MDedge Psychiatry

As humans live longer, a renewed focus on quality of life has made the prompt diagnosis and treatment of sleep-related disorders in older adults increasingly necessary.¹ Normative aging results in multiple changes in sleep architecture, including decreased total sleep time, decreased sleep efficiency, decreased slow-wave sleep (SWS), and increased awakenings after sleep onset.² Sleep disturbances in older adults are increasingly recognized as multifactorial health conditions requiring comprehensive modification of risk factors, diagnosis, and treatment.³

In this article, we discuss the effects of aging on sleep architecture and provide an overview of primary sleep disorders in older adults. We also summarize strategies for diagnosing and treating sleep disorders in these patients.

Elements of the sleep cycle

The human sleep cycle begins with light sleep (sleep stages 1 and 2), progresses into SWS (sleep stage 3), and culminates in rapid eye movement (REM) sleep. The first 3 stages are referred to as non-rapid eye movement sleep (NREM). Throughout the night, this coupling of NREM and REM cycles occurs 4 to 6 times, with each successive cycle decreasing in length until awakening.⁴

Two complex neurologic pathways intersect to regulate the timing of sleep and wakefulness on arousal. The first pathway, the circadian system, is located within the suprachiasmatic nucleus of the hypothalamus and is highly dependent on external stimuli (light, food, etc.) to synchronize sleep/wake cycles. The suprachiasmatic nucleus regulates melatonin secretion by the pineal gland, which signals day-night transitions. The other pathway, the homeostatic system, modifies the amount of sleep needed daily. When multiple days of poor sleep occur, homeostatic sleep pressure (colloquially described as sleep debt) compensates by increasing the amount of sleep required in the following days. Together, the circadian and homeostatic systems work in conjunction to regulate sleep quantity to approximately one-third of the total sleep-wake cycle.^2,5

Age-related dysfunction of the regulatory sleep pathways leads to blunting of the ability to initiate and sustain high-quality sleep.⁶ Dysregulation of homeostatic sleep pressure decreases time spent in SWS, and failure of the circadian signaling apparatus results in delays in sleep/wake timing.² While research into the underlying neurobiology of sleep reveals that some of these changes are inherent to aging (Box^7-14), significant underdiagnosed pathologies may adversely affect sleep architecture, including polypharmacy, comorbid neuropathology (eg, synucleinopathies, tauopathies, etc.), and primary sleep disorders (insomnias, hypersomnias, and parasomnias).¹⁵

Box

Primary sleep disorders

Obstructive sleep apnea (OSA) is one of the most common, yet frequently underdiagnosed reversible causes of sleep disturbances. It is characterized by partial or complete airway obstruction culminating in periods of involuntary cessation of respirations during sleep. The resultant fragmentation in sleep leads to significant downstream effects over time, including excessive daytime sleepiness and fatigue, poor occupational and social performance, and substantial cognitive impairment.³ While it is well known that OSA increases in prevalence throughout middle age, this relationship plateaus after age 60.¹⁶ An estimated 40% to 60% of Americans age >60 are affected by OSA.¹⁷ The hypoxemia and fragmented sleep caused by unrecognized OSA are associated with a significant decline in activities of daily living (ADL).¹⁸ Untreated OSA is strongly linked to the development and progression of several major health conditions, including cardiovascular disease, diabetes mellitus, hypertension, stroke, and depression.¹⁹ In studies of long-term care facility residents—many of whom may have comorbid cognitive decline—researchers found that unrecognized OSA often mimics the progressive cognitive decline seen in major neurocognitive disorders.²⁰ However, classic symptoms of OSA may not always be present in these patients, and their daytime sleepiness is often attributed to old age rather than to a pathological etiology.¹⁶ Screening for OSA and prompt initiation of the appropriate treatment may reverse OSA-induced cognitive changes in these patients.²¹

The primary presenting symptom of OSA is snoring, which is correlated with pauses in breathing. Risk factors include increased body mass index (BMI), thick neck circumference, male sex, and advanced age. In older adults, BMI has a lower impact on the Apnea-Hypopnea Index, an indicator of the number of pauses in breathing per hour, when compared with young and middle-age adults.¹⁶ Validated screening questionnaires for OSA include the STOP-Bang Questionnaire (Table 1²²), OSA50, Berlin Questionnaire, and Epworth Sleepiness Scale, each of which is used in different subpopulations. The current diagnostic standard for OSA is nocturnal polysomnography in a sleep laboratory, but recent advances in home sleep apnea testing have made it a viable, low-cost alternative for patients who do not have significant medical comorbidities.²³ Standard utilized cutoffs for diagnosis are ≥5 events/hour (hypopneas associated with at least 4% oxygen desaturations) in conjunction with clinical symptoms of OSA.²⁴

Continue to: Treatment

Treatment. First-line treatment for OSA is continuous positive airway pressure therapy, but adherence rates vary widely with patient education and regular follow-up.²⁵ Adjunctive therapy includes weight loss, oral appliances, and uvulopalatopharyngoplasty, a procedure in which tissue in the throat is remodeled or removed.

Central sleep apnea (CSA) is a pause in breathing without evidence of associated respiratory effort. In adults, the development of CSA is indicative of underlying lower brainstem dysfunction, due to intermittent failures in the pontomedullary centers responsible for regulation of rhythmic breathing.²⁶ This can occur as a consequence of multiple diseases, including congestive heart failure, stroke, renal failure, chronic medication use (opioids), and brain tumors.

The Sleep Heart Health Study—the largest community-based cohort study to date examining CSA—estimated that the prevalence of CSA among adults age >65 was 1.1% (compared with 0.4% in those age <65).²⁷ Subgroup analysis revealed that men had significantly higher rates of CSA compared with women (2.7% vs 0.2%, respectively).

CSA may present similarly to OSA (excessive daytime somnolence, insomnia, poor sleep quality, difficulties with attention and concentration). Symptoms may also mimic those of coexisting medical conditions in older adults, such as nocturnal angina or paroxysmal nocturnal dyspnea.²⁷ Any older patient with daytime sleepiness and risk factors for CSA should be referred for in-laboratory nocturnal polysomnography, the gold standard diagnostic test. Unlike in OSA, ambulatory diagnostic measures (home sleep apnea testing) have not been validated for this disorder.²⁷

Treatment. The primary treatment for CSA is to address the underlying medical problem. Positive pressure ventilation has been attempted with mixed results. Supplemental oxygen and medical management (acetazolamide or theophylline) can help stimulate breathing. Newer studies have shown favorable outcomes with transvenous neurostimulation or adaptive servoventilation.^28-30

Continue to: Insomnia

Insomnia. For a primary diagnosis of insomnia, DSM-5 requires at least 3 nights per week of sleep disturbances that induce distress or functional impairment for at least 3 months.³¹ The International Classification of Disease, 10th Edition requires at least 1 month of symptoms (lying awake for a long time before falling asleep, sleeping for short periods, being awake for most of the night, feeling lack of sleep, waking up early) after ruling out other sleep disorders, substance use, or other medical conditions.⁴ Clinically, insomnia tends to present in older adults as a subjective complaint of dissatisfaction with the quality and/or quantity of their sleep. Insomnia has been consistently shown to be a significant risk factor for both the development or exacerbation of depression in older adults.^32-34

