MDedge Psychiatry

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

 

 

Bottom Line

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

 

 

Bottom Line

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

 

 

Bottom Line

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

 

 

Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

 

 

Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

 

 

Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

Maternal autoimmune diseases significantly increased the risk of ADHD in children, based on data from a large cohort study of more than 800,000 mothers and children and a subsequent meta-analysis.

“There is growing evidence that immune-related cells and proteins play a role in brain development and function and that maternal immune activation, including infection, autoimmune disease, and chronic inflammation during pregnancy, increases the risk of neurodevelopmental disorders among children,” wrote Timothy C. Nielsen, MPH, of the University of Sydney, and colleagues.

Previous research has examined a link between maternal autoimmune disorders and autism spectrum disorders in children, but associations with ADHD have not been well studied, they said.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 831,718 mothers and their 831,718 singleton infants in Australia. A total of 12,787 infants were born to mothers with an autoimmune diagnosis; 12,610 of them were matched to 50,440 control infants. ADHD was determined based on prescription for a stimulant treatment or a hospital diagnosis; children with a first ADHD event younger than 3 years were excluded.

In the total cohort of 63,050 infants, the presence of any maternal autoimmune disease was associated with a significantly increased risk of ADHD (hazard ratio, 1.30) as was the presence of several specific conditions: type 1 diabetes (HR, 2.23), psoriasis (HR, 1.66), and rheumatic fever or rheumatic carditis (HR, 1.75).

In addition, the researchers conducted a meta-analysis of the current study and four additional studies that yielded similar results. In the meta-analysis, the risk of ADHD was significantly associated with any maternal autoimmune disease in two studies (HR, 1.20); with maternal type 1 diabetes in four studies (HR, 1.53); with maternal hyperthyroidism in three studies (HR 1.15); and with maternal psoriasis in two studies (HR, 1.31).

Type 1 diabetes (T1D) had the highest HR and was the most often studied condition. However, “the observed association may also be related to nonimmune aspects of T1D, such as glycemic control, as nonautoimmune diabetes has been associated with ADHD among children,” the researchers wrote.

The study findings were limited by several factors, including the lack of outpatient and primary care records to identify maternal autoimmune disease, and lack of data on any medication used to managed diseases during pregnancy, as well as a lack of data on children with ADHD who might not have been treated with medication, the researchers noted. In addition, “given differences in study design and definitions, the pooled HRs presented in the meta-analysis need to be treated cautiously.”

However, the results were strengthened by the hybrid study design and large study population, and were generally consistent with previous research supporting an effect of maternal immune function on fetal neurodevelopment, they noted.

“Our study provides justification for future studies that examine the effect of maternal autoimmune diseases, including biomarkers, condition severity, and management in pregnancy and in the periconception period, on neurodevelopmental disorders in children,” they concluded.

Studies need to explore mechanism of action

The current study, with its hybrid design, adds support to the evidence of an association between any maternal autoimmune disease and ADHD in children, as well as an association between the specific conditions of type 1 diabetes, hyperthyroidism, and psoriasis in mothers and ADHD in children, Søren Dalsgaard, MD, of Aarhus (Denmark) University, wrote in an accompanying editorial.

“Importantly, Nielsen et al. emphasized in their article that, for the many different autoimmune diseases, different underlying mechanisms for the associations with disorders of the central nervous system were likely. They mentioned that, for T1D, low glycemic control may play a role, as type 2 diabetes has been associated with ADHD,” said Dr. Dalsgaard.

“Overall, these mechanisms are thought to include shared genetic and environmental risk factors or direct effects of maternal autoantibodies or cytokines crossing the placenta and altering the fetal immune response, which in turns leads to changes in the central nervous system,” Dr. Dalsgaard explained. However, the current study and previous studies have not identified the mechanisms to explain the association between ADHD in children and maternal autoimmune disease.

“To understand more about these associations, future studies should include researchers and data from different scientific disciplines, such as epidemiology, animal modeling, genetics, and neuroimmunology,” he concluded.
 

Association is not causality

Overall, the study findings add to the evidence of a correlation between autoimmune diseases and neurologic disease, said Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., in an interview. “Anything that might contribute to behavioral problems is worth investigating.” However, it is important to remember that association is not causation.

“There is some literature and evidence that autoimmune disease is associated with mental health issues, but the mechanisms of action are unknown,” said Dr. Lessin. ADHD is highly heritable, so the association may be caused by a similar genetic predisposition, or it may be something related to autoimmunity that is impacting the fetus by passing through the placenta.

The current study’s strengths include the large size and hybrid design, but limitations such as the identification of ADHD based on medication prescriptions may have led to underreporting, and identifying maternal autoimmune disease via inpatient hospital diagnosis could have selected for more severe disease, he said.

From a clinical standpoint, the study suggests a correlation that should be noted in a family history and potentially used to inform a diagnosis, especially in cases of type 1 diabetes where the association was strongest, Dr. Lessin said. The findings also support the value of further research to look for mechanisms that might explain whether the association between autoimmune disease and ADHD is autoimmune system causality or shared genetic susceptibility.

The study received no outside funding. One coauthor disclosed receiving grants from the National Blood Authority Australia and the Australian National Health and Medical Research Council during the conduct of the study. Dr. Dalsgaard had no financial conflicts to disclose. Dr. Lessin disclosed serving as editor of the ADHD toolkit for the American Academy of Pediatrics and coauthor of the current ADHD clinical guidelines. He also serves in advisory capacity to Cognoa, a company involved in diagnosis of autism, and Corium/KemPharm, companies involved in the development of ADHD treatments.

Maternal autoimmune diseases significantly increased the risk of ADHD in children, based on data from a large cohort study of more than 800,000 mothers and children and a subsequent meta-analysis.

“There is growing evidence that immune-related cells and proteins play a role in brain development and function and that maternal immune activation, including infection, autoimmune disease, and chronic inflammation during pregnancy, increases the risk of neurodevelopmental disorders among children,” wrote Timothy C. Nielsen, MPH, of the University of Sydney, and colleagues.

