gegenhalten (oppositional paratonia), waxy flexibility, and echolalia. Ms. N also has an episode of urinary incontinence. At some parts of the day, she is alert and oriented to self and location; at other times, she is somnolent and disoriented. The treatment team continues Ms. N’s previous medication regimen of clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily. Unfortunately, at times Ms. N spits out and hides her administered oral medications, which leads to the decision to discontinue clozapine. Once medically cleared, Ms. N is transferred to the psychiatric floor.

[polldaddy:10869949]

Continue to: TREATMENT

TREATMENT Bifrontal ECT initiated

On hospital Day 3 Ms. N is administered a trial of IM lorazepam, titrated up to 6 mg/d (maximum tolerated dose) while the treatment team initiates the legal process to conduct ECT because she is unable to give consent. Once Ms. N begins tolerating oral medications, amantadine, 100 mg twice daily, is added to treat her catatonia. As in prior hospitalizations, Ms. N is unresponsive to pharmacotherapy alone for her catatonic symptoms. On hospital Day 8, forced ECT is granted, which is 5 days after the process of filing paperwork was started. Bifrontal ECT is utilized with the following settings: frequency 70 Hz, pulse width 1.5 ms, 100% energy dose, 504 mC. Ms. N does not experience a significant improvement until she receives 10 ECT treatments as part of a 3-times-per-week acute series protocol. The Bush-Francis Catatonia Rating Scale (BFCRS) and the KANNER scale are used to monitor her progress. Her initial BFCRS score is 17 and initial KANNER scale, part 2 score is 26.

Ms. N spends a total of 61 days in the hospital, which is significantly longer than her previous hospital admissions on our psychiatric unit; these previous admissions were for treatment of both stuporous and excited subtypes of catatonia. This increased length of stay coincides with a significantly longer duration of untreated catatonia. Knowledge of her history of both the stuporous and excited subtypes of catatonia would have allowed for faster diagnosis and treatment.¹

The authors’ observations

Originally conceptualized as a separate syndrome by Karl Kahlbaum, catatonia was considered only as a specifier for neuropsychiatric conditions (primarily schizophrenia) as recently as DSM-IV-TR.² DSM-5 describes catatonia as a marked psychomotor disturbance and acknowledges its connection to schizophrenia by keeping it in the same chapter.³ DSM-5 includes separate diagnoses for catatonia, catatonia due to a general medical condition, and unspecified catatonia (for catatonia without a known underlying disorder).³ A recent meta-analysis found the prevalence of catatonia is higher in patients with medical/neurologic illness, bipolar disorder, and autism than in those with schizophrenia.⁴

Table 1³ highlights the DSM-5 criteria for catatonia. DSM-5 requires 3 of 12 symptoms to be present, although symptoms may fluctuate with time.³ If a clinician is not specifically looking for catatonia, it can be a difficult syndrome to diagnose. Does rigidity indicate catatonia, or excessive dopamine blockade from an antipsychotic? How can seemingly contradictory symptoms be part of the same syndrome? Many clinicians associate catatonia with the stuporous subtype (immobility, posturing, catalepsy), which is more prevalent, but the excited subtype, which may involve severe agitation, autonomic dysfunction, and impaired consciousness, can be lethal.² The diversity in presentation of catatonia is not unlike the challenging variety of symptoms of heart attacks.

A retrospective study of all adults admitted to a hospital found that only 41% of patients who met criteria for catatonia received this diagnosis.⁵ Further complicating the diagnosis, delirium and catatonia can co-exist; one study found this was the case in 1 of 3 critically ill patients.⁶ DSM-5 criteria for catatonia due to another medical condition exclude the diagnosis if delirium is present, but this study and others suggest this needs to be reconsidered.³   

Continue to: A standardized evaluation is key

A standardized evaluation is key

Just as a patient who presents with chest pain requires a standardized evaluation, including a pertinent history, laboratory workup, and ECG, psychiatrists may also use standardized diagnostic instruments to aid in the diagnosis of catatonia. One study of hospitalized patients with schizophrenia found that using a standardized diagnostic procedure for catatonia resulted in a 7-fold increase in the diagnosis.⁷ The BFCRS is the most common standardized instrument for catatonia, likely due to its high inter-rater reliability.⁸ Other scales include the KANNER scale and Northoff Catatonia Scale, which emphasize different aspects of the disease or for certain clinical populations (eg, the KANNER scale adjusts for patients who are nonverbal at baseline). One study suggested that BFCRS has lower reliability for less-severe illness.⁹ These differences emphasize that psychiatry does not have a thorough understanding of the intricacies of catatonia. However, using validated screening tools can lead to more consistent diagnoses and continue important research on this often-misunderstood illness.

Dangers of untreated catatonia

Rapid treatment of catatonia is necessary to prevent mortality. A study of patients in Kentucky’s state psychiatric hospitals found that untreated catatonia with resultant death from pulmonary embolism was the leading cause of preventable death.¹⁰ A 17-year retrospective study of patients with schizophrenia admitted to 1 hospital found that those with catatonia were >4 times as likely to die during hospitalization than those without catatonia.¹¹ The significant morbidity and mortality from untreated catatonia are typically attributed to the consequences of poorly controlled movements, immobility, autonomic instability, and poor/no oral intake. Reduced oral intake can result in malnutrition, dehydration, arrhythmias, and increased risk of infections. Furthermore, chronic catatonic episodes are more difficult to treat.¹² In addition to the aggressive management of neuropsychiatric symptoms, it is vital to evaluate relevant medical etiologies that may be contributing to the syndrome (Table 2¹³). Tracking vital signs and laboratory values, such as creatine kinase, electrolytes, and complete blood count, is required to ensure the medical condition does not become life-threatening.

Treatment options

Studies and expert opinion suggest that benzodiazepines (specifically lorazepam, because it is the most studied agent) are the first-line treatment for catatonia. A lorazepam challenge test—providing 1 or 2 mg of IV lorazepam—is considered diagnostic and therapeutic given the high rate of response within 10 minutes.¹⁴ Patients with limited response to lorazepam or who are medically compromised should undergo ECT. Electroconvulsive therapy is considered the gold-standard treatment for catatonia; estimated response rates range from 59% to 100%, even in patients who fail to respond to pharmacotherapy.¹⁵ Although highly effective, ECT is often hindered by the time required to initiate treatment, stigma, lack of access, and other logistical challenges. 

Table 3^14-18 highlights the advantages and disadvantages of treatment options for catatonia. Some researchers have suggested a zolpidem challenge test could augment lorazepam because some patients respond only to zolpidem.¹⁴ The efficacy of these medications along with some evidence of anti-N-methyl-d-aspartate medications, such as amantadine and memantine, suggest that there is an underactivation of gamma-aminobutyric acid (GABA) and overactivation of glutamate in the brain,¹⁶ with some researchers noting the similarity between catatonia and the fear response.¹⁷ Consequently, excessive dopamine D2 antagonism or withdrawal of dopamine agonists can either bring on or worsen the symptoms of catatonia, with researchers identifying an overlap between neuroleptic malignant syndrome and catatonia.¹⁸ Although some studies suggest that second-generation antipsychotics (SGAs), particularly lower-potency agents such as olanzapine, may help treat catatonia, other studies suggest using caution when initiating in patients without an underlying psychotic illness. The treating clinician may want to consider switching a patient receiving a high-potency antipsychotic to one with a lower potency, lowering the dose of high-potency agent, or discontinuing the medication altogether.