While the diagnosis of insomnia is mainly clinical via a thorough sleep and medication history, assistive ancillary testing can include wrist actigraphy and screening questionnaires (the Insomnia Severity Index and the Pittsburgh Sleep Quality Index).⁴ Because population studies of older adults have found discrepancies between objective and subjective methods of assessing sleep quality, relying on the accuracy of self-reported symptoms alone is questionable.³⁵

Treatment. Given that drug elimination half-life increases with age, and the risks of adverse effects are increased in older adults, the preferred treatment modalities for insomnia are nonpharmacologic.⁴ Sleep hygiene education (Table 2) and cognitive-behavioral therapy (CBT) for insomnia are often the first-line therapies.^4,36,37 It is crucial to manage comorbidities such as heart disease and obesity, as well as sources of discomfort from conditions such as arthritic pain.^38,39 If nonpharmacologic therapies are not effective, pharmacologic options can be considered.⁴ Before prescribing sleep medications, it may be more fruitful to treat underlying psychiatric disorders such as depression and anxiety with antidepressants.⁴ Although benzodiazepines are helpful for their sedative effects, they are not recommended for older adults because of an increased risk of falls, rebound insomnia, potential tolerance, and associated cognitive impairment.⁴⁰ Benzodiazepine receptor agonists (eg, zolpidem, eszopiclone, zaleplon) were initially developed as a first-line treatment for insomnia to replace the reliance on benzodiazepines, but these medications have a “black-box” warning of a serious risk of complex sleep behaviors, including life-threatening parasomnias.⁴¹ As a result, guidelines suggest a shorter duration of treatment with a benzodiazepine receptor agonist may still provide benefit while limiting the risk of adverse effects.⁴²

Doxepin is the only antidepressant FDA-approved for insomnia; it improves sleep latency (time taken to initiate sleep after lying down), duration, and quality in adults age >65.⁴³ Melatonin receptor agonists such as ramelteon and melatonin have shown positive results in older patients with insomnia. In clinical trials of patients age ≥65, ramelteon, which is FDA-approved for insomnia, produced no rebound insomnia, withdrawal effects, memory impairment, or gait instability.^44-46 Suvorexant, an orexin receptor antagonist, decreases sleep latency and increases total sleep time equally in both young and older adults.^47-49Table 3^40-51 provides a list of medications used to treat insomnia (including off-label agents) and their common adverse effects in older adults.

Parasomnias are undesirable behaviors that occur during sleep, commonly associated with the sleep-wake transition period. These behaviors can occur during REM sleep (nightmare disorder, sleep paralysis, REM sleep behavior disorder) or NREM sleep (somnambulism [sleepwalking], confusional arousals, sleep terrors). According to a cross-sectional Norwegian study of parasomnias, the estimated lifetime prevalence of sleep walking is 22.4%; sleep talking, 66.8%; confusional arousal, 18.5%; and sleep terror, 10.4%.⁵²

Continue to: When evaluating a patient...

When evaluating a patient with parasomnias, it is important to review their drug and substance use as well as coexisting medical conditions. Drugs and substances that can affect sleep include prescription medications (second-generation antidepressants, stimulants, dopamine agonists), excessive caffeine, alcohol, certain foods (coffee, chocolate milk, black tea, caffeinated soft drinks), environmental exposures (smoking, pesticides), and recreational drugs (amphetamines).^53-56 Certain medical conditions are correlated with specific parasomnias (eg, sleep paralysis and narcolepsy, REM sleep behavior disorder and Parkinson’s disease [PD], etc.).⁵⁴ Diagnosis of parasomnias is mainly clinical but supporting evidence can be obtained through in-lab polysomnography.

Treatment. For parasomnias, treatment is primarily supportive and includes creating a safe sleeping environment to reduce the risk of self-harm. Recommendations include sleeping in a room on the ground floor, minimizing furniture in the bedroom, padding any bedside furniture, child-proofing doorknobs, and locking up weapons and other dangerous household items.⁵⁴

REM sleep behavior disorder (RBD). This disorder is characterized by a loss of the typical REM sleep-associated atonia and the presence of motor activity during dreaming (dream-enacted behaviors). While the estimated incidence of RBD in the general adult population is approximately 0.5%, it increases to 7.7% among those age >60.⁵⁷ RBD occurs most commonly in the setting of the alpha-synucleinopathies (PD, Lewy body dementia, multisystem atrophy), but can also be found in patients with cerebral ischemia, demyelinating disorders, or alcohol misuse, or can be medication-induced (primarily antidepressants and antipsychotics).⁵⁸ In patients with PD, the presence of RBD is associated with a more impaired cognitive profile, suggestive of widespread neurodegeneration.⁵⁹ Recent studies revealed that RBD may also be a prodromal state of neurodegenerative diseases such as PD, which should prompt close monitoring and long-term follow up.⁶⁰ Similar to other parasomnias, the diagnosis of RBD is primarily clinical, but polysomnography plays an important role in demonstrating loss of REM-related atonia.⁵⁴

Treatment. Clonazepam and melatonin have been shown to be effective in treating the symptoms of RBD.⁵⁴

Depression, anxiety, and sleep disturbances

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) affect sleep in patients of all ages, but are underreported in older adults. According to national epidemiologic surveys, the estimated prevalence of MDD and GAD among older adults is 13% and 11.4%, respectively.^61,62 Rates as high as 42% and 39% have been reported in meta-regression analyses among patients with Alzheimer’s dementia.⁶³

Continue to: Depression and anxiety

Depression and anxiety may have additive effects and manifest as poor sleep satisfaction, increased sleep latency, insomnia, and daytime sleepiness.⁶⁴ However, they may also have independent effects. Studies showed that patients with depression alone reported overall poor sleep satisfaction, whereas patients with anxiety alone reported problems with sleep latency, daytime drowsiness, and waking up at night in addition to their overall poor sleep satisfaction.^65-67 Both depression and anxiety are risk factors for developing cognitive decline, and may be an early sign/prodrome of neurodegenerative diseases (dementias).⁶⁸ The bidirectional relationship between depression/anxiety and sleep is complex and needs further investigation.

Treatment. Pharmacologic treatments for patients with depression/anxiety and sleep disturbances include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and other serotonin receptor agonists.^69-72 Nonpharmacologic treatments include CBT for both depression and anxiety, and problem-solving therapy for patients with mild cognitive impairment and depression.^73,74 For severe depression and/or anxiety, electroconvulsive therapy is effective.⁷⁵

Bottom Line

Sleep disorders in older adults are common but often underdiagnosed. Timely recognition of obstructive sleep apnea, central sleep apnea, insomnia, parasomnias, and other sleep disturbances can facilitate effective treatment and greatly improve older adults’ quality of life.