Previous research has examined a link between maternal autoimmune disorders and autism spectrum disorders in children, but associations with ADHD have not been well studied, they said.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 831,718 mothers and their 831,718 singleton infants in Australia. A total of 12,787 infants were born to mothers with an autoimmune diagnosis; 12,610 of them were matched to 50,440 control infants. ADHD was determined based on prescription for a stimulant treatment or a hospital diagnosis; children with a first ADHD event younger than 3 years were excluded.

In the total cohort of 63,050 infants, the presence of any maternal autoimmune disease was associated with a significantly increased risk of ADHD (hazard ratio, 1.30) as was the presence of several specific conditions: type 1 diabetes (HR, 2.23), psoriasis (HR, 1.66), and rheumatic fever or rheumatic carditis (HR, 1.75).

In addition, the researchers conducted a meta-analysis of the current study and four additional studies that yielded similar results. In the meta-analysis, the risk of ADHD was significantly associated with any maternal autoimmune disease in two studies (HR, 1.20); with maternal type 1 diabetes in four studies (HR, 1.53); with maternal hyperthyroidism in three studies (HR 1.15); and with maternal psoriasis in two studies (HR, 1.31).

Type 1 diabetes (T1D) had the highest HR and was the most often studied condition. However, “the observed association may also be related to nonimmune aspects of T1D, such as glycemic control, as nonautoimmune diabetes has been associated with ADHD among children,” the researchers wrote.

The study findings were limited by several factors, including the lack of outpatient and primary care records to identify maternal autoimmune disease, and lack of data on any medication used to managed diseases during pregnancy, as well as a lack of data on children with ADHD who might not have been treated with medication, the researchers noted. In addition, “given differences in study design and definitions, the pooled HRs presented in the meta-analysis need to be treated cautiously.”

However, the results were strengthened by the hybrid study design and large study population, and were generally consistent with previous research supporting an effect of maternal immune function on fetal neurodevelopment, they noted.

“Our study provides justification for future studies that examine the effect of maternal autoimmune diseases, including biomarkers, condition severity, and management in pregnancy and in the periconception period, on neurodevelopmental disorders in children,” they concluded.

Studies need to explore mechanism of action

The current study, with its hybrid design, adds support to the evidence of an association between any maternal autoimmune disease and ADHD in children, as well as an association between the specific conditions of type 1 diabetes, hyperthyroidism, and psoriasis in mothers and ADHD in children, Søren Dalsgaard, MD, of Aarhus (Denmark) University, wrote in an accompanying editorial.

“Importantly, Nielsen et al. emphasized in their article that, for the many different autoimmune diseases, different underlying mechanisms for the associations with disorders of the central nervous system were likely. They mentioned that, for T1D, low glycemic control may play a role, as type 2 diabetes has been associated with ADHD,” said Dr. Dalsgaard.

“Overall, these mechanisms are thought to include shared genetic and environmental risk factors or direct effects of maternal autoantibodies or cytokines crossing the placenta and altering the fetal immune response, which in turns leads to changes in the central nervous system,” Dr. Dalsgaard explained. However, the current study and previous studies have not identified the mechanisms to explain the association between ADHD in children and maternal autoimmune disease.

“To understand more about these associations, future studies should include researchers and data from different scientific disciplines, such as epidemiology, animal modeling, genetics, and neuroimmunology,” he concluded.
 

Association is not causality

Overall, the study findings add to the evidence of a correlation between autoimmune diseases and neurologic disease, said Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., in an interview. “Anything that might contribute to behavioral problems is worth investigating.” However, it is important to remember that association is not causation.

“There is some literature and evidence that autoimmune disease is associated with mental health issues, but the mechanisms of action are unknown,” said Dr. Lessin. ADHD is highly heritable, so the association may be caused by a similar genetic predisposition, or it may be something related to autoimmunity that is impacting the fetus by passing through the placenta.

The current study’s strengths include the large size and hybrid design, but limitations such as the identification of ADHD based on medication prescriptions may have led to underreporting, and identifying maternal autoimmune disease via inpatient hospital diagnosis could have selected for more severe disease, he said.

From a clinical standpoint, the study suggests a correlation that should be noted in a family history and potentially used to inform a diagnosis, especially in cases of type 1 diabetes where the association was strongest, Dr. Lessin said. The findings also support the value of further research to look for mechanisms that might explain whether the association between autoimmune disease and ADHD is autoimmune system causality or shared genetic susceptibility.

The study received no outside funding. One coauthor disclosed receiving grants from the National Blood Authority Australia and the Australian National Health and Medical Research Council during the conduct of the study. Dr. Dalsgaard had no financial conflicts to disclose. Dr. Lessin disclosed serving as editor of the ADHD toolkit for the American Academy of Pediatrics and coauthor of the current ADHD clinical guidelines. He also serves in advisory capacity to Cognoa, a company involved in diagnosis of autism, and Corium/KemPharm, companies involved in the development of ADHD treatments.

Maternal autoimmune diseases significantly increased the risk of ADHD in children, based on data from a large cohort study of more than 800,000 mothers and children and a subsequent meta-analysis.

“There is growing evidence that immune-related cells and proteins play a role in brain development and function and that maternal immune activation, including infection, autoimmune disease, and chronic inflammation during pregnancy, increases the risk of neurodevelopmental disorders among children,” wrote Timothy C. Nielsen, MPH, of the University of Sydney, and colleagues.

Previous research has examined a link between maternal autoimmune disorders and autism spectrum disorders in children, but associations with ADHD have not been well studied, they said.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 831,718 mothers and their 831,718 singleton infants in Australia. A total of 12,787 infants were born to mothers with an autoimmune diagnosis; 12,610 of them were matched to 50,440 control infants. ADHD was determined based on prescription for a stimulant treatment or a hospital diagnosis; children with a first ADHD event younger than 3 years were excluded.