Ms. N was ultimately diagnosed with bipolar disorder, current episode mixed, with psychotic and catatonic features. Ms. N had symptoms of mania including grandiosity, periods of lack of sleep, delusions as well as depressive symptoms of tearfulness and low mood. The treatment team had considered that Ms. N had delirious mania because she had fluctuating sensorium, which included varying degrees of orientation and ability to answer questioning. However, the literature supporting the differentiation between delirious mania and excited catatonia is unclear, and both conditions may respond to ECT.¹⁸ A diagnosis of catatonia allowed the team to use rating scales to track Ms. N’s progress by monitoring for specific signs, such as grasp reflex and waxy flexibility.

Continue to: OUTCOME

OUTCOME Return to baseline

Before discharge, Ms. N’s BFCRS score decreases from the initial score of 17 to 0, and her KANNER scale score decreases from the initial score of 26 to 4, which correlates with vast improvement in clinical presentation. Once Ms. N completes the acute ECT treatment, she returns to her baseline level of functioning, and is discharged to live with her boyfriend. She is advised to continue weekly ECT for the first several months to ensure clinical stability. This regimen is later transitioned to biweekly and then monthly. Electroconvulsive therapy protocols from previous research were utilized in Ms. N’s case, but ultimately the lowest number of ECT treatments needed to maintain stability is determined clinically over many years.¹⁹ Ms. N is discharged on aripiprazole, 15 mg/d; bupropion ER, 300 mg/d (added after depressive symptoms emerge while catatonia symptoms improve midway through her lengthy hospitalization); and memantine, 10 mg/d. Ideally, clozapine would have been continued; however, due to her history of nonadherence and frequent restarting of the medication at a low dose, clozapine was discontinued and aripiprazole initiated.

More than 1 year later, Ms. N remains stable and continues to receive monthly ECT maintenance treatments.

Bottom Line

Catatonia should always be considered in a patient who presents with acute neuropsychiatric symptoms. Rapid diagnosis with standardized screening instruments and aggressive treatment are vital to prevent morbidity and mortality.

Related Resource

• Freudenreich O, Francis A, Fricchione GL. Chapter 9. Psychosis, mania, and catatonia. In: Levenson, James L, ed. The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. 3rd ed. American Psychiatric Association Publishing; 2019.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Baclofen • Ozobax
Bupropion ER • Wellbutrin XL
Clonazepam • Klonopin
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Metoclopramide • Reglan
Memantine • Namenda
Topiramate • Topamax
Zolpidem • Ambien

CASE Aggressive behaviors, psychosis

Ms. N, age 58, has a long history of bipolar disorder with psychotic features. She presents to our emergency department (ED) after an acute fall and frequent violent behaviors at her nursing home, where she had resided since being diagnosed with an unspecified neurocognitive disorder. For several weeks before her fall, she was physically aggressive, throwing objects at nursing home staff, and was unable to have her behavior redirected.

While in the ED, Ms. N rambles and appears to be responding to internal stimuli. Suddenly, she stops responding and begins to stare.

HISTORY Severe, chronic psychosis and hospitalization

Ms. N is well-known at our inpatient psychiatry and electroconvulsive therapy (ECT) services. During the last 10 years, she has had worsening manic, psychotic, and catatonic (both excited and stuporous subtype) episodes. Three years ago, she had experienced a period of severe, chronic psychosis and excited catatonia that required extended inpatient treatment. While hospitalized, Ms. N had marginal responses to clozapine and benzodiazepines, but improved dramatically with ECT. After Ms. N left the hospital, she went to live with her boyfriend. She remained stable on monthly maintenance ECT treatments (bifrontal) before she was lost to follow-up 14 months prior to the current presentation. Ms. N’s family reports that she needed a cardiac clearance before continuing ECT treatment; however, she was hospitalized at another hospital with pneumonia and subsequent complications that interrupted the maintenance ECT treatments.

Approximately 3 months after medical issues requiring hospitalization began, Ms. N received a diagnosis of neurocognitive disorder due to difficulty with activities of daily living and cognitive decline. She was transferred to a nursing home by the outside hospital. When Ms. N’s symptoms of psychosis returned and she required inpatient psychiatric care, she was transferred to a nearby facility that did not have ECT available or knowledge of her history of catatonia resistant to pharmacologic management. Ms. N had a documented history of catatonia that spanned 10 years. During the last 4 years, Ms. N often required ECT treatment. Her current medication regimen prescribed by an outpatient psychiatrist includes clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily, both for bipolar disorder.

EVALUATION An unusual mix of symptoms

In the ED, Ms. N undergoes a CT of the head, which is found to be nonacute. Laboratory results show that her white blood cell count is 14.3 K/µL, which is mildly elevated. Results from a urinalysis and electrocardiogram (ECG) are unremarkable.

After Ms. N punches a radiology technician, she is administered IV lorazepam, 2 mg once, for her agitation. Twenty minutes after receiving IV lorazepam, she is calm and cooperative. However, approximately 4 hours later, Ms. N is yelling, tearful, and expressing delusions of grandeur—she believes she is God.

After she is admitted to the medical floor, Ms. N is seen by our consultation and liaison psychiatry service. She exhibits several signs of catatonia, including grasp reflex, gegenhalten (oppositional paratonia), waxy flexibility, and echolalia. Ms. N also has an episode of urinary incontinence. At some parts of the day, she is alert and oriented to self and location; at other times, she is somnolent and disoriented. The treatment team continues Ms. N’s previous medication regimen of clozapine, 300 mg twice daily, and clonazepam, 0.5 mg twice daily. Unfortunately, at times Ms. N spits out and hides her administered oral medications, which leads to the decision to discontinue clozapine. Once medically cleared, Ms. N is transferred to the psychiatric floor.

[polldaddy:10869949]

Continue to: TREATMENT

TREATMENT Bifrontal ECT initiated

On hospital Day 3 Ms. N is administered a trial of IM lorazepam, titrated up to 6 mg/d (maximum tolerated dose) while the treatment team initiates the legal process to conduct ECT because she is unable to give consent. Once Ms. N begins tolerating oral medications, amantadine, 100 mg twice daily, is added to treat her catatonia. As in prior hospitalizations, Ms. N is unresponsive to pharmacotherapy alone for her catatonic symptoms. On hospital Day 8, forced ECT is granted, which is 5 days after the process of filing paperwork was started. Bifrontal ECT is utilized with the following settings: frequency 70 Hz, pulse width 1.5 ms, 100% energy dose, 504 mC. Ms. N does not experience a significant improvement until she receives 10 ECT treatments as part of a 3-times-per-week acute series protocol. The Bush-Francis Catatonia Rating Scale (BFCRS) and the KANNER scale are used to monitor her progress. Her initial BFCRS score is 17 and initial KANNER scale, part 2 score is 26.