Related Resources

• American Academy of Sleep Medicine. International Classification of Sleep Disorders—Third Edition. https://aasm.org
• SleepFoundation.org. Sleep hygiene. https://www.sleepfoundation.org/articles/sleep-hygiene

Drug Brand Names

Acetazolamide • Diamox
Clonazepam • Klonopin
Doxepin • Silenor
Eszopiclone • Lunesta
Gabapentin • Neurontin
Mirtazapine • Remeron
Pramipexole • Mirapex
Quetiapine • Seroquel
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Theophylline • Elixophyllin
Tiagabine • Gabitril
Trazadone • Desyrel
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien

As humans live longer, a renewed focus on quality of life has made the prompt diagnosis and treatment of sleep-related disorders in older adults increasingly necessary.¹ Normative aging results in multiple changes in sleep architecture, including decreased total sleep time, decreased sleep efficiency, decreased slow-wave sleep (SWS), and increased awakenings after sleep onset.² Sleep disturbances in older adults are increasingly recognized as multifactorial health conditions requiring comprehensive modification of risk factors, diagnosis, and treatment.³

In this article, we discuss the effects of aging on sleep architecture and provide an overview of primary sleep disorders in older adults. We also summarize strategies for diagnosing and treating sleep disorders in these patients.

Elements of the sleep cycle

The human sleep cycle begins with light sleep (sleep stages 1 and 2), progresses into SWS (sleep stage 3), and culminates in rapid eye movement (REM) sleep. The first 3 stages are referred to as non-rapid eye movement sleep (NREM). Throughout the night, this coupling of NREM and REM cycles occurs 4 to 6 times, with each successive cycle decreasing in length until awakening.⁴

Two complex neurologic pathways intersect to regulate the timing of sleep and wakefulness on arousal. The first pathway, the circadian system, is located within the suprachiasmatic nucleus of the hypothalamus and is highly dependent on external stimuli (light, food, etc.) to synchronize sleep/wake cycles. The suprachiasmatic nucleus regulates melatonin secretion by the pineal gland, which signals day-night transitions. The other pathway, the homeostatic system, modifies the amount of sleep needed daily. When multiple days of poor sleep occur, homeostatic sleep pressure (colloquially described as sleep debt) compensates by increasing the amount of sleep required in the following days. Together, the circadian and homeostatic systems work in conjunction to regulate sleep quantity to approximately one-third of the total sleep-wake cycle.^2,5

Age-related dysfunction of the regulatory sleep pathways leads to blunting of the ability to initiate and sustain high-quality sleep.⁶ Dysregulation of homeostatic sleep pressure decreases time spent in SWS, and failure of the circadian signaling apparatus results in delays in sleep/wake timing.² While research into the underlying neurobiology of sleep reveals that some of these changes are inherent to aging (Box^7-14), significant underdiagnosed pathologies may adversely affect sleep architecture, including polypharmacy, comorbid neuropathology (eg, synucleinopathies, tauopathies, etc.), and primary sleep disorders (insomnias, hypersomnias, and parasomnias).¹⁵

Box

Primary sleep disorders

Obstructive sleep apnea (OSA) is one of the most common, yet frequently underdiagnosed reversible causes of sleep disturbances. It is characterized by partial or complete airway obstruction culminating in periods of involuntary cessation of respirations during sleep. The resultant fragmentation in sleep leads to significant downstream effects over time, including excessive daytime sleepiness and fatigue, poor occupational and social performance, and substantial cognitive impairment.³ While it is well known that OSA increases in prevalence throughout middle age, this relationship plateaus after age 60.¹⁶ An estimated 40% to 60% of Americans age >60 are affected by OSA.¹⁷ The hypoxemia and fragmented sleep caused by unrecognized OSA are associated with a significant decline in activities of daily living (ADL).¹⁸ Untreated OSA is strongly linked to the development and progression of several major health conditions, including cardiovascular disease, diabetes mellitus, hypertension, stroke, and depression.¹⁹ In studies of long-term care facility residents—many of whom may have comorbid cognitive decline—researchers found that unrecognized OSA often mimics the progressive cognitive decline seen in major neurocognitive disorders.²⁰ However, classic symptoms of OSA may not always be present in these patients, and their daytime sleepiness is often attributed to old age rather than to a pathological etiology.¹⁶ Screening for OSA and prompt initiation of the appropriate treatment may reverse OSA-induced cognitive changes in these patients.²¹

The primary presenting symptom of OSA is snoring, which is correlated with pauses in breathing. Risk factors include increased body mass index (BMI), thick neck circumference, male sex, and advanced age. In older adults, BMI has a lower impact on the Apnea-Hypopnea Index, an indicator of the number of pauses in breathing per hour, when compared with young and middle-age adults.¹⁶ Validated screening questionnaires for OSA include the STOP-Bang Questionnaire (Table 1²²), OSA50, Berlin Questionnaire, and Epworth Sleepiness Scale, each of which is used in different subpopulations. The current diagnostic standard for OSA is nocturnal polysomnography in a sleep laboratory, but recent advances in home sleep apnea testing have made it a viable, low-cost alternative for patients who do not have significant medical comorbidities.²³ Standard utilized cutoffs for diagnosis are ≥5 events/hour (hypopneas associated with at least 4% oxygen desaturations) in conjunction with clinical symptoms of OSA.²⁴

Continue to: Treatment

Treatment. First-line treatment for OSA is continuous positive airway pressure therapy, but adherence rates vary widely with patient education and regular follow-up.²⁵ Adjunctive therapy includes weight loss, oral appliances, and uvulopalatopharyngoplasty, a procedure in which tissue in the throat is remodeled or removed.

Central sleep apnea (CSA) is a pause in breathing without evidence of associated respiratory effort. In adults, the development of CSA is indicative of underlying lower brainstem dysfunction, due to intermittent failures in the pontomedullary centers responsible for regulation of rhythmic breathing.²⁶ This can occur as a consequence of multiple diseases, including congestive heart failure, stroke, renal failure, chronic medication use (opioids), and brain tumors.

The Sleep Heart Health Study—the largest community-based cohort study to date examining CSA—estimated that the prevalence of CSA among adults age >65 was 1.1% (compared with 0.4% in those age <65).²⁷ Subgroup analysis revealed that men had significantly higher rates of CSA compared with women (2.7% vs 0.2%, respectively).