In the total cohort of 63,050 infants, the presence of any maternal autoimmune disease was associated with a significantly increased risk of ADHD (hazard ratio, 1.30) as was the presence of several specific conditions: type 1 diabetes (HR, 2.23), psoriasis (HR, 1.66), and rheumatic fever or rheumatic carditis (HR, 1.75).

In addition, the researchers conducted a meta-analysis of the current study and four additional studies that yielded similar results. In the meta-analysis, the risk of ADHD was significantly associated with any maternal autoimmune disease in two studies (HR, 1.20); with maternal type 1 diabetes in four studies (HR, 1.53); with maternal hyperthyroidism in three studies (HR 1.15); and with maternal psoriasis in two studies (HR, 1.31).

Type 1 diabetes (T1D) had the highest HR and was the most often studied condition. However, “the observed association may also be related to nonimmune aspects of T1D, such as glycemic control, as nonautoimmune diabetes has been associated with ADHD among children,” the researchers wrote.

The study findings were limited by several factors, including the lack of outpatient and primary care records to identify maternal autoimmune disease, and lack of data on any medication used to managed diseases during pregnancy, as well as a lack of data on children with ADHD who might not have been treated with medication, the researchers noted. In addition, “given differences in study design and definitions, the pooled HRs presented in the meta-analysis need to be treated cautiously.”

However, the results were strengthened by the hybrid study design and large study population, and were generally consistent with previous research supporting an effect of maternal immune function on fetal neurodevelopment, they noted.

“Our study provides justification for future studies that examine the effect of maternal autoimmune diseases, including biomarkers, condition severity, and management in pregnancy and in the periconception period, on neurodevelopmental disorders in children,” they concluded.

Studies need to explore mechanism of action

The current study, with its hybrid design, adds support to the evidence of an association between any maternal autoimmune disease and ADHD in children, as well as an association between the specific conditions of type 1 diabetes, hyperthyroidism, and psoriasis in mothers and ADHD in children, Søren Dalsgaard, MD, of Aarhus (Denmark) University, wrote in an accompanying editorial.

“Importantly, Nielsen et al. emphasized in their article that, for the many different autoimmune diseases, different underlying mechanisms for the associations with disorders of the central nervous system were likely. They mentioned that, for T1D, low glycemic control may play a role, as type 2 diabetes has been associated with ADHD,” said Dr. Dalsgaard.

“Overall, these mechanisms are thought to include shared genetic and environmental risk factors or direct effects of maternal autoantibodies or cytokines crossing the placenta and altering the fetal immune response, which in turns leads to changes in the central nervous system,” Dr. Dalsgaard explained. However, the current study and previous studies have not identified the mechanisms to explain the association between ADHD in children and maternal autoimmune disease.

“To understand more about these associations, future studies should include researchers and data from different scientific disciplines, such as epidemiology, animal modeling, genetics, and neuroimmunology,” he concluded.
 

Association is not causality

Overall, the study findings add to the evidence of a correlation between autoimmune diseases and neurologic disease, said Herschel Lessin, MD, of Children’s Medical Group, Poughkeepsie, N.Y., in an interview. “Anything that might contribute to behavioral problems is worth investigating.” However, it is important to remember that association is not causation.

“There is some literature and evidence that autoimmune disease is associated with mental health issues, but the mechanisms of action are unknown,” said Dr. Lessin. ADHD is highly heritable, so the association may be caused by a similar genetic predisposition, or it may be something related to autoimmunity that is impacting the fetus by passing through the placenta.

The current study’s strengths include the large size and hybrid design, but limitations such as the identification of ADHD based on medication prescriptions may have led to underreporting, and identifying maternal autoimmune disease via inpatient hospital diagnosis could have selected for more severe disease, he said.

From a clinical standpoint, the study suggests a correlation that should be noted in a family history and potentially used to inform a diagnosis, especially in cases of type 1 diabetes where the association was strongest, Dr. Lessin said. The findings also support the value of further research to look for mechanisms that might explain whether the association between autoimmune disease and ADHD is autoimmune system causality or shared genetic susceptibility.

The study received no outside funding. One coauthor disclosed receiving grants from the National Blood Authority Australia and the Australian National Health and Medical Research Council during the conduct of the study. Dr. Dalsgaard had no financial conflicts to disclose. Dr. Lessin disclosed serving as editor of the ADHD toolkit for the American Academy of Pediatrics and coauthor of the current ADHD clinical guidelines. He also serves in advisory capacity to Cognoa, a company involved in diagnosis of autism, and Corium/KemPharm, companies involved in the development of ADHD treatments.

COVID has changed our world very rapidly. There are good changes, such as cleaner air and the ability to use telehealth widely. But there are devastating changes. As we are all aware, we have lost more than 400,000 people in America, and that number is climbing.

How can we mitigate some of the psychological effects of the pandemic? It is time to bring lessons learned on the battlefield to civilian psychiatrists and health care systems.

Despite having participated in mass casualty drills, no health system was trained or psychologically prepared for this once-in-a-century event.

The military dictum, “train like you fight; fight like you train” falls short considering the speed of viral replication, the serious flaws and disparities in our health care system revealed by COVID-19, and the public’s disturbingly variable adherence to preventive measures.

Like combat troops, health care workers put the needs of others ahead of their own. They suck up strain and step back from their own needs in favor of the mission.

Whether in combat or pandemic, leaders have valuable opportunities to promote the effectiveness of those on the front lines by caring for them. Those in charge may, themselves, be profoundly affected. While other team members focus on defined roles, leaders are forced to deal with many unknowns. They must often act without adequate information or resources.

Some of us have worked at hospitals treating many COVID patients and have been on “the front lines” for almost a year. We are asked a lot of questions, to which we often answer, "I don't know" or "there are no good choices."

All leaders work hard to model strength, but a difficult lesson that the military has had to learn is that leaders may strengthen cohesion by showing their grief, modeling self-care, drawing attention to even small successes in the face of overwhelming loss, and, when necessary, finding words for those losses.