Ms. N spends a total of 61 days in the hospital, which is significantly longer than her previous hospital admissions on our psychiatric unit; these previous admissions were for treatment of both stuporous and excited subtypes of catatonia. This increased length of stay coincides with a significantly longer duration of untreated catatonia. Knowledge of her history of both the stuporous and excited subtypes of catatonia would have allowed for faster diagnosis and treatment.¹

The authors’ observations

Originally conceptualized as a separate syndrome by Karl Kahlbaum, catatonia was considered only as a specifier for neuropsychiatric conditions (primarily schizophrenia) as recently as DSM-IV-TR.² DSM-5 describes catatonia as a marked psychomotor disturbance and acknowledges its connection to schizophrenia by keeping it in the same chapter.³ DSM-5 includes separate diagnoses for catatonia, catatonia due to a general medical condition, and unspecified catatonia (for catatonia without a known underlying disorder).³ A recent meta-analysis found the prevalence of catatonia is higher in patients with medical/neurologic illness, bipolar disorder, and autism than in those with schizophrenia.⁴

Table 1³ highlights the DSM-5 criteria for catatonia. DSM-5 requires 3 of 12 symptoms to be present, although symptoms may fluctuate with time.³ If a clinician is not specifically looking for catatonia, it can be a difficult syndrome to diagnose. Does rigidity indicate catatonia, or excessive dopamine blockade from an antipsychotic? How can seemingly contradictory symptoms be part of the same syndrome? Many clinicians associate catatonia with the stuporous subtype (immobility, posturing, catalepsy), which is more prevalent, but the excited subtype, which may involve severe agitation, autonomic dysfunction, and impaired consciousness, can be lethal.² The diversity in presentation of catatonia is not unlike the challenging variety of symptoms of heart attacks.

A retrospective study of all adults admitted to a hospital found that only 41% of patients who met criteria for catatonia received this diagnosis.⁵ Further complicating the diagnosis, delirium and catatonia can co-exist; one study found this was the case in 1 of 3 critically ill patients.⁶ DSM-5 criteria for catatonia due to another medical condition exclude the diagnosis if delirium is present, but this study and others suggest this needs to be reconsidered.³   

Continue to: A standardized evaluation is key

A standardized evaluation is key

Just as a patient who presents with chest pain requires a standardized evaluation, including a pertinent history, laboratory workup, and ECG, psychiatrists may also use standardized diagnostic instruments to aid in the diagnosis of catatonia. One study of hospitalized patients with schizophrenia found that using a standardized diagnostic procedure for catatonia resulted in a 7-fold increase in the diagnosis.⁷ The BFCRS is the most common standardized instrument for catatonia, likely due to its high inter-rater reliability.⁸ Other scales include the KANNER scale and Northoff Catatonia Scale, which emphasize different aspects of the disease or for certain clinical populations (eg, the KANNER scale adjusts for patients who are nonverbal at baseline). One study suggested that BFCRS has lower reliability for less-severe illness.⁹ These differences emphasize that psychiatry does not have a thorough understanding of the intricacies of catatonia. However, using validated screening tools can lead to more consistent diagnoses and continue important research on this often-misunderstood illness.

Dangers of untreated catatonia

Rapid treatment of catatonia is necessary to prevent mortality. A study of patients in Kentucky’s state psychiatric hospitals found that untreated catatonia with resultant death from pulmonary embolism was the leading cause of preventable death.¹⁰ A 17-year retrospective study of patients with schizophrenia admitted to 1 hospital found that those with catatonia were >4 times as likely to die during hospitalization than those without catatonia.¹¹ The significant morbidity and mortality from untreated catatonia are typically attributed to the consequences of poorly controlled movements, immobility, autonomic instability, and poor/no oral intake. Reduced oral intake can result in malnutrition, dehydration, arrhythmias, and increased risk of infections. Furthermore, chronic catatonic episodes are more difficult to treat.¹² In addition to the aggressive management of neuropsychiatric symptoms, it is vital to evaluate relevant medical etiologies that may be contributing to the syndrome (Table 2¹³). Tracking vital signs and laboratory values, such as creatine kinase, electrolytes, and complete blood count, is required to ensure the medical condition does not become life-threatening.

Treatment options

Studies and expert opinion suggest that benzodiazepines (specifically lorazepam, because it is the most studied agent) are the first-line treatment for catatonia. A lorazepam challenge test—providing 1 or 2 mg of IV lorazepam—is considered diagnostic and therapeutic given the high rate of response within 10 minutes.¹⁴ Patients with limited response to lorazepam or who are medically compromised should undergo ECT. Electroconvulsive therapy is considered the gold-standard treatment for catatonia; estimated response rates range from 59% to 100%, even in patients who fail to respond to pharmacotherapy.¹⁵ Although highly effective, ECT is often hindered by the time required to initiate treatment, stigma, lack of access, and other logistical challenges. 

Table 3^14-18 highlights the advantages and disadvantages of treatment options for catatonia. Some researchers have suggested a zolpidem challenge test could augment lorazepam because some patients respond only to zolpidem.¹⁴ The efficacy of these medications along with some evidence of anti-N-methyl-d-aspartate medications, such as amantadine and memantine, suggest that there is an underactivation of gamma-aminobutyric acid (GABA) and overactivation of glutamate in the brain,¹⁶ with some researchers noting the similarity between catatonia and the fear response.¹⁷ Consequently, excessive dopamine D2 antagonism or withdrawal of dopamine agonists can either bring on or worsen the symptoms of catatonia, with researchers identifying an overlap between neuroleptic malignant syndrome and catatonia.¹⁸ Although some studies suggest that second-generation antipsychotics (SGAs), particularly lower-potency agents such as olanzapine, may help treat catatonia, other studies suggest using caution when initiating in patients without an underlying psychotic illness. The treating clinician may want to consider switching a patient receiving a high-potency antipsychotic to one with a lower potency, lowering the dose of high-potency agent, or discontinuing the medication altogether.

Ms. N was ultimately diagnosed with bipolar disorder, current episode mixed, with psychotic and catatonic features. Ms. N had symptoms of mania including grandiosity, periods of lack of sleep, delusions as well as depressive symptoms of tearfulness and low mood. The treatment team had considered that Ms. N had delirious mania because she had fluctuating sensorium, which included varying degrees of orientation and ability to answer questioning. However, the literature supporting the differentiation between delirious mania and excited catatonia is unclear, and both conditions may respond to ECT.¹⁸ A diagnosis of catatonia allowed the team to use rating scales to track Ms. N’s progress by monitoring for specific signs, such as grasp reflex and waxy flexibility.

Continue to: OUTCOME

OUTCOME Return to baseline

Before discharge, Ms. N’s BFCRS score decreases from the initial score of 17 to 0, and her KANNER scale score decreases from the initial score of 26 to 4, which correlates with vast improvement in clinical presentation. Once Ms. N completes the acute ECT treatment, she returns to her baseline level of functioning, and is discharged to live with her boyfriend. She is advised to continue weekly ECT for the first several months to ensure clinical stability. This regimen is later transitioned to biweekly and then monthly. Electroconvulsive therapy protocols from previous research were utilized in Ms. N’s case, but ultimately the lowest number of ECT treatments needed to maintain stability is determined clinically over many years.¹⁹ Ms. N is discharged on aripiprazole, 15 mg/d; bupropion ER, 300 mg/d (added after depressive symptoms emerge while catatonia symptoms improve midway through her lengthy hospitalization); and memantine, 10 mg/d. Ideally, clozapine would have been continued; however, due to her history of nonadherence and frequent restarting of the medication at a low dose, clozapine was discontinued and aripiprazole initiated.

More than 1 year later, Ms. N remains stable and continues to receive monthly ECT maintenance treatments.

Bottom Line

Catatonia should always be considered in a patient who presents with acute neuropsychiatric symptoms. Rapid diagnosis with standardized screening instruments and aggressive treatment are vital to prevent morbidity and mortality.