CSA may present similarly to OSA (excessive daytime somnolence, insomnia, poor sleep quality, difficulties with attention and concentration). Symptoms may also mimic those of coexisting medical conditions in older adults, such as nocturnal angina or paroxysmal nocturnal dyspnea.²⁷ Any older patient with daytime sleepiness and risk factors for CSA should be referred for in-laboratory nocturnal polysomnography, the gold standard diagnostic test. Unlike in OSA, ambulatory diagnostic measures (home sleep apnea testing) have not been validated for this disorder.²⁷

Treatment. The primary treatment for CSA is to address the underlying medical problem. Positive pressure ventilation has been attempted with mixed results. Supplemental oxygen and medical management (acetazolamide or theophylline) can help stimulate breathing. Newer studies have shown favorable outcomes with transvenous neurostimulation or adaptive servoventilation.^28-30

Continue to: Insomnia

Insomnia. For a primary diagnosis of insomnia, DSM-5 requires at least 3 nights per week of sleep disturbances that induce distress or functional impairment for at least 3 months.³¹ The International Classification of Disease, 10th Edition requires at least 1 month of symptoms (lying awake for a long time before falling asleep, sleeping for short periods, being awake for most of the night, feeling lack of sleep, waking up early) after ruling out other sleep disorders, substance use, or other medical conditions.⁴ Clinically, insomnia tends to present in older adults as a subjective complaint of dissatisfaction with the quality and/or quantity of their sleep. Insomnia has been consistently shown to be a significant risk factor for both the development or exacerbation of depression in older adults.^32-34

While the diagnosis of insomnia is mainly clinical via a thorough sleep and medication history, assistive ancillary testing can include wrist actigraphy and screening questionnaires (the Insomnia Severity Index and the Pittsburgh Sleep Quality Index).⁴ Because population studies of older adults have found discrepancies between objective and subjective methods of assessing sleep quality, relying on the accuracy of self-reported symptoms alone is questionable.³⁵

Treatment. Given that drug elimination half-life increases with age, and the risks of adverse effects are increased in older adults, the preferred treatment modalities for insomnia are nonpharmacologic.⁴ Sleep hygiene education (Table 2) and cognitive-behavioral therapy (CBT) for insomnia are often the first-line therapies.^4,36,37 It is crucial to manage comorbidities such as heart disease and obesity, as well as sources of discomfort from conditions such as arthritic pain.^38,39 If nonpharmacologic therapies are not effective, pharmacologic options can be considered.⁴ Before prescribing sleep medications, it may be more fruitful to treat underlying psychiatric disorders such as depression and anxiety with antidepressants.⁴ Although benzodiazepines are helpful for their sedative effects, they are not recommended for older adults because of an increased risk of falls, rebound insomnia, potential tolerance, and associated cognitive impairment.⁴⁰ Benzodiazepine receptor agonists (eg, zolpidem, eszopiclone, zaleplon) were initially developed as a first-line treatment for insomnia to replace the reliance on benzodiazepines, but these medications have a “black-box” warning of a serious risk of complex sleep behaviors, including life-threatening parasomnias.⁴¹ As a result, guidelines suggest a shorter duration of treatment with a benzodiazepine receptor agonist may still provide benefit while limiting the risk of adverse effects.⁴²

Doxepin is the only antidepressant FDA-approved for insomnia; it improves sleep latency (time taken to initiate sleep after lying down), duration, and quality in adults age >65.⁴³ Melatonin receptor agonists such as ramelteon and melatonin have shown positive results in older patients with insomnia. In clinical trials of patients age ≥65, ramelteon, which is FDA-approved for insomnia, produced no rebound insomnia, withdrawal effects, memory impairment, or gait instability.^44-46 Suvorexant, an orexin receptor antagonist, decreases sleep latency and increases total sleep time equally in both young and older adults.^47-49Table 3^40-51 provides a list of medications used to treat insomnia (including off-label agents) and their common adverse effects in older adults.

Parasomnias are undesirable behaviors that occur during sleep, commonly associated with the sleep-wake transition period. These behaviors can occur during REM sleep (nightmare disorder, sleep paralysis, REM sleep behavior disorder) or NREM sleep (somnambulism [sleepwalking], confusional arousals, sleep terrors). According to a cross-sectional Norwegian study of parasomnias, the estimated lifetime prevalence of sleep walking is 22.4%; sleep talking, 66.8%; confusional arousal, 18.5%; and sleep terror, 10.4%.⁵²

Continue to: When evaluating a patient...

When evaluating a patient with parasomnias, it is important to review their drug and substance use as well as coexisting medical conditions. Drugs and substances that can affect sleep include prescription medications (second-generation antidepressants, stimulants, dopamine agonists), excessive caffeine, alcohol, certain foods (coffee, chocolate milk, black tea, caffeinated soft drinks), environmental exposures (smoking, pesticides), and recreational drugs (amphetamines).^53-56 Certain medical conditions are correlated with specific parasomnias (eg, sleep paralysis and narcolepsy, REM sleep behavior disorder and Parkinson’s disease [PD], etc.).⁵⁴ Diagnosis of parasomnias is mainly clinical but supporting evidence can be obtained through in-lab polysomnography.

Treatment. For parasomnias, treatment is primarily supportive and includes creating a safe sleeping environment to reduce the risk of self-harm. Recommendations include sleeping in a room on the ground floor, minimizing furniture in the bedroom, padding any bedside furniture, child-proofing doorknobs, and locking up weapons and other dangerous household items.⁵⁴

REM sleep behavior disorder (RBD). This disorder is characterized by a loss of the typical REM sleep-associated atonia and the presence of motor activity during dreaming (dream-enacted behaviors). While the estimated incidence of RBD in the general adult population is approximately 0.5%, it increases to 7.7% among those age >60.⁵⁷ RBD occurs most commonly in the setting of the alpha-synucleinopathies (PD, Lewy body dementia, multisystem atrophy), but can also be found in patients with cerebral ischemia, demyelinating disorders, or alcohol misuse, or can be medication-induced (primarily antidepressants and antipsychotics).⁵⁸ In patients with PD, the presence of RBD is associated with a more impaired cognitive profile, suggestive of widespread neurodegeneration.⁵⁹ Recent studies revealed that RBD may also be a prodromal state of neurodegenerative diseases such as PD, which should prompt close monitoring and long-term follow up.⁶⁰ Similar to other parasomnias, the diagnosis of RBD is primarily clinical, but polysomnography plays an important role in demonstrating loss of REM-related atonia.⁵⁴

Treatment. Clonazepam and melatonin have been shown to be effective in treating the symptoms of RBD.⁵⁴

Depression, anxiety, and sleep disturbances

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) affect sleep in patients of all ages, but are underreported in older adults. According to national epidemiologic surveys, the estimated prevalence of MDD and GAD among older adults is 13% and 11.4%, respectively.^61,62 Rates as high as 42% and 39% have been reported in meta-regression analyses among patients with Alzheimer’s dementia.⁶³

Continue to: Depression and anxiety

Depression and anxiety may have additive effects and manifest as poor sleep satisfaction, increased sleep latency, insomnia, and daytime sleepiness.⁶⁴ However, they may also have independent effects. Studies showed that patients with depression alone reported overall poor sleep satisfaction, whereas patients with anxiety alone reported problems with sleep latency, daytime drowsiness, and waking up at night in addition to their overall poor sleep satisfaction.^65-67 Both depression and anxiety are risk factors for developing cognitive decline, and may be an early sign/prodrome of neurodegenerative diseases (dementias).⁶⁸ The bidirectional relationship between depression/anxiety and sleep is complex and needs further investigation.