Peer support is particularly important in high-stress situations. Mental health providers are uniquely qualified to share information, pick up on signs of severe stress, and provide support at the point of need.

Military combat stress control doctrine does, however, provide best practices that can be implemented across civilian health care systems. Its key elements are:

• Confidence in leadership at all levels – requiring visibility (“battlespace circulation”) of leaders who listen and share timely, accurate information.
• Realistic training – especially for those who, because of staff shortages, assume unfamiliar duties.
• Self-care – including regular meals, adequate sleep, and ongoing contact with family and friends. Here of course, the contact should be virtual as much as possible.
• Belief in the Mission – compassion satisfaction is a buffer against burnout.
• Esprit de corps – cohesive teams suffer significantly fewer combat stress casualties.

It is true that these principles have more often been tested in short-term crisis rather than the long slog that is COVID-19. This pandemic is more like an ongoing civil war than a distant battlefield because your home and those close to you share the risk.

There is no easy path ahead for America’s civilian health care system. These military principles, tested under fire, offer valuable opportunities in the ongoing battle against COVID-19.

Dr. Ritchie practices psychiatry in Washington. She has no disclosures.

Dr. Kudler is associate consulting professor of psychiatry and behavioral sciences at Duke University in Durham. N.C., and recently retired from his post as chief consultant for mental health, at the Department of Veterans Affairs. He has no relevant financial relationships.

Dr. Yehuda is professor of psychiatry and neuroscience and director of the traumatic stress studies division at the Mount Sinai School of Medicine, New York. She also serves as director of mental health at the James J. Peters Veterans Affairs Medical Center, also in New York. Dr. Yehuda has no disclosures.

Dr. Koffman is the senior consultant for Integrative Medicine & Behavioral Health at the National Intrepid Center of Excellence, Bethesda, Md. He has no disclosures.

COVID has changed our world very rapidly. There are good changes, such as cleaner air and the ability to use telehealth widely. But there are devastating changes. As we are all aware, we have lost more than 400,000 people in America, and that number is climbing.

How can we mitigate some of the psychological effects of the pandemic? It is time to bring lessons learned on the battlefield to civilian psychiatrists and health care systems.

Despite having participated in mass casualty drills, no health system was trained or psychologically prepared for this once-in-a-century event.

The military dictum, “train like you fight; fight like you train” falls short considering the speed of viral replication, the serious flaws and disparities in our health care system revealed by COVID-19, and the public’s disturbingly variable adherence to preventive measures.

Like combat troops, health care workers put the needs of others ahead of their own. They suck up strain and step back from their own needs in favor of the mission.

Whether in combat or pandemic, leaders have valuable opportunities to promote the effectiveness of those on the front lines by caring for them. Those in charge may, themselves, be profoundly affected. While other team members focus on defined roles, leaders are forced to deal with many unknowns. They must often act without adequate information or resources.

Some of us have worked at hospitals treating many COVID patients and have been on “the front lines” for almost a year. We are asked a lot of questions, to which we often answer, "I don't know" or "there are no good choices."

All leaders work hard to model strength, but a difficult lesson that the military has had to learn is that leaders may strengthen cohesion by showing their grief, modeling self-care, drawing attention to even small successes in the face of overwhelming loss, and, when necessary, finding words for those losses.

Peer support is particularly important in high-stress situations. Mental health providers are uniquely qualified to share information, pick up on signs of severe stress, and provide support at the point of need.

Military combat stress control doctrine does, however, provide best practices that can be implemented across civilian health care systems. Its key elements are:

• Confidence in leadership at all levels – requiring visibility (“battlespace circulation”) of leaders who listen and share timely, accurate information.
• Realistic training – especially for those who, because of staff shortages, assume unfamiliar duties.
• Self-care – including regular meals, adequate sleep, and ongoing contact with family and friends. Here of course, the contact should be virtual as much as possible.
• Belief in the Mission – compassion satisfaction is a buffer against burnout.
• Esprit de corps – cohesive teams suffer significantly fewer combat stress casualties.

It is true that these principles have more often been tested in short-term crisis rather than the long slog that is COVID-19. This pandemic is more like an ongoing civil war than a distant battlefield because your home and those close to you share the risk.

There is no easy path ahead for America’s civilian health care system. These military principles, tested under fire, offer valuable opportunities in the ongoing battle against COVID-19.

Dr. Ritchie practices psychiatry in Washington. She has no disclosures.

Dr. Kudler is associate consulting professor of psychiatry and behavioral sciences at Duke University in Durham. N.C., and recently retired from his post as chief consultant for mental health, at the Department of Veterans Affairs. He has no relevant financial relationships.

Dr. Yehuda is professor of psychiatry and neuroscience and director of the traumatic stress studies division at the Mount Sinai School of Medicine, New York. She also serves as director of mental health at the James J. Peters Veterans Affairs Medical Center, also in New York. Dr. Yehuda has no disclosures.

Dr. Koffman is the senior consultant for Integrative Medicine & Behavioral Health at the National Intrepid Center of Excellence, Bethesda, Md. He has no disclosures.

COVID has changed our world very rapidly. There are good changes, such as cleaner air and the ability to use telehealth widely. But there are devastating changes. As we are all aware, we have lost more than 400,000 people in America, and that number is climbing.

How can we mitigate some of the psychological effects of the pandemic? It is time to bring lessons learned on the battlefield to civilian psychiatrists and health care systems.

Despite having participated in mass casualty drills, no health system was trained or psychologically prepared for this once-in-a-century event.

The military dictum, “train like you fight; fight like you train” falls short considering the speed of viral replication, the serious flaws and disparities in our health care system revealed by COVID-19, and the public’s disturbingly variable adherence to preventive measures.

Like combat troops, health care workers put the needs of others ahead of their own. They suck up strain and step back from their own needs in favor of the mission.

Whether in combat or pandemic, leaders have valuable opportunities to promote the effectiveness of those on the front lines by caring for them. Those in charge may, themselves, be profoundly affected. While other team members focus on defined roles, leaders are forced to deal with many unknowns. They must often act without adequate information or resources.