Related Resource

• Freudenreich O, Francis A, Fricchione GL. Chapter 9. Psychosis, mania, and catatonia. In: Levenson, James L, ed. The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. 3rd ed. American Psychiatric Association Publishing; 2019.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Baclofen • Ozobax
Bupropion ER • Wellbutrin XL
Clonazepam • Klonopin
Clozapine • Clozaril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Metoclopramide • Reglan
Memantine • Namenda
Topiramate • Topamax
Zolpidem • Ambien

Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

Telepsychiatry appointments (eg, video conferencing) initially replaced face-to-face outpatient encounters during the first phase of the COVID-19 pandemic. However, as offices reopened for in-person appointments, many patients still prefer “virtual” appointments. Telepsychiatry allows for easier delivery of mental health services, including psychotherapy, and may become the new normal.

Although therapy conducted via video conferencing allows you to connect with patients at a safe distance, it alters the basic conditions under which therapy occurs, such as being in the same room.¹ While focusing on preserving the verbal elements of communication, you might inadvertently forget the nonverbal elements, which at times might render your words ineffective.¹ The main elements of nonverbal communication are facial expression, gaze, posture, gesture, and proxemics (ie, how much space you take up, and your distance from others).² The following tips can help you preserve the nonverbal elements of communication when conducting telepsychiatry sessions.

Reduce gaze error. Gaze error is the deviation from direct eye contact that occurs during video conferencing. It results from the distance between the image of the person on your screen and the camera above it.¹ Gaze error can muddy intended cues and communicate unintended cues.² Examples of gaze errors include downcast eyes (the most common gaze error), sideways gaze, or gazing over the person’s head.² These errors can communicate social deference, evasion, insincerity, or even boredom.² To lessen gaze error, move the patient’s image as close as possible to your camera.¹ In addition, avoid looking at yourself on the screen; some video conferencing platforms allow users to hide their self-view.

Create distance and incorporate upper body language. In the office, sitting very close to your patient and staring directly at their face for an hour would be awkward and intrusive.¹ Doing so online is no different. While you may be tempted to move close to the screen to compensate for feeling distant or having difficulty hearing or seeing your patient, you should back away from the camera. Doing so will help both parties feel less self-conscious, more at ease, and more focused on the session.¹ Backing up from the camera will allow patients to see your upper body language (eg, hand gestures, posture) as well as your facial expressions.¹ Empathy improves when patients can see your upper-body cues.² Keep in mind that the angle of your camera is just as important as the distance. For example, if your camera is positioned so that it is looking up toward your eyes, patients may perceive that you are looking down at them.¹ This problem can be remedied by stacking books under the monitor to raise the camera.

Be aware of your facial expressions, posture, gestures, and proxemics. Ensure that your face does not go slack when you are listening to patients talk.³ Just as you would do in person, a slight head tilt and occasional head nod lets patients know that you are engaged and actively listening.³ Maintain an open body posture by keeping your feet firmly on the ground and putting your hands on the table in front of you.³ Lean in when patients share intimate information, just as you would in person. Avoid hunching over the laptop/keyboard because this could make you seem tired or tense.³ Pay attention to your arm and hand movements so that you do not exaggerate them.

Maintain office professionalism. The office setting conveys a therapeutic formality that can get lost online.¹ As tempting as it may be to conduct online sessions in pajamas or sweatpants, continue to dress as if you were in the office. Be mindful of your backdrop, set all cell phones to silent, turn off your email alerts, and lock the room.^1,3 Stick to the clock as you would in the office, and encourage patients to do the same.

Minor technological improvements—such as headphones with a built-in microphone, a high-definition camera, a larger monitor, or a faster internet connection—might be needed to improve your nonverbal communication during telepsychiatry sessions.¹ Although this is not an exhaustive list, these tips can serve as a starting point to ensure effective communication while you are physically distanced from your patients.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

The peak age of onset of schizophrenia coincides with the peak childbearing age of 25 to 35 years.¹ So it would not be unusual for your patient with schizophrenia to tell you she is trying to get pregnant, or thinks she might be pregnant. In these situations, you must carefully weigh the risks to the mother (eg, relapse, complications) and to the fetus (eg, possible miscarriage, teratogenesis) when deciding whether to continue or change her treatment regimen. When faced with making these decisions, keep the following factors in mind.

1. Most importantly: Do not make knee-jerk changes. Do not suddenly stop medications. Proceed in a thoughtful and measured way.

2. Discuss the risks with your patient. There is no such thing as a risk-free decision. There are potential risks from untreated psychosis as well as from medications. Mothers with untreated psychosis have an increased risk of suicide and violence, as well as poor self-care. Schizophrenia may be associated with an increased risk of poor birth outcomes, including preterm delivery, low birthweight, and neonatal complications.² Avoid making absolute statements about specific medications during pregnancy; there needs to be an individualized risk-benefit discussion for each patient, and for each medication.

3. Involve the patient’s partner and family in treatment planning if possible. The patient’s family can be important in promoting mental health during pregnancy and the postpartum. Educating the family as well as the patient regarding medications and the risks of untreated mental illness can go a long way toward compliance.

4. Do not rely on what pregnancy category a medication was. There are multiple dimensions to evaluate when considering the use of an antipsychotic agent during pregnancy. Does it increase the risk of miscarriage? Malformations? Preterm birth? Perinatal toxicity? Behavioral teratogenesis (neurodevelopmental sequelae)? Looking for a simple summary or single letter grade minimizes the understanding of the specific outcome of concern in the specific mother. Instead, look at the Pregnancy section under Use in Specific Populations on the medication’s package insert (prescribing information), consult a web site such as MotherToBaby (mothertobaby.org/healthcare-professionals/), and/or search for the latest research on PubMed.

5. Collaborate with the patient’s obstetrician or family medicine physician. Make sure that you are on the same page regarding treating the patient’s psychosis. Other clinicians often will agree with your treatment plan because they understand the risks of untreated psychosis compared with other risks the patient is facing. However, if you don’t communicate with your patient’s other health care professionals, she might receive mixed messages.

6. As for medication choice, pregnancy is the most important time to conduct a careful medication history to inform your choice of medication. Was Medication X ineffective, or did the patient not pick it up from the pharmacy? Did she really have a trial of 3 months, or did she only take it for a week before she decided to stop?

Continue to: Determine which medication has worked for the patient in the past

7. Determine which medication has worked for the patient in the past. If Medication Y worked before she was pregnant, it is likely to still work during pregnancy. If it is a relatively safe option, it may be the best choice.

8. Avoid multiple medication exposures wherever possible. If a patient is taking Medication Z, it is working, and she tells you she is 3 months pregnant, it is often better to continue it (assuming it is a relatively safe medication) than to switch to Medication A, which has slightly better “safety data.” By switching to a different antipsychotic, you would be exposing the fetus to a second agent that may not even work for the mother.

9. Focus on treating the patient’s present symptoms. Medication doses may need to change due to pregnancy-related changes in symptoms, drug distribution, and/or metabolism.

10. Remain vigilant for other risks. Keep in mind that pregnant women with psychosis often face risks other than psychiatric medications and psychosis. Comorbidities such as substance use disorders, obesity, and poor prenatal care must also be addressed.³

11. Follow your patient more closely during pregnancy. Pregnancy is an uncertain time for any new mother. Be sure to have an open line of communication with the patient, and be responsive to her concerns.

Continue to: Provide psychoeducation about the postpartum period

12. Provide psychoeducation about the postpartum period. Pregnancy is the time to educate your patient about the importance of sleep, warning signs of exacerbation of psychosis, and breastfeeding safety.