Treatment. Pharmacologic treatments for patients with depression/anxiety and sleep disturbances include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and other serotonin receptor agonists.^69-72 Nonpharmacologic treatments include CBT for both depression and anxiety, and problem-solving therapy for patients with mild cognitive impairment and depression.^73,74 For severe depression and/or anxiety, electroconvulsive therapy is effective.⁷⁵

Bottom Line

Sleep disorders in older adults are common but often underdiagnosed. Timely recognition of obstructive sleep apnea, central sleep apnea, insomnia, parasomnias, and other sleep disturbances can facilitate effective treatment and greatly improve older adults’ quality of life.

Related Resources

• American Academy of Sleep Medicine. International Classification of Sleep Disorders—Third Edition. https://aasm.org
• SleepFoundation.org. Sleep hygiene. https://www.sleepfoundation.org/articles/sleep-hygiene

Drug Brand Names

Acetazolamide • Diamox
Clonazepam • Klonopin
Doxepin • Silenor
Eszopiclone • Lunesta
Gabapentin • Neurontin
Mirtazapine • Remeron
Pramipexole • Mirapex
Quetiapine • Seroquel
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Theophylline • Elixophyllin
Tiagabine • Gabitril
Trazadone • Desyrel
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien

As humans live longer, a renewed focus on quality of life has made the prompt diagnosis and treatment of sleep-related disorders in older adults increasingly necessary.¹ Normative aging results in multiple changes in sleep architecture, including decreased total sleep time, decreased sleep efficiency, decreased slow-wave sleep (SWS), and increased awakenings after sleep onset.² Sleep disturbances in older adults are increasingly recognized as multifactorial health conditions requiring comprehensive modification of risk factors, diagnosis, and treatment.³

In this article, we discuss the effects of aging on sleep architecture and provide an overview of primary sleep disorders in older adults. We also summarize strategies for diagnosing and treating sleep disorders in these patients.

Elements of the sleep cycle

The human sleep cycle begins with light sleep (sleep stages 1 and 2), progresses into SWS (sleep stage 3), and culminates in rapid eye movement (REM) sleep. The first 3 stages are referred to as non-rapid eye movement sleep (NREM). Throughout the night, this coupling of NREM and REM cycles occurs 4 to 6 times, with each successive cycle decreasing in length until awakening.⁴

Two complex neurologic pathways intersect to regulate the timing of sleep and wakefulness on arousal. The first pathway, the circadian system, is located within the suprachiasmatic nucleus of the hypothalamus and is highly dependent on external stimuli (light, food, etc.) to synchronize sleep/wake cycles. The suprachiasmatic nucleus regulates melatonin secretion by the pineal gland, which signals day-night transitions. The other pathway, the homeostatic system, modifies the amount of sleep needed daily. When multiple days of poor sleep occur, homeostatic sleep pressure (colloquially described as sleep debt) compensates by increasing the amount of sleep required in the following days. Together, the circadian and homeostatic systems work in conjunction to regulate sleep quantity to approximately one-third of the total sleep-wake cycle.^2,5

Age-related dysfunction of the regulatory sleep pathways leads to blunting of the ability to initiate and sustain high-quality sleep.⁶ Dysregulation of homeostatic sleep pressure decreases time spent in SWS, and failure of the circadian signaling apparatus results in delays in sleep/wake timing.² While research into the underlying neurobiology of sleep reveals that some of these changes are inherent to aging (Box^7-14), significant underdiagnosed pathologies may adversely affect sleep architecture, including polypharmacy, comorbid neuropathology (eg, synucleinopathies, tauopathies, etc.), and primary sleep disorders (insomnias, hypersomnias, and parasomnias).¹⁵

Box

Primary sleep disorders

Obstructive sleep apnea (OSA) is one of the most common, yet frequently underdiagnosed reversible causes of sleep disturbances. It is characterized by partial or complete airway obstruction culminating in periods of involuntary cessation of respirations during sleep. The resultant fragmentation in sleep leads to significant downstream effects over time, including excessive daytime sleepiness and fatigue, poor occupational and social performance, and substantial cognitive impairment.³ While it is well known that OSA increases in prevalence throughout middle age, this relationship plateaus after age 60.¹⁶ An estimated 40% to 60% of Americans age >60 are affected by OSA.¹⁷ The hypoxemia and fragmented sleep caused by unrecognized OSA are associated with a significant decline in activities of daily living (ADL).¹⁸ Untreated OSA is strongly linked to the development and progression of several major health conditions, including cardiovascular disease, diabetes mellitus, hypertension, stroke, and depression.¹⁹ In studies of long-term care facility residents—many of whom may have comorbid cognitive decline—researchers found that unrecognized OSA often mimics the progressive cognitive decline seen in major neurocognitive disorders.²⁰ However, classic symptoms of OSA may not always be present in these patients, and their daytime sleepiness is often attributed to old age rather than to a pathological etiology.¹⁶ Screening for OSA and prompt initiation of the appropriate treatment may reverse OSA-induced cognitive changes in these patients.²¹

The primary presenting symptom of OSA is snoring, which is correlated with pauses in breathing. Risk factors include increased body mass index (BMI), thick neck circumference, male sex, and advanced age. In older adults, BMI has a lower impact on the Apnea-Hypopnea Index, an indicator of the number of pauses in breathing per hour, when compared with young and middle-age adults.¹⁶ Validated screening questionnaires for OSA include the STOP-Bang Questionnaire (Table 1²²), OSA50, Berlin Questionnaire, and Epworth Sleepiness Scale, each of which is used in different subpopulations. The current diagnostic standard for OSA is nocturnal polysomnography in a sleep laboratory, but recent advances in home sleep apnea testing have made it a viable, low-cost alternative for patients who do not have significant medical comorbidities.²³ Standard utilized cutoffs for diagnosis are ≥5 events/hour (hypopneas associated with at least 4% oxygen desaturations) in conjunction with clinical symptoms of OSA.²⁴

Continue to: Treatment

Treatment. First-line treatment for OSA is continuous positive airway pressure therapy, but adherence rates vary widely with patient education and regular follow-up.²⁵ Adjunctive therapy includes weight loss, oral appliances, and uvulopalatopharyngoplasty, a procedure in which tissue in the throat is remodeled or removed.

Central sleep apnea (CSA) is a pause in breathing without evidence of associated respiratory effort. In adults, the development of CSA is indicative of underlying lower brainstem dysfunction, due to intermittent failures in the pontomedullary centers responsible for regulation of rhythmic breathing.²⁶ This can occur as a consequence of multiple diseases, including congestive heart failure, stroke, renal failure, chronic medication use (opioids), and brain tumors.

The Sleep Heart Health Study—the largest community-based cohort study to date examining CSA—estimated that the prevalence of CSA among adults age >65 was 1.1% (compared with 0.4% in those age <65).²⁷ Subgroup analysis revealed that men had significantly higher rates of CSA compared with women (2.7% vs 0.2%, respectively).