Some of us have worked at hospitals treating many COVID patients and have been on “the front lines” for almost a year. We are asked a lot of questions, to which we often answer, "I don't know" or "there are no good choices."

All leaders work hard to model strength, but a difficult lesson that the military has had to learn is that leaders may strengthen cohesion by showing their grief, modeling self-care, drawing attention to even small successes in the face of overwhelming loss, and, when necessary, finding words for those losses.

Peer support is particularly important in high-stress situations. Mental health providers are uniquely qualified to share information, pick up on signs of severe stress, and provide support at the point of need.

Military combat stress control doctrine does, however, provide best practices that can be implemented across civilian health care systems. Its key elements are:

• Confidence in leadership at all levels – requiring visibility (“battlespace circulation”) of leaders who listen and share timely, accurate information.
• Realistic training – especially for those who, because of staff shortages, assume unfamiliar duties.
• Self-care – including regular meals, adequate sleep, and ongoing contact with family and friends. Here of course, the contact should be virtual as much as possible.
• Belief in the Mission – compassion satisfaction is a buffer against burnout.
• Esprit de corps – cohesive teams suffer significantly fewer combat stress casualties.

It is true that these principles have more often been tested in short-term crisis rather than the long slog that is COVID-19. This pandemic is more like an ongoing civil war than a distant battlefield because your home and those close to you share the risk.

There is no easy path ahead for America’s civilian health care system. These military principles, tested under fire, offer valuable opportunities in the ongoing battle against COVID-19.

Dr. Ritchie practices psychiatry in Washington. She has no disclosures.

Dr. Kudler is associate consulting professor of psychiatry and behavioral sciences at Duke University in Durham. N.C., and recently retired from his post as chief consultant for mental health, at the Department of Veterans Affairs. He has no relevant financial relationships.

Dr. Yehuda is professor of psychiatry and neuroscience and director of the traumatic stress studies division at the Mount Sinai School of Medicine, New York. She also serves as director of mental health at the James J. Peters Veterans Affairs Medical Center, also in New York. Dr. Yehuda has no disclosures.

Dr. Koffman is the senior consultant for Integrative Medicine & Behavioral Health at the National Intrepid Center of Excellence, Bethesda, Md. He has no disclosures.

During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

During the ongoing COVID-19 pandemic, many people are spending endless hours at home looking at computer, phone, and television screens. Our population has turned to Internet use and television watching as a coping mechanism to deal with their isolation, boredom, stress, and fear of the virus. Indeed, some people have become addicted to watching television and binge-watching entire series in a single sitting on subscription streaming services.

A U.K. study showed that, during the lockdown, adults averaged spending 40% of their waking hours in front of a screen. After a long binge-watch, folks often forget what happened in the episodes or even the name of the program they viewed. When someone finds himself in this situation and can’t remember very much about what he actually watched, he feels as though he has wasted his own time and might become dysphoric and depressed. This type of viewer feels disconnected and forgets what he watched because he is experiencing passive enjoyment, rather than actively relating to the world.

So should television binge-watching give people feelings of guilt?

Fortunately, there are some positive factors about spending excessive time engrossed in these screens during a pandemic; some people use television viewing as a coping mechanism to deal with the reality and the fear of the coronavirus. Some beneficial aspects of television watching include:

• Escaping from the reality and stress of the pandemic in an emotionally safe, isolated cocoon.
• Experiencing safety from contracting COVID-19 by sheltering in place, isolating, and physical distancing from other people in the outside world.
• Experiencing a subdued, private, and mentally relaxing environment.
• Being productive and multitasking while watching television, for example, knit, sew, fold clothes, pay bills, write a letter, etc.

Despite many beneficial aspects of excessive television watching during the pandemic, we have to ask: Can too much television prove detrimental to our mental or physical well-being?
 

Associated mental, and physical problems

Cause and effect between excessive screen time and sleep disturbances is scientifically unproven, but there is an association between those factors.

Excessive screen time is associated with a sleep deficit, and a proper amount of sleep is necessary for optimal brain function, a healthy immune system, good memory, and overall well-being. Sleep cleans out the short-term memory stage from the information learned that day to make room for new memories. This allows us to store memories every day. An inadequate amount of sleep causes memory problems and cognitive deficits because we are not storing as many memories from days when we are sleep deprived. A good night’s sleep will prevent stress from one day to be carried over to the next day.

Lack of sleep affects people differently, but in some cases, a shortage of sleep can cause feelings of depression and isolation. Television, computer, and phone screens convey excessive damaging LED and blue light, detrimentally affecting our melatonin production and circadian rhythm. Blue light has wavelengths between 380 nm and 500 nm, and although blue wavelengths are beneficial in the day and increase positive mental mood, attention, and reaction times, blue wavelengths are destructive at night. Blue-light exposure suppresses the secretion of melatonin, which, as we know, is a hormone that influences circadian rhythms. The negative disruption of circadian rhythm throws the body’s biological clock in disarray and makes it more difficult for the mind to shut down at night.

Unfortunately, electronics with LED screens increase the amount of exposure to these blue wavelengths. In addition, the U.S. National Toxicology Program has suggested that a link exists between blue-light exposure at night to diabetes, heart disease, cancer, and obesity (Sci Tot Environ. 2017 Dec 31;[607-8]:1073-84).
 

Advice for patients and clinicians

Time spent watching television and using the Internet should be done in moderation. Make sure that patients understand that they should not feel guilty about watching television during these periods of isolation.

Encourage patients to be selective in their television viewing and to research available programs on streaming services and TV – and limit their screen time only to programs that truly interest them. Discourage them from watching television endlessly, hour after hour. Also, discourage patients from watching too much news. Instead, tell them to limit news to 1 hour per day, because news they perceive as bad might increase their overall anxiety.