13. Be proactive with future female pa­tients of childbearing age, regardless of whether they tell you they are sexually active. Women with psychosis have higher rates of unplanned pregnancy.^3,4 When initiating treatment of psychosis in a woman of childbearing age, rather than treating her with the newest available medication that does not yet have safety data in pregnancy, it is best to start with a medication already known to be relatively safe in pregnancy. This way, if she were to become pregnant, your treatment plan would already be safe and appropriate.

14. Consult a reproductive psychiatrist if needed.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Since receiving FDA approval in March 2019, intranasal esketamine—the S-enantiomer of ketamine—has become a valuable treatment option for adults with treatment-resistant depression (TRD), owing to its limited adverse effects profile, rapid onset, and potential for significant improvement in depressive symptoms. In August 2020, the FDA expanded esketamine’s indication to include treatment of depressive symptoms in adults with acute suicidal ideation or behavior, thus providing psychiatrists with an additional option for improving the care of their most seriously ill patients. In this article, we review 4 factors to consider before recommending esketamine.

1. Confirm that the patient’s depression qualifies as treatment-resistant. A patient is considered to have TRD if they have long-standing depression that meets DSM-5 criteria for major depressive disorder, and have not adequately responded to at least 2 antidepressant trials of adequate dose and duration.

2. Confirm that the patient’s suicidal ideation and/or suicidal behavior does not require acute hospitalization. The time between the onset of suicidal ideation and a suicide attempt typically is short, which highlights the need to intervene quickly in these patients.¹ Being able to provide a treatment that works quickly and effectively may be lifesaving. However, to receive esketamine, patients must be enrolled in the Risk Evaluation Mitigation Strategy (REMS) patient registry through a certified treatment center, and prior authorization from insurance generally is required. These steps take time, so patients at high or imminent risk for suicide may initially require psychiatric hospitalization before they are able to begin esketamine treatment. Parsing out whether the suicidal ideation is chronic or acute can help clinicians assess current dangerousness and determine if esketamine treatment might be appropriate. If a patient with chronic suicidal ideation is stable for outpatient treatment with close monitoring, esketamine might provide an effective treatment option for treating both depression and suicidality. Esketamine’s rapid effect may be an integral part of the treatment for a suicidal patient by bridging the gap caused by the delayed onset of action in typical antidepressants.²

3. Identify a local certified treatment center. Use the online database at www.spravato.com/find-a-center to locate a nearby certified esketamine treatment center. Choosing a center that you can collaborate with regularly is important to determine if the treatment is effective, to provide updates on the treatment course, and to consider tailoring of ongoing treatment.

4. Ensure the patient is also treated with an oral antidepressant. Esketamine should be administered in conjunction with an oral antidepressant. As such, patients must be willing and able to tolerate treatment with a medication that can be construed as an antidepressant while undergoing esketamine treatment. A long-term maintenance trial found that patients with TRD who experienced remission or response after esketamine treatment had a delayed relapse of symptoms when they continued esketamine in addition to an oral antidepressant.³

Considering its rapid onset of action and low adverse effects profile with manageable tolerability, esketamine adjunctive to an oral antidepressant is a reasonable option to consider for patients with TRD, including those with suicidality.

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.

Guillain-Barré syndrome, a rare peripheral nerve disorder that can occur after certain types of viral and bacterial infections, has not to date been definitively linked to infection by SARS-CoV-2 or with vaccination against the virus, despite surveillance searching for such associations.

Spikes in Guillain-Barré syndrome incidence have previously, but rarely, been associated with outbreaks of other viral diseases, including Zika, but not with vaccination, except for a 1976-1977 swine influenza vaccine campaign in the United States that was seen associated with a slight elevation in risk, and was halted when that risk became known. Since then, all sorts of vaccines in the European Union and United States have come with warnings about Guillain-Barré syndrome in their package inserts – a fact that some Guillain-Barré syndrome experts lament as perpetuating the notion that vaccines cause Guillain-Barré syndrome.

Epidemiologic studies in the United Kingdom and Singapore did not detect increases in Guillain-Barré syndrome incidence during the COVID-19 pandemic. And as mass vaccination against COVID-19 got underway early this year, experts cautioned against the temptation to attribute incident Guillain-Barré syndrome cases following vaccination to SARS-CoV-2 without careful statistical and epidemiological analysis. Until now reports of Guillain-Barré syndrome have been scant: clinical trials of a viral vector vaccine developed by Johnson & Johnson saw one in the placebo arm and another in the intervention arm, while another case was reported following administration of a Pfizer mRNA SARS-Cov-2 vaccine.
 

Recent case reports

Two reports published this month in the Annals of Neurology – one from India and one from the United Kingdom – describe multiple cases of Guillain-Barré syndrome following a first dose of the ChAdOx1-S/nCoV-19, (Covishield, AstraZeneca) vector vaccine. None of the patients had evidence of current SARS-CoV-2 infection.

From India, Boby V. Maramattom, MD, of Aster Medcity in Kochi, India, and colleagues reported on seven severe cases of Guillain-Barré syndrome occurring between 10 and 14 days after a first dose of the AstraZeneca vaccine. All but one of the patients were women, all had bilateral facial paresis, all progressed to areflexic quadriplegia, and six required respiratory support. Patients’ ages ranged from 43 to 70. Four developed other cranial neuropathies, including abducens palsy and trigeminal sensory nerve involvement, which are rare in reports of Guillain-Barré syndrome from India, Dr. Maramattom and colleagues noted.

The authors argued that their findings “should prompt all physicians to be vigilant in recognizing Guillain-Barré syndrome in patients who have received the AstraZeneca vaccine. While the risk per patient (5.8 per million) may be relatively low, our observations suggest that this clinically distinct [Guillain-Barré syndrome] variant is more severe than usual and may require mechanical ventilation.”

The U.K. cases, reported by Christopher Martin Allen, MD, and colleagues at Nottingham (England) University Hospitals NHS Trust, describe bifacial weakness and normal facial sensation in four men between 11 and 22 days after their first doses of the Astra-Zeneca vaccine. This type of facial palsy, the authors wrote, was unusual Guillain-Barré syndrome variant that one rapid review found in 3 of 42 European patients diagnosed with Guillain-Barré syndrome following SARS-CoV-2 infection.

Dr. Allen and colleagues acknowledged that causality could not be assumed from the temporal relationship of immunization to onset of bifacial weakness in their report, but argued that their findings argued for “robust postvaccination surveillance” and that “the report of a similar syndrome in the setting of SARS-CoV-2 infection suggests an immunologic response to the spike protein.” If the link is casual, they wrote, “it could be due to a cross-reactive immune response to the SARS-CoV-2 spike protein and components of the peripheral immune system.”
 

‘The jury is still out’

Asked for comment, neurologist Anthony Amato, MD, of Brigham and Women’s Hospital, Boston, said that he did not see what the two new studies add to what is already known. “Guillain-Barré syndrome has already been reported temporally following COVID-19 along with accompanying editorials that such temporal occurrences do not imply causation and there is a need for surveillance and epidemiological studies.”

Robert Lisak, MD, of Wayne State University, Detroit, and a longtime adviser to the GBS-CIDP Foundation International, commented that “the relationship between vaccines and association with Guillain-Barré syndrome continues to be controversial in part because Guillain-Barré syndrome, a rare disorder, has many reported associated illnesses including infections. Many vaccines have been implicated but with the probable exception of the ‘swine flu’ vaccine in the 1970s, most have not stood up to scrutiny.”