CSA may present similarly to OSA (excessive daytime somnolence, insomnia, poor sleep quality, difficulties with attention and concentration). Symptoms may also mimic those of coexisting medical conditions in older adults, such as nocturnal angina or paroxysmal nocturnal dyspnea.²⁷ Any older patient with daytime sleepiness and risk factors for CSA should be referred for in-laboratory nocturnal polysomnography, the gold standard diagnostic test. Unlike in OSA, ambulatory diagnostic measures (home sleep apnea testing) have not been validated for this disorder.²⁷

Treatment. The primary treatment for CSA is to address the underlying medical problem. Positive pressure ventilation has been attempted with mixed results. Supplemental oxygen and medical management (acetazolamide or theophylline) can help stimulate breathing. Newer studies have shown favorable outcomes with transvenous neurostimulation or adaptive servoventilation.^28-30

Continue to: Insomnia

Insomnia. For a primary diagnosis of insomnia, DSM-5 requires at least 3 nights per week of sleep disturbances that induce distress or functional impairment for at least 3 months.³¹ The International Classification of Disease, 10th Edition requires at least 1 month of symptoms (lying awake for a long time before falling asleep, sleeping for short periods, being awake for most of the night, feeling lack of sleep, waking up early) after ruling out other sleep disorders, substance use, or other medical conditions.⁴ Clinically, insomnia tends to present in older adults as a subjective complaint of dissatisfaction with the quality and/or quantity of their sleep. Insomnia has been consistently shown to be a significant risk factor for both the development or exacerbation of depression in older adults.^32-34

While the diagnosis of insomnia is mainly clinical via a thorough sleep and medication history, assistive ancillary testing can include wrist actigraphy and screening questionnaires (the Insomnia Severity Index and the Pittsburgh Sleep Quality Index).⁴ Because population studies of older adults have found discrepancies between objective and subjective methods of assessing sleep quality, relying on the accuracy of self-reported symptoms alone is questionable.³⁵

Treatment. Given that drug elimination half-life increases with age, and the risks of adverse effects are increased in older adults, the preferred treatment modalities for insomnia are nonpharmacologic.⁴ Sleep hygiene education (Table 2) and cognitive-behavioral therapy (CBT) for insomnia are often the first-line therapies.^4,36,37 It is crucial to manage comorbidities such as heart disease and obesity, as well as sources of discomfort from conditions such as arthritic pain.^38,39 If nonpharmacologic therapies are not effective, pharmacologic options can be considered.⁴ Before prescribing sleep medications, it may be more fruitful to treat underlying psychiatric disorders such as depression and anxiety with antidepressants.⁴ Although benzodiazepines are helpful for their sedative effects, they are not recommended for older adults because of an increased risk of falls, rebound insomnia, potential tolerance, and associated cognitive impairment.⁴⁰ Benzodiazepine receptor agonists (eg, zolpidem, eszopiclone, zaleplon) were initially developed as a first-line treatment for insomnia to replace the reliance on benzodiazepines, but these medications have a “black-box” warning of a serious risk of complex sleep behaviors, including life-threatening parasomnias.⁴¹ As a result, guidelines suggest a shorter duration of treatment with a benzodiazepine receptor agonist may still provide benefit while limiting the risk of adverse effects.⁴²

Doxepin is the only antidepressant FDA-approved for insomnia; it improves sleep latency (time taken to initiate sleep after lying down), duration, and quality in adults age >65.⁴³ Melatonin receptor agonists such as ramelteon and melatonin have shown positive results in older patients with insomnia. In clinical trials of patients age ≥65, ramelteon, which is FDA-approved for insomnia, produced no rebound insomnia, withdrawal effects, memory impairment, or gait instability.^44-46 Suvorexant, an orexin receptor antagonist, decreases sleep latency and increases total sleep time equally in both young and older adults.^47-49Table 3^40-51 provides a list of medications used to treat insomnia (including off-label agents) and their common adverse effects in older adults.

Parasomnias are undesirable behaviors that occur during sleep, commonly associated with the sleep-wake transition period. These behaviors can occur during REM sleep (nightmare disorder, sleep paralysis, REM sleep behavior disorder) or NREM sleep (somnambulism [sleepwalking], confusional arousals, sleep terrors). According to a cross-sectional Norwegian study of parasomnias, the estimated lifetime prevalence of sleep walking is 22.4%; sleep talking, 66.8%; confusional arousal, 18.5%; and sleep terror, 10.4%.⁵²

Continue to: When evaluating a patient...

When evaluating a patient with parasomnias, it is important to review their drug and substance use as well as coexisting medical conditions. Drugs and substances that can affect sleep include prescription medications (second-generation antidepressants, stimulants, dopamine agonists), excessive caffeine, alcohol, certain foods (coffee, chocolate milk, black tea, caffeinated soft drinks), environmental exposures (smoking, pesticides), and recreational drugs (amphetamines).^53-56 Certain medical conditions are correlated with specific parasomnias (eg, sleep paralysis and narcolepsy, REM sleep behavior disorder and Parkinson’s disease [PD], etc.).⁵⁴ Diagnosis of parasomnias is mainly clinical but supporting evidence can be obtained through in-lab polysomnography.

Treatment. For parasomnias, treatment is primarily supportive and includes creating a safe sleeping environment to reduce the risk of self-harm. Recommendations include sleeping in a room on the ground floor, minimizing furniture in the bedroom, padding any bedside furniture, child-proofing doorknobs, and locking up weapons and other dangerous household items.⁵⁴

REM sleep behavior disorder (RBD). This disorder is characterized by a loss of the typical REM sleep-associated atonia and the presence of motor activity during dreaming (dream-enacted behaviors). While the estimated incidence of RBD in the general adult population is approximately 0.5%, it increases to 7.7% among those age >60.⁵⁷ RBD occurs most commonly in the setting of the alpha-synucleinopathies (PD, Lewy body dementia, multisystem atrophy), but can also be found in patients with cerebral ischemia, demyelinating disorders, or alcohol misuse, or can be medication-induced (primarily antidepressants and antipsychotics).⁵⁸ In patients with PD, the presence of RBD is associated with a more impaired cognitive profile, suggestive of widespread neurodegeneration.⁵⁹ Recent studies revealed that RBD may also be a prodromal state of neurodegenerative diseases such as PD, which should prompt close monitoring and long-term follow up.⁶⁰ Similar to other parasomnias, the diagnosis of RBD is primarily clinical, but polysomnography plays an important role in demonstrating loss of REM-related atonia.⁵⁴

Treatment. Clonazepam and melatonin have been shown to be effective in treating the symptoms of RBD.⁵⁴

Depression, anxiety, and sleep disturbances

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) affect sleep in patients of all ages, but are underreported in older adults. According to national epidemiologic surveys, the estimated prevalence of MDD and GAD among older adults is 13% and 11.4%, respectively.^61,62 Rates as high as 42% and 39% have been reported in meta-regression analyses among patients with Alzheimer’s dementia.⁶³

Continue to: Depression and anxiety

Depression and anxiety may have additive effects and manifest as poor sleep satisfaction, increased sleep latency, insomnia, and daytime sleepiness.⁶⁴ However, they may also have independent effects. Studies showed that patients with depression alone reported overall poor sleep satisfaction, whereas patients with anxiety alone reported problems with sleep latency, daytime drowsiness, and waking up at night in addition to their overall poor sleep satisfaction.^65-67 Both depression and anxiety are risk factors for developing cognitive decline, and may be an early sign/prodrome of neurodegenerative diseases (dementias).⁶⁸ The bidirectional relationship between depression/anxiety and sleep is complex and needs further investigation.