Tell patients to engage in physical exercise every day; walk or run outside if possible. When inside, advise them to get up and walk around at least once per hour. Other advice we would like to offer patients and clinicians alike are:

• Put yourself on a schedule and go to sleep the same time each night and try to get 8 hours of sleep in a 24-hour period.
• Put away your devices 1 hour before going to bed or at least use dark mode, and wear blue-block glasses, since they are easier on the eyes and brain. Do not use television to put yourself to sleep. Spending too much time reading news stories is not a good idea, either, because doing so is mentally stimulating and can cause more uncertainty – making it difficult to sleep.
• Protect your eye health by purchasing and installing light bulbs with more internal red coating than blue. These bulbs will produce a warmer tone than the blue, and warmer tones will be less likely to shift circadian rhythm and suppress melatonin, thus reducing blue-light exposure. Blink your eyes often, and use eye solution for dry eyes.
• Sleep in total darkness to reduce your exposure to blue light. Take supplements with lutein and zeaxanthin, which may reduce the oxidative effects of blue light.

Encouraging patients to follow these guidelines – and adhering to them ourselves – should help us emerge from the COVID-19 pandemic mentally and physically healthy.

Dr. Cohen is board certified in psychiatry and has had a private practice in Philadelphia for more than 35 years. His areas of specialty include sports psychiatry, agoraphobia, depression, and substance abuse. In addition, Dr. Cohen is a former professor of psychiatry, family medicine, and otolaryngology at Thomas Jefferson University, Philadelphia. He has no conflicts of interest.

Ms. Cohen holds an MBA from Temple University, Philadelphia, with a focus on health care administration. Previously, Ms. Cohen was an associate administrator at Hahnemann University Hospital and an executive at the Health Services Council, both in Philadelphia. She currently writes biographical summaries of notable 18th- and 19th-century women. Ms. Cohen has no conflicts of interest.

The United States is nearly 6 weeks into its historic campaign to vaccinate Americans against the virus that causes COVID-19, and so far, the two vaccines in use look remarkably low risk, according to new data presented today at a meeting of vaccine experts that advise the Centers for Disease Control and Prevention.

With 23.5 million doses of the Pfizer and Moderna vaccines now given, there have been very few serious side effects. In addition, deaths reported after people got the vaccine do not seem to be related to it.

The most common symptoms reported after vaccination were pain where people got the shot, fatigue, headache, and muscle soreness. These were more common after the second dose. In addition, about one in four people reported fever and chills after the second shot.

“On the whole, I thought it was very reassuring,” said William Schaffner, MD, an infectious disease expert with Vanderbilt University, Nashville, Tenn., who listened to the presentations.

The CDC is collecting safety information through multiple channels. These include a new smartphone-based app called V-Safe, which collects daily information from people who’ve been vaccinated; the federal Vaccine Adverse Event Reporting System, which accepts reports from anyone; and the Vaccine Safety Datalink, which is a collaboration between the CDC and nine major hospital systems. There’s also the Clinical Immunization Safety Assessment Project, a collaboration between the CDC and vaccine safety experts.

After surveying these systems, experts heading the safety committee for the CDC’s Advisory Committee on Immunization Practices said there have been few serious side effects reported.

Very rarely, severe allergic reactions – called anaphylaxis – have occurred after vaccination. There have been 50 of these cases reported after the Pfizer vaccine and 21 cases reported after the Moderna vaccine to date. Nearly all of them – 94% of the anaphylaxis cases after Pfizer vaccines and 100% of those after Moderna’s vaccine – have been in women, though it’s not clear why.

That translates to a rate of about five cases of anaphylaxis for every million doses of the Pfizer vaccine and about three for every million doses of the Moderna vaccine. Most of these occur within 15 minutes after getting a vaccine dose, with one reported as long as 20 hours after the shot.

The CDC suspects these may be related to an ingredient called polyethylene glycol (PEG). PEG is a part of the particles that slip the vaccines’ mRNA into cells with instructions to make the spike protein of the virus. Cells then express these spikes on their surfaces so the immune system can learn to recognize them and make defenses against them. PEG is a common ingredient in many drugs and occasionally triggers anaphylaxis.
 

Reported deaths seem unrelated to vaccines

Through Jan. 18, 196 people have died after getting a vaccine.

Most of these deaths (129) were in patients in long term care facilities. These deaths are still being investigated, but when they were compared with the number of deaths that might be expected over the same period because of natural causes, they seemed to be coincidental and not caused by the vaccine, said Tom Shimabukuro, MD, deputy director of the Immunization Safety Office at the CDC, who studied the data.

In fact, death rates were lower among vaccinated nursing home residents, compared with those who had not been vaccinated.

“These findings suggest that short-term mortality rates appear unrelated to vaccination for COVID-19,” Dr. Shimabukuro said.

This also appeared to be true for younger adults who died after their shots.

There were 28 people aged under 65 years who died after being vaccinated. Most of these deaths were heart related, according to autopsy reports. When investigators compared the number of sudden cardiac deaths expected to occur in this population naturally, they found people who were vaccinated had a lower rate than would have been expected without vaccination. This suggests that these deaths were also unrelated to the vaccine.
 

More vaccines on the horizon

The panel also heard an update from drug company AstraZeneca on its vaccine. It’s being used in 18 countries but has not yet been authorized in the United States.

That vaccine is currently in phase 3 of its U.S. clinical trials, and more than 26,000 people who have volunteered to get the shot had received their second dose as of Jan. 21, the company said.

The Food and Drug Administration requires at least 2 months of follow-up before it will evaluate a vaccine for an emergency-use authorization, which means the company would be ready to submit by the end of March, with a possible approval by April.

The AstraZeneca vaccine uses a more traditional method to create immunity, slipping a key part of the virus that causes COVID-19 into the shell of an adenovirus – a virus that causes cold-like symptoms – that normally infects monkeys. When the immune system sees the virus, it generates protective defenses against it.

The two-dose vaccine can be stored in a regular refrigerator for up to 6 months, which makes it easier to handle than the mRNA vaccines, which require much colder storage. Another advantage appears to be that it’s less likely to trigger severe allergic reactions. So far, there have been no cases of anaphylaxis reported after this shot.