With SARS-Cov-2 infection and vaccines, “the jury is still out,” Dr. Lisak said. “The report from the U.K. is intriguing since they report several cases of an uncommon variant, but the cases from India seem to be more of the usual forms of Guillain-Barré syndrome.”

Dr. Lisak noted that, even if an association turns out to be valid, “we are talking about a very low incidence of Guillain-Barré syndrome associated with COVID-19 vaccines,” one that would not justify avoiding them because of a possible association with Guillain-Barré syndrome.

The GBS-CIDP Foundation, which supports research into Guillain-Barré syndrome and related diseases, has likewise stressed the low risk presented by SARS-CoV-2 vaccines, noting on its website that “the risk of death or long-term complications from COVID in adults still far exceeds the risk of any possible risk of Guillain-Barré syndrome by several orders of magnitude.”

None of the study authors reported financial conflicts of interest related to their research. Dr. Amato is an adviser to the pharmaceutical firms Alexion and Argenx, while Dr. Lisak has received research support or honoraria from Alexion, Novartis, Hoffmann–La Roche, and others.

If you, a friend, or a loved one remain unvaccinated against COVID-19 at this point – for whatever reason – you are at higher risk of dying if you become infected.

That’s the conclusion of a new report released by the Associated Press looking at COVID-19 deaths during May 2021.

Of more than 18,000 people who died from COVID-19, for example, only about 150 were fully vaccinated. That’s less than 1%.

“Recently, I was working in the emergency room [and] I saw a 21-year-old African American who came in with shortness of breath,” said Vino K. Palli, MD, MPH, a physician specializing in emergency medicine, internal medicine, and urgent care.

The patient rapidly deteriorated and required intubation and ventilation. She was transferred to a specialized hospital for possible extracorporeal membrane oxygenation (ECMO) treatment.

“This patient was unvaccinated, along with her entire family. This would have been easily preventable,” added Dr. Palli, who is also founder and CEO of MiDoctor Urgent Care in New York City.

“Vaccine misinformation, compounded with vaccine inertia and vaccine access, have contributed to this,” he added. “Even though we have a surplus amount of vaccines at this time, we are only seeing 50% to 55% of completely vaccinated patients.”

Authors of the Associated Press report also acknowledge that some people who are fully vaccinated can get a breakthrough infection. These occurred in fewer than 1,200 of more than 853,000 people hospitalized for COVID-19 in May, or about 0.1%.

The Associated Press came up with these numbers using data from the Centers for Disease Control and Prevention. The CDC tracks the numbers of cases, hospitalizations, and deaths but does not breakdown rates by vaccination status.  
 

Stronger argument for vaccination?

“The fact that only 0.8% of COVID-19 deaths are in the fully vaccinated should persuade those people still hesitant about vaccination,” said Hugh Cassiere, MD, medical director of Respiratory Therapy Services at North Shore University Hospital in Manhasset, New York.

Stuart C. Ray, MD, professor of medicine and oncology in the Division of Infectious Diseases at Johns Hopkins University, Baltimore, agreed. “It seems compelling, even for skeptics, that unvaccinated people represent 99% of those now dying from COVID-19 when they represent less than 50% of the adult population in the United States.”

The findings from the study could be more persuasive than previous arguments made in favor of immunization, Dr. Ray said. “These recent findings of striking reductions in risk of death in the vaccinated are more directly attributable and harder to ignore or dismiss.”

Brian Labus, PhD, MPH, of the University of Nevada Las Vegas (UNLV) is less convinced. “While this might change some peoples’ minds, it probably won’t make a major difference. People have many different reasons for not getting vaccinated, and this is only one of the things they consider.”

The study adds information that was not available before, said Dr. Labus, assistant professor in the Department of Epidemiology and Biostatistics at the UNLV School of Public Health. “We study the vaccine under tightly controlled, ideal conditions. This is the evidence that it works as well in the real world as it did in the trials, and that is what is most important in implementing a vaccination program,” added Dr. Labus.

“The scientific data has honed in on one thing: Vaccines are effective in preventing hospitalizations, ICU admissions, ventilations, and deaths,” agreed Dr. Palli.

“We now know that almost all deaths occurred in patients who were not vaccinated. We also know that all vaccines are effective against various strains that are in circulation right now, including the Delta variant, which is rapidly spreading,” Dr. Palli said.

Dr. Cassiere pointed out that the unvaccinated are not only at higher risk of developing COVID-19 but also of spreading, being hospitalized for, and dying from the infection. Avoiding “long hauler” symptoms is another argument in favor of immunization, he added.

As of June 28, the CDC reports that 63% of Americans 12 years and older have received at least one dose of a COVID-19 vaccine, and 54% are fully vaccinated.
 

Worldwide worry?

Although overall rates of U.S. COVID-19 hospitalizations and deaths are down, the outlook may not remain as encouraging. “I hope I’m wrong about this, but I anticipate that the coming fall and winter will bring increasingly localized versions of similar findings – severe disease and death due to SARS-CoV-2 infection in regions or groups with lower vaccination rates,” Dr. Ray said.

There could be a silver lining, he added: “If this unfortunate surge occurs, the health and economic consequences seem likely to erode much of the remaining hesitancy regarding vaccination.”

The rise of more infectious SARS-CoV-2 variants, such as the Delta variant, could also throw a wrench in controlling COVID-19. “This isn’t just a domestic issue,” Dr. Ray said. “We have learned that the world is a small place in pandemic times.”

The Associated Press investigators state that their findings support the high efficacy of the vaccine. Also, given the current widespread availability of COVID-19 vaccines in the United States, they believe many of the COVID-19 deaths now occurring are preventable.

Public health measures should have continued longer to protect unvaccinated individuals, especially Black Americans, Hispanic Americans, and other minorities, Dr. Palli said. “Only time will tell if re-opening and abandoning all public health measures by the CDC was premature.”

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

If you, a friend, or a loved one remain unvaccinated against COVID-19 at this point – for whatever reason – you are at higher risk of dying if you become infected.

That’s the conclusion of a new report released by the Associated Press looking at COVID-19 deaths during May 2021.

Of more than 18,000 people who died from COVID-19, for example, only about 150 were fully vaccinated. That’s less than 1%.

“Recently, I was working in the emergency room [and] I saw a 21-year-old African American who came in with shortness of breath,” said Vino K. Palli, MD, MPH, a physician specializing in emergency medicine, internal medicine, and urgent care.

The patient rapidly deteriorated and required intubation and ventilation. She was transferred to a specialized hospital for possible extracorporeal membrane oxygenation (ECMO) treatment.

“This patient was unvaccinated, along with her entire family. This would have been easily preventable,” added Dr. Palli, who is also founder and CEO of MiDoctor Urgent Care in New York City.

“Vaccine misinformation, compounded with vaccine inertia and vaccine access, have contributed to this,” he added. “Even though we have a surplus amount of vaccines at this time, we are only seeing 50% to 55% of completely vaccinated patients.”

Authors of the Associated Press report also acknowledge that some people who are fully vaccinated can get a breakthrough infection. These occurred in fewer than 1,200 of more than 853,000 people hospitalized for COVID-19 in May, or about 0.1%.

The Associated Press came up with these numbers using data from the Centers for Disease Control and Prevention. The CDC tracks the numbers of cases, hospitalizations, and deaths but does not breakdown rates by vaccination status.  
 

Stronger argument for vaccination?

“The fact that only 0.8% of COVID-19 deaths are in the fully vaccinated should persuade those people still hesitant about vaccination,” said Hugh Cassiere, MD, medical director of Respiratory Therapy Services at North Shore University Hospital in Manhasset, New York.