Treatment. Pharmacologic treatments for patients with depression/anxiety and sleep disturbances include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and other serotonin receptor agonists.^69-72 Nonpharmacologic treatments include CBT for both depression and anxiety, and problem-solving therapy for patients with mild cognitive impairment and depression.^73,74 For severe depression and/or anxiety, electroconvulsive therapy is effective.⁷⁵

Bottom Line

Sleep disorders in older adults are common but often underdiagnosed. Timely recognition of obstructive sleep apnea, central sleep apnea, insomnia, parasomnias, and other sleep disturbances can facilitate effective treatment and greatly improve older adults’ quality of life.

Related Resources

• American Academy of Sleep Medicine. International Classification of Sleep Disorders—Third Edition. https://aasm.org
• SleepFoundation.org. Sleep hygiene. https://www.sleepfoundation.org/articles/sleep-hygiene

Drug Brand Names

Acetazolamide • Diamox
Clonazepam • Klonopin
Doxepin • Silenor
Eszopiclone • Lunesta
Gabapentin • Neurontin
Mirtazapine • Remeron
Pramipexole • Mirapex
Quetiapine • Seroquel
Ramelteon • Rozerem
Suvorexant • Belsomra
Temazepam • Restoril
Theophylline • Elixophyllin
Tiagabine • Gabitril
Trazadone • Desyrel
Triazolam • Halcion
Zaleplon • Sonata
Zolpidem • Ambien

Editor’s note: Readers’ Forum is a new department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.

Since the completion of the human genome project, the role of pharmacogenomics in treating mental health disorders has become more prevalent. Recently discovered genetic polymorphisms and mutations in the methylenetetrahydrofolate reductase (MTHFR) gene have led clinicians to seek out new therapeutic approaches to personalize mental health care. MTHFR is a key enzyme of folate metabolism, and changes in its gene can result in reduced enzyme activity, which has been associated with psychiatric illnesses such as schizophrenia, major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism.¹ Supplementation with L-methylfolate, the active form of folate, has been found to improve clinical and social recovery in patients with psychiatric illnesses such as schizophrenia and MDD.² While L-methylfolate is classified as an FDA-approved medicinal food for patients with depression and schizophrenia, its role in ADHD remains controversial.³ L-methylfolate modulates the synthesis of monoamines such as dopamine and norepinephrine, which are pivotal in reducing inattentiveness and hyperactivity in patients with ADHD.^4,5 As a result, it could play an important role in the management of ADHD in patients with MTHFR deficiency.

Despite its high prevalence in many children, ADHD can persist into adulthood with impairing symptoms that have long-term social and economic impacts. Conventional methods of treating ADHD include stimulant medications such as methylphenidate, which can increase the levels of dopamine and norepinephrine in the brain. Unfortunately, stimulants’ cost, adverse effect profile, and high potential for abuse can hinder their use and contribute to treatment resistance.⁶ Because L-methylfolate can cross the blood-brain barrier and lacks the adverse effect profile of stimulants, it represents an alternative that could improve the quality of life for ADHD patients, particularly those with MTHFR polymorphisms or mutations.

Conflicting evidence

Several researchers have investigated the role of L-methylfolate as a supplement or alternative to stimulant therapy for patients with ADHD. While some preliminary studies have found some benefit, others have not. Here we describe 2 studies with differing results.

Quilliin⁷ (2013). In an open-label study at a children’s hospital in Texas, Quillin⁷ investi­gated L-methylfolate for alleviating attention-deficit disorder/ADHD symptoms in 59 patients age 5 to 18. Twenty-seven patients received stimulant therapy. All patients were treated with L-methylfolate, 0.2 mg/kg/d in a chewable tablet form, for 6 weeks. The primary endpoint was change on the average Vanderbilt Assessment Scale Total Symptom Score (TSS), which was 30 at baseline. At the study’s conclusion, the average TSS score was 22, a 27% reduction. Patients who were taking only L-methylfolate had an average score of 21 at the end of the study, which was a 34% improvement, compared with an average TSS score of 23 in those who were taking stimulants.

Surman et al³ (2019). In this 12-week, double-blind, placebo-controlled clinical trial, researchers assessed the efficacy and tolerability of L-methylfolate when added to osmotic-release oral system methylphenidate (OROS-MPH).³ Surman et al³ randomized 44 adult patients (age 18 to 55) who met the DSM-5 criteria for ADHD to a placebo group or an active group. The placebo group was treated with placebo plus OROS-MPH, while the active group received L-methylfolate, 15 mg/d, plus OROS-MPH. OROS-MPH was started at 36 mg/d and titrated to optimal response. The primary endpoint was change in score from baseline on the Adult ADHD Investigator Symptom Report scale. Although it was well tolerated, L-methylfolate was not associated with a significant change in measures of ADHD or mental health function.³ However, researchers noticed that patients who received L-methylfolate needed to receive higher doses of methylphenidate over time. This suggests that supplementation with L-methylfolate could reduce the effectiveness of methylphenidate in adult patients with ADHD.³

While more research is needed, the contradictory results of these studies suggests that the relationship between L-methylfolate and ADHD could be impacted by dosing, as well as by differences in adult and childhood ADHD that are not yet fully understood.

Continue to: An area warranting future research

An area warranting future research

The growth of pharmacogenomics represents an important opportunity to bridge the gap between our understanding of psychiatric illnesses and new ways to treat them. Using L-methylfolate to treat ADHD might help bridge this gap. For this to occur, psychiatrists need to use evidence-based pharmacogenetic research to inform their decision-making. The differing results in studies evaluating the use of L-methylfolate in adult and pediatric patients pose interesting questions that will require more robust research to answer. Clinicians should be cautious in the use of L-methylfolate and recognize the importance of evaluating every patient with ADHD for MTHFR deficiency. This could help personalize care in ways that may improve the quality of life for patients and their families.

Editor’s note: Readers’ Forum is a new department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.