In total, four serious side effects have been reported with the AstraZeneca vaccine, including two cases of transverse myelitis, a serious condition that causes swelling of the spinal cord, leading to pain, muscle weakness, and paralysis. One of these was in the group that got the placebo. The reports paused the trial, but it was allowed to continue after a safety review.

This vaccine also appears to be less effective than the mRNA shots. Data presented to the panel show it appears to cut the risk of developing a COVID infection that has symptoms by 62%. That’s over the 50% threshold the FDA set for approval but less than seen with the mRNA vaccines, which are more than 90% effective at preventing infections.

“Is the average person going to want to take the AstraZeneca shot? What role is this going to play in our vaccination program?” Dr. Schaffner said.

Johnson & Johnson will have enough data from its clinical trials to submit it to the FDA within the next week, the company said in a call with shareholders on Tuesday. So far, its one-dose shots looks to be about as effective as both the Pfizer and Moderna vaccines.

“It could be that we wind up with four vaccines: Three that can run very fast, and one that’s not so fast,” Dr. Schaffner said.

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

The United States is nearly 6 weeks into its historic campaign to vaccinate Americans against the virus that causes COVID-19, and so far, the two vaccines in use look remarkably low risk, according to new data presented today at a meeting of vaccine experts that advise the Centers for Disease Control and Prevention.

With 23.5 million doses of the Pfizer and Moderna vaccines now given, there have been very few serious side effects. In addition, deaths reported after people got the vaccine do not seem to be related to it.

The most common symptoms reported after vaccination were pain where people got the shot, fatigue, headache, and muscle soreness. These were more common after the second dose. In addition, about one in four people reported fever and chills after the second shot.

“On the whole, I thought it was very reassuring,” said William Schaffner, MD, an infectious disease expert with Vanderbilt University, Nashville, Tenn., who listened to the presentations.

The CDC is collecting safety information through multiple channels. These include a new smartphone-based app called V-Safe, which collects daily information from people who’ve been vaccinated; the federal Vaccine Adverse Event Reporting System, which accepts reports from anyone; and the Vaccine Safety Datalink, which is a collaboration between the CDC and nine major hospital systems. There’s also the Clinical Immunization Safety Assessment Project, a collaboration between the CDC and vaccine safety experts.

After surveying these systems, experts heading the safety committee for the CDC’s Advisory Committee on Immunization Practices said there have been few serious side effects reported.

Very rarely, severe allergic reactions – called anaphylaxis – have occurred after vaccination. There have been 50 of these cases reported after the Pfizer vaccine and 21 cases reported after the Moderna vaccine to date. Nearly all of them – 94% of the anaphylaxis cases after Pfizer vaccines and 100% of those after Moderna’s vaccine – have been in women, though it’s not clear why.

That translates to a rate of about five cases of anaphylaxis for every million doses of the Pfizer vaccine and about three for every million doses of the Moderna vaccine. Most of these occur within 15 minutes after getting a vaccine dose, with one reported as long as 20 hours after the shot.

The CDC suspects these may be related to an ingredient called polyethylene glycol (PEG). PEG is a part of the particles that slip the vaccines’ mRNA into cells with instructions to make the spike protein of the virus. Cells then express these spikes on their surfaces so the immune system can learn to recognize them and make defenses against them. PEG is a common ingredient in many drugs and occasionally triggers anaphylaxis.
 

Reported deaths seem unrelated to vaccines

Through Jan. 18, 196 people have died after getting a vaccine.

Most of these deaths (129) were in patients in long term care facilities. These deaths are still being investigated, but when they were compared with the number of deaths that might be expected over the same period because of natural causes, they seemed to be coincidental and not caused by the vaccine, said Tom Shimabukuro, MD, deputy director of the Immunization Safety Office at the CDC, who studied the data.

In fact, death rates were lower among vaccinated nursing home residents, compared with those who had not been vaccinated.

“These findings suggest that short-term mortality rates appear unrelated to vaccination for COVID-19,” Dr. Shimabukuro said.

This also appeared to be true for younger adults who died after their shots.

There were 28 people aged under 65 years who died after being vaccinated. Most of these deaths were heart related, according to autopsy reports. When investigators compared the number of sudden cardiac deaths expected to occur in this population naturally, they found people who were vaccinated had a lower rate than would have been expected without vaccination. This suggests that these deaths were also unrelated to the vaccine.
 

More vaccines on the horizon

The panel also heard an update from drug company AstraZeneca on its vaccine. It’s being used in 18 countries but has not yet been authorized in the United States.

That vaccine is currently in phase 3 of its U.S. clinical trials, and more than 26,000 people who have volunteered to get the shot had received their second dose as of Jan. 21, the company said.

The Food and Drug Administration requires at least 2 months of follow-up before it will evaluate a vaccine for an emergency-use authorization, which means the company would be ready to submit by the end of March, with a possible approval by April.

The AstraZeneca vaccine uses a more traditional method to create immunity, slipping a key part of the virus that causes COVID-19 into the shell of an adenovirus – a virus that causes cold-like symptoms – that normally infects monkeys. When the immune system sees the virus, it generates protective defenses against it.

The two-dose vaccine can be stored in a regular refrigerator for up to 6 months, which makes it easier to handle than the mRNA vaccines, which require much colder storage. Another advantage appears to be that it’s less likely to trigger severe allergic reactions. So far, there have been no cases of anaphylaxis reported after this shot.

In total, four serious side effects have been reported with the AstraZeneca vaccine, including two cases of transverse myelitis, a serious condition that causes swelling of the spinal cord, leading to pain, muscle weakness, and paralysis. One of these was in the group that got the placebo. The reports paused the trial, but it was allowed to continue after a safety review.

This vaccine also appears to be less effective than the mRNA shots. Data presented to the panel show it appears to cut the risk of developing a COVID infection that has symptoms by 62%. That’s over the 50% threshold the FDA set for approval but less than seen with the mRNA vaccines, which are more than 90% effective at preventing infections.