Stuart C. Ray, MD, professor of medicine and oncology in the Division of Infectious Diseases at Johns Hopkins University, Baltimore, agreed. “It seems compelling, even for skeptics, that unvaccinated people represent 99% of those now dying from COVID-19 when they represent less than 50% of the adult population in the United States.”

The findings from the study could be more persuasive than previous arguments made in favor of immunization, Dr. Ray said. “These recent findings of striking reductions in risk of death in the vaccinated are more directly attributable and harder to ignore or dismiss.”

Brian Labus, PhD, MPH, of the University of Nevada Las Vegas (UNLV) is less convinced. “While this might change some peoples’ minds, it probably won’t make a major difference. People have many different reasons for not getting vaccinated, and this is only one of the things they consider.”

The study adds information that was not available before, said Dr. Labus, assistant professor in the Department of Epidemiology and Biostatistics at the UNLV School of Public Health. “We study the vaccine under tightly controlled, ideal conditions. This is the evidence that it works as well in the real world as it did in the trials, and that is what is most important in implementing a vaccination program,” added Dr. Labus.

“The scientific data has honed in on one thing: Vaccines are effective in preventing hospitalizations, ICU admissions, ventilations, and deaths,” agreed Dr. Palli.

“We now know that almost all deaths occurred in patients who were not vaccinated. We also know that all vaccines are effective against various strains that are in circulation right now, including the Delta variant, which is rapidly spreading,” Dr. Palli said.

Dr. Cassiere pointed out that the unvaccinated are not only at higher risk of developing COVID-19 but also of spreading, being hospitalized for, and dying from the infection. Avoiding “long hauler” symptoms is another argument in favor of immunization, he added.

As of June 28, the CDC reports that 63% of Americans 12 years and older have received at least one dose of a COVID-19 vaccine, and 54% are fully vaccinated.
 

Worldwide worry?

Although overall rates of U.S. COVID-19 hospitalizations and deaths are down, the outlook may not remain as encouraging. “I hope I’m wrong about this, but I anticipate that the coming fall and winter will bring increasingly localized versions of similar findings – severe disease and death due to SARS-CoV-2 infection in regions or groups with lower vaccination rates,” Dr. Ray said.

There could be a silver lining, he added: “If this unfortunate surge occurs, the health and economic consequences seem likely to erode much of the remaining hesitancy regarding vaccination.”

The rise of more infectious SARS-CoV-2 variants, such as the Delta variant, could also throw a wrench in controlling COVID-19. “This isn’t just a domestic issue,” Dr. Ray said. “We have learned that the world is a small place in pandemic times.”

The Associated Press investigators state that their findings support the high efficacy of the vaccine. Also, given the current widespread availability of COVID-19 vaccines in the United States, they believe many of the COVID-19 deaths now occurring are preventable.

Public health measures should have continued longer to protect unvaccinated individuals, especially Black Americans, Hispanic Americans, and other minorities, Dr. Palli said. “Only time will tell if re-opening and abandoning all public health measures by the CDC was premature.”

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

If you, a friend, or a loved one remain unvaccinated against COVID-19 at this point – for whatever reason – you are at higher risk of dying if you become infected.

That’s the conclusion of a new report released by the Associated Press looking at COVID-19 deaths during May 2021.

Of more than 18,000 people who died from COVID-19, for example, only about 150 were fully vaccinated. That’s less than 1%.

“Recently, I was working in the emergency room [and] I saw a 21-year-old African American who came in with shortness of breath,” said Vino K. Palli, MD, MPH, a physician specializing in emergency medicine, internal medicine, and urgent care.

The patient rapidly deteriorated and required intubation and ventilation. She was transferred to a specialized hospital for possible extracorporeal membrane oxygenation (ECMO) treatment.

“This patient was unvaccinated, along with her entire family. This would have been easily preventable,” added Dr. Palli, who is also founder and CEO of MiDoctor Urgent Care in New York City.

“Vaccine misinformation, compounded with vaccine inertia and vaccine access, have contributed to this,” he added. “Even though we have a surplus amount of vaccines at this time, we are only seeing 50% to 55% of completely vaccinated patients.”

Authors of the Associated Press report also acknowledge that some people who are fully vaccinated can get a breakthrough infection. These occurred in fewer than 1,200 of more than 853,000 people hospitalized for COVID-19 in May, or about 0.1%.

The Associated Press came up with these numbers using data from the Centers for Disease Control and Prevention. The CDC tracks the numbers of cases, hospitalizations, and deaths but does not breakdown rates by vaccination status.  
 

Stronger argument for vaccination?

“The fact that only 0.8% of COVID-19 deaths are in the fully vaccinated should persuade those people still hesitant about vaccination,” said Hugh Cassiere, MD, medical director of Respiratory Therapy Services at North Shore University Hospital in Manhasset, New York.

Stuart C. Ray, MD, professor of medicine and oncology in the Division of Infectious Diseases at Johns Hopkins University, Baltimore, agreed. “It seems compelling, even for skeptics, that unvaccinated people represent 99% of those now dying from COVID-19 when they represent less than 50% of the adult population in the United States.”

The findings from the study could be more persuasive than previous arguments made in favor of immunization, Dr. Ray said. “These recent findings of striking reductions in risk of death in the vaccinated are more directly attributable and harder to ignore or dismiss.”

Brian Labus, PhD, MPH, of the University of Nevada Las Vegas (UNLV) is less convinced. “While this might change some peoples’ minds, it probably won’t make a major difference. People have many different reasons for not getting vaccinated, and this is only one of the things they consider.”

The study adds information that was not available before, said Dr. Labus, assistant professor in the Department of Epidemiology and Biostatistics at the UNLV School of Public Health. “We study the vaccine under tightly controlled, ideal conditions. This is the evidence that it works as well in the real world as it did in the trials, and that is what is most important in implementing a vaccination program,” added Dr. Labus.

“The scientific data has honed in on one thing: Vaccines are effective in preventing hospitalizations, ICU admissions, ventilations, and deaths,” agreed Dr. Palli.

“We now know that almost all deaths occurred in patients who were not vaccinated. We also know that all vaccines are effective against various strains that are in circulation right now, including the Delta variant, which is rapidly spreading,” Dr. Palli said.

Dr. Cassiere pointed out that the unvaccinated are not only at higher risk of developing COVID-19 but also of spreading, being hospitalized for, and dying from the infection. Avoiding “long hauler” symptoms is another argument in favor of immunization, he added.

As of June 28, the CDC reports that 63% of Americans 12 years and older have received at least one dose of a COVID-19 vaccine, and 54% are fully vaccinated.
 

Worldwide worry?

Although overall rates of U.S. COVID-19 hospitalizations and deaths are down, the outlook may not remain as encouraging. “I hope I’m wrong about this, but I anticipate that the coming fall and winter will bring increasingly localized versions of similar findings – severe disease and death due to SARS-CoV-2 infection in regions or groups with lower vaccination rates,” Dr. Ray said.

There could be a silver lining, he added: “If this unfortunate surge occurs, the health and economic consequences seem likely to erode much of the remaining hesitancy regarding vaccination.”

The rise of more infectious SARS-CoV-2 variants, such as the Delta variant, could also throw a wrench in controlling COVID-19. “This isn’t just a domestic issue,” Dr. Ray said. “We have learned that the world is a small place in pandemic times.”