Since the completion of the human genome project, the role of pharmacogenomics in treating mental health disorders has become more prevalent. Recently discovered genetic polymorphisms and mutations in the methylenetetrahydrofolate reductase (MTHFR) gene have led clinicians to seek out new therapeutic approaches to personalize mental health care. MTHFR is a key enzyme of folate metabolism, and changes in its gene can result in reduced enzyme activity, which has been associated with psychiatric illnesses such as schizophrenia, major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism.¹ Supplementation with L-methylfolate, the active form of folate, has been found to improve clinical and social recovery in patients with psychiatric illnesses such as schizophrenia and MDD.² While L-methylfolate is classified as an FDA-approved medicinal food for patients with depression and schizophrenia, its role in ADHD remains controversial.³ L-methylfolate modulates the synthesis of monoamines such as dopamine and norepinephrine, which are pivotal in reducing inattentiveness and hyperactivity in patients with ADHD.^4,5 As a result, it could play an important role in the management of ADHD in patients with MTHFR deficiency.

Despite its high prevalence in many children, ADHD can persist into adulthood with impairing symptoms that have long-term social and economic impacts. Conventional methods of treating ADHD include stimulant medications such as methylphenidate, which can increase the levels of dopamine and norepinephrine in the brain. Unfortunately, stimulants’ cost, adverse effect profile, and high potential for abuse can hinder their use and contribute to treatment resistance.⁶ Because L-methylfolate can cross the blood-brain barrier and lacks the adverse effect profile of stimulants, it represents an alternative that could improve the quality of life for ADHD patients, particularly those with MTHFR polymorphisms or mutations.

Conflicting evidence

Several researchers have investigated the role of L-methylfolate as a supplement or alternative to stimulant therapy for patients with ADHD. While some preliminary studies have found some benefit, others have not. Here we describe 2 studies with differing results.

Quilliin⁷ (2013). In an open-label study at a children’s hospital in Texas, Quillin⁷ investi­gated L-methylfolate for alleviating attention-deficit disorder/ADHD symptoms in 59 patients age 5 to 18. Twenty-seven patients received stimulant therapy. All patients were treated with L-methylfolate, 0.2 mg/kg/d in a chewable tablet form, for 6 weeks. The primary endpoint was change on the average Vanderbilt Assessment Scale Total Symptom Score (TSS), which was 30 at baseline. At the study’s conclusion, the average TSS score was 22, a 27% reduction. Patients who were taking only L-methylfolate had an average score of 21 at the end of the study, which was a 34% improvement, compared with an average TSS score of 23 in those who were taking stimulants.

Surman et al³ (2019). In this 12-week, double-blind, placebo-controlled clinical trial, researchers assessed the efficacy and tolerability of L-methylfolate when added to osmotic-release oral system methylphenidate (OROS-MPH).³ Surman et al³ randomized 44 adult patients (age 18 to 55) who met the DSM-5 criteria for ADHD to a placebo group or an active group. The placebo group was treated with placebo plus OROS-MPH, while the active group received L-methylfolate, 15 mg/d, plus OROS-MPH. OROS-MPH was started at 36 mg/d and titrated to optimal response. The primary endpoint was change in score from baseline on the Adult ADHD Investigator Symptom Report scale. Although it was well tolerated, L-methylfolate was not associated with a significant change in measures of ADHD or mental health function.³ However, researchers noticed that patients who received L-methylfolate needed to receive higher doses of methylphenidate over time. This suggests that supplementation with L-methylfolate could reduce the effectiveness of methylphenidate in adult patients with ADHD.³

While more research is needed, the contradictory results of these studies suggests that the relationship between L-methylfolate and ADHD could be impacted by dosing, as well as by differences in adult and childhood ADHD that are not yet fully understood.

Continue to: An area warranting future research

An area warranting future research

The growth of pharmacogenomics represents an important opportunity to bridge the gap between our understanding of psychiatric illnesses and new ways to treat them. Using L-methylfolate to treat ADHD might help bridge this gap. For this to occur, psychiatrists need to use evidence-based pharmacogenetic research to inform their decision-making. The differing results in studies evaluating the use of L-methylfolate in adult and pediatric patients pose interesting questions that will require more robust research to answer. Clinicians should be cautious in the use of L-methylfolate and recognize the importance of evaluating every patient with ADHD for MTHFR deficiency. This could help personalize care in ways that may improve the quality of life for patients and their families.

Editor’s note: Readers’ Forum is a new department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.

Since the completion of the human genome project, the role of pharmacogenomics in treating mental health disorders has become more prevalent. Recently discovered genetic polymorphisms and mutations in the methylenetetrahydrofolate reductase (MTHFR) gene have led clinicians to seek out new therapeutic approaches to personalize mental health care. MTHFR is a key enzyme of folate metabolism, and changes in its gene can result in reduced enzyme activity, which has been associated with psychiatric illnesses such as schizophrenia, major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism.¹ Supplementation with L-methylfolate, the active form of folate, has been found to improve clinical and social recovery in patients with psychiatric illnesses such as schizophrenia and MDD.² While L-methylfolate is classified as an FDA-approved medicinal food for patients with depression and schizophrenia, its role in ADHD remains controversial.³ L-methylfolate modulates the synthesis of monoamines such as dopamine and norepinephrine, which are pivotal in reducing inattentiveness and hyperactivity in patients with ADHD.^4,5 As a result, it could play an important role in the management of ADHD in patients with MTHFR deficiency.

Despite its high prevalence in many children, ADHD can persist into adulthood with impairing symptoms that have long-term social and economic impacts. Conventional methods of treating ADHD include stimulant medications such as methylphenidate, which can increase the levels of dopamine and norepinephrine in the brain. Unfortunately, stimulants’ cost, adverse effect profile, and high potential for abuse can hinder their use and contribute to treatment resistance.⁶ Because L-methylfolate can cross the blood-brain barrier and lacks the adverse effect profile of stimulants, it represents an alternative that could improve the quality of life for ADHD patients, particularly those with MTHFR polymorphisms or mutations.

Conflicting evidence

Several researchers have investigated the role of L-methylfolate as a supplement or alternative to stimulant therapy for patients with ADHD. While some preliminary studies have found some benefit, others have not. Here we describe 2 studies with differing results.

Quilliin⁷ (2013). In an open-label study at a children’s hospital in Texas, Quillin⁷ investi­gated L-methylfolate for alleviating attention-deficit disorder/ADHD symptoms in 59 patients age 5 to 18. Twenty-seven patients received stimulant therapy. All patients were treated with L-methylfolate, 0.2 mg/kg/d in a chewable tablet form, for 6 weeks. The primary endpoint was change on the average Vanderbilt Assessment Scale Total Symptom Score (TSS), which was 30 at baseline. At the study’s conclusion, the average TSS score was 22, a 27% reduction. Patients who were taking only L-methylfolate had an average score of 21 at the end of the study, which was a 34% improvement, compared with an average TSS score of 23 in those who were taking stimulants.

Surman et al³ (2019). In this 12-week, double-blind, placebo-controlled clinical trial, researchers assessed the efficacy and tolerability of L-methylfolate when added to osmotic-release oral system methylphenidate (OROS-MPH).³ Surman et al³ randomized 44 adult patients (age 18 to 55) who met the DSM-5 criteria for ADHD to a placebo group or an active group. The placebo group was treated with placebo plus OROS-MPH, while the active group received L-methylfolate, 15