“Is the average person going to want to take the AstraZeneca shot? What role is this going to play in our vaccination program?” Dr. Schaffner said.

Johnson & Johnson will have enough data from its clinical trials to submit it to the FDA within the next week, the company said in a call with shareholders on Tuesday. So far, its one-dose shots looks to be about as effective as both the Pfizer and Moderna vaccines.

“It could be that we wind up with four vaccines: Three that can run very fast, and one that’s not so fast,” Dr. Schaffner said.

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

The United States is nearly 6 weeks into its historic campaign to vaccinate Americans against the virus that causes COVID-19, and so far, the two vaccines in use look remarkably low risk, according to new data presented today at a meeting of vaccine experts that advise the Centers for Disease Control and Prevention.

With 23.5 million doses of the Pfizer and Moderna vaccines now given, there have been very few serious side effects. In addition, deaths reported after people got the vaccine do not seem to be related to it.

The most common symptoms reported after vaccination were pain where people got the shot, fatigue, headache, and muscle soreness. These were more common after the second dose. In addition, about one in four people reported fever and chills after the second shot.

“On the whole, I thought it was very reassuring,” said William Schaffner, MD, an infectious disease expert with Vanderbilt University, Nashville, Tenn., who listened to the presentations.

The CDC is collecting safety information through multiple channels. These include a new smartphone-based app called V-Safe, which collects daily information from people who’ve been vaccinated; the federal Vaccine Adverse Event Reporting System, which accepts reports from anyone; and the Vaccine Safety Datalink, which is a collaboration between the CDC and nine major hospital systems. There’s also the Clinical Immunization Safety Assessment Project, a collaboration between the CDC and vaccine safety experts.

After surveying these systems, experts heading the safety committee for the CDC’s Advisory Committee on Immunization Practices said there have been few serious side effects reported.

Very rarely, severe allergic reactions – called anaphylaxis – have occurred after vaccination. There have been 50 of these cases reported after the Pfizer vaccine and 21 cases reported after the Moderna vaccine to date. Nearly all of them – 94% of the anaphylaxis cases after Pfizer vaccines and 100% of those after Moderna’s vaccine – have been in women, though it’s not clear why.

That translates to a rate of about five cases of anaphylaxis for every million doses of the Pfizer vaccine and about three for every million doses of the Moderna vaccine. Most of these occur within 15 minutes after getting a vaccine dose, with one reported as long as 20 hours after the shot.

The CDC suspects these may be related to an ingredient called polyethylene glycol (PEG). PEG is a part of the particles that slip the vaccines’ mRNA into cells with instructions to make the spike protein of the virus. Cells then express these spikes on their surfaces so the immune system can learn to recognize them and make defenses against them. PEG is a common ingredient in many drugs and occasionally triggers anaphylaxis.
 

Reported deaths seem unrelated to vaccines

Through Jan. 18, 196 people have died after getting a vaccine.

Most of these deaths (129) were in patients in long term care facilities. These deaths are still being investigated, but when they were compared with the number of deaths that might be expected over the same period because of natural causes, they seemed to be coincidental and not caused by the vaccine, said Tom Shimabukuro, MD, deputy director of the Immunization Safety Office at the CDC, who studied the data.

In fact, death rates were lower among vaccinated nursing home residents, compared with those who had not been vaccinated.

“These findings suggest that short-term mortality rates appear unrelated to vaccination for COVID-19,” Dr. Shimabukuro said.

This also appeared to be true for younger adults who died after their shots.

There were 28 people aged under 65 years who died after being vaccinated. Most of these deaths were heart related, according to autopsy reports. When investigators compared the number of sudden cardiac deaths expected to occur in this population naturally, they found people who were vaccinated had a lower rate than would have been expected without vaccination. This suggests that these deaths were also unrelated to the vaccine.
 

More vaccines on the horizon

The panel also heard an update from drug company AstraZeneca on its vaccine. It’s being used in 18 countries but has not yet been authorized in the United States.

That vaccine is currently in phase 3 of its U.S. clinical trials, and more than 26,000 people who have volunteered to get the shot had received their second dose as of Jan. 21, the company said.

The Food and Drug Administration requires at least 2 months of follow-up before it will evaluate a vaccine for an emergency-use authorization, which means the company would be ready to submit by the end of March, with a possible approval by April.

The AstraZeneca vaccine uses a more traditional method to create immunity, slipping a key part of the virus that causes COVID-19 into the shell of an adenovirus – a virus that causes cold-like symptoms – that normally infects monkeys. When the immune system sees the virus, it generates protective defenses against it.

The two-dose vaccine can be stored in a regular refrigerator for up to 6 months, which makes it easier to handle than the mRNA vaccines, which require much colder storage. Another advantage appears to be that it’s less likely to trigger severe allergic reactions. So far, there have been no cases of anaphylaxis reported after this shot.

In total, four serious side effects have been reported with the AstraZeneca vaccine, including two cases of transverse myelitis, a serious condition that causes swelling of the spinal cord, leading to pain, muscle weakness, and paralysis. One of these was in the group that got the placebo. The reports paused the trial, but it was allowed to continue after a safety review.

This vaccine also appears to be less effective than the mRNA shots. Data presented to the panel show it appears to cut the risk of developing a COVID infection that has symptoms by 62%. That’s over the 50% threshold the FDA set for approval but less than seen with the mRNA vaccines, which are more than 90% effective at preventing infections.

“Is the average person going to want to take the AstraZeneca shot? What role is this going to play in our vaccination program?” Dr. Schaffner said.

Johnson & Johnson will have enough data from its clinical trials to submit it to the FDA within the next week, the company said in a call with shareholders on Tuesday. So far, its one-dose shots looks to be about as effective as both the Pfizer and Moderna vaccines.

“It could be that we wind up with four vaccines: Three that can run very fast, and one that’s not so fast,” Dr. Schaffner said.

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