The Associated Press investigators state that their findings support the high efficacy of the vaccine. Also, given the current widespread availability of COVID-19 vaccines in the United States, they believe many of the COVID-19 deaths now occurring are preventable.

Public health measures should have continued longer to protect unvaccinated individuals, especially Black Americans, Hispanic Americans, and other minorities, Dr. Palli said. “Only time will tell if re-opening and abandoning all public health measures by the CDC was premature.”

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

Fidaa Wishah, MD, a pediatric radiologist at Phoenix Children’s Hospital in Arizona, has been fired after the hospital reviewed evidence that included her anti-Israel comments on social media, according to the hospital’s statement.

On May 26, Dr. Wishah posted, “We will uncover your thirst to kill our Palestinian children. … We sense your fear. The fear of your collapse. A state based on atrocity, inhumanity, racism and cannibalism never last long! Hey #israel … your end is coming sooner than you think.”

Phoenix Children’s Hospital did not respond to this news organization’s request for comment but said in a statement to the Jewish News Syndicate : “After a thorough review of the facts related to this matter, this individual is no longer providing care at Phoenix Children’s. All children in the care of Phoenix Children’s receive hope, healing and the best possible health care, regardless of race, color, disability, religion, gender, gender identity, sexual orientation or national origin.”

Dr. Wishah’s profile has been removed from the hospital website. Her LinkedIn profile indicates she had been a pediatric radiology fellow at Stanford (Calif.) University, specializing in advanced magnetic resonance imaging and fetal imaging and had been a senior staff pediatric radiologist at Henry Ford Health System in Detroit.

It wasn’t the first time antisemitic comments have led to the firing of a physician. Last year, this news organization wrote about Lara Kollab, DO, a first-year resident fired for her antisemitic tweets. She was subsequently barred from medicine.

In the same post from May 26, Dr. Wishah also wrote: “We will not be #censored anymore! Bomb our media buildings and we have the phones[.] Bribe the mainstream media and we have our small #socialmedia platforms[.] From our windows ... from our streets ... next the rubble we will expose you to the world[.] We will expose the #massacre and #genocide you #zionists are proud of[.]”

Today, CAIR-AZ, a group whose mission is to “enhance understanding of Islam, protect civil rights, promote justice, and empower American Muslims,” according to its website, announced that it, along with three private law firms, will represent Dr. Wishah in what they referred to as “her wrongful termination case against Phoenix Children’s Hospital.”

The announcement, which mentions that Dr. Wishah was born and raised in Gaza, said, “Dr. Wishah has been a medical doctor since 2010 and has spent the vast majority of her career as a pediatric physician. Despite caring for thousands of children, many of whom are Jewish, she has never been accused of discriminating against any of her patients or colleagues.”

The statement added, “PCH’s decision to terminate Dr. Wishah is shameful and an attack on freedom of speech.”

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

Fidaa Wishah, MD, a pediatric radiologist at Phoenix Children’s Hospital in Arizona, has been fired after the hospital reviewed evidence that included her anti-Israel comments on social media, according to the hospital’s statement.

On May 26, Dr. Wishah posted, “We will uncover your thirst to kill our Palestinian children. … We sense your fear. The fear of your collapse. A state based on atrocity, inhumanity, racism and cannibalism never last long! Hey #israel … your end is coming sooner than you think.”

Phoenix Children’s Hospital did not respond to this news organization’s request for comment but said in a statement to the Jewish News Syndicate : “After a thorough review of the facts related to this matter, this individual is no longer providing care at Phoenix Children’s. All children in the care of Phoenix Children’s receive hope, healing and the best possible health care, regardless of race, color, disability, religion, gender, gender identity, sexual orientation or national origin.”

Dr. Wishah’s profile has been removed from the hospital website. Her LinkedIn profile indicates she had been a pediatric radiology fellow at Stanford (Calif.) University, specializing in advanced magnetic resonance imaging and fetal imaging and had been a senior staff pediatric radiologist at Henry Ford Health System in Detroit.

It wasn’t the first time antisemitic comments have led to the firing of a physician. Last year, this news organization wrote about Lara Kollab, DO, a first-year resident fired for her antisemitic tweets. She was subsequently barred from medicine.

In the same post from May 26, Dr. Wishah also wrote: “We will not be #censored anymore! Bomb our media buildings and we have the phones[.] Bribe the mainstream media and we have our small #socialmedia platforms[.] From our windows ... from our streets ... next the rubble we will expose you to the world[.] We will expose the #massacre and #genocide you #zionists are proud of[.]”

Today, CAIR-AZ, a group whose mission is to “enhance understanding of Islam, protect civil rights, promote justice, and empower American Muslims,” according to its website, announced that it, along with three private law firms, will represent Dr. Wishah in what they referred to as “her wrongful termination case against Phoenix Children’s Hospital.”

The announcement, which mentions that Dr. Wishah was born and raised in Gaza, said, “Dr. Wishah has been a medical doctor since 2010 and has spent the vast majority of her career as a pediatric physician. Despite caring for thousands of children, many of whom are Jewish, she has never been accused of discriminating against any of her patients or colleagues.”

The statement added, “PCH’s decision to terminate Dr. Wishah is shameful and an attack on freedom of speech.”

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

Fidaa Wishah, MD, a pediatric radiologist at Phoenix Children’s Hospital in Arizona, has been fired after the hospital reviewed evidence that included her anti-Israel comments on social media, according to the hospital’s statement.

On May 26, Dr. Wishah posted, “We will uncover your thirst to kill our Palestinian children. … We sense your fear. The fear of your collapse. A state based on atrocity, inhumanity, racism and cannibalism never last long! Hey #israel … your end is coming sooner than you think.”

Phoenix Children’s Hospital did not respond to this news organization’s request for comment but said in a statement to the Jewish News Syndicate : “After a thorough review of the facts related to this matter, this individual is no longer providing care at Phoenix Children’s. All children in the care of Phoenix Children’s receive hope, healing and the best possible health care, regardless of race, color, disability, religion, gender, gender identity, sexual orientation or national origin.”

Dr. Wishah’s profile has been removed from the hospital website. Her LinkedIn profile indicates she had been a pediatric radiology fellow at Stanford (Calif.) University, specializing in advanced magnetic resonance imaging and fetal imaging and had been a senior staff pediatric radiologist at Henry Ford Health System in Detroit.

It wasn’t the first time antisemitic comments have led to the firing of a physician. Last year, this news organization wrote about Lara Kollab, DO, a first-year resident fired for her antisemitic tweets. She was subsequently barred from medicine.

In the same post from May 26, Dr. Wishah also wrote: “We will not be #censored anymore! Bomb our media buildings and we have the phones[.] Bribe the mainstream media and we have our small #socialmedia platforms[.] From our windows ... from our streets ... next the rubble we will expose you to the world[.] We will expose the #massacre and #genocide you #zionists are proud of[.]”

Today, CAIR-AZ, a group whose mission is to “enhance understanding of Islam, protect civil rights, promote justice, and empower American Muslims,” according to its website, announced that it, along with three private law firms, will represent Dr. Wishah in what they referred to as “her wrongful termination case against Phoenix Children’s Hospital.”

The announcement, which mentions that Dr. Wishah was born and raised in Gaza, said, “Dr. Wishah has been a medical doctor since 2010 and has spent the vast majority of her career as a pediatric physician. Despite caring for thousands of children, many of whom are Jewish, she has never been accused of discriminating against any of her patients or colleagues.”

The statement added, “PCH’s decision to terminate Dr. Wishah is shameful and an attack on freedom of speech.”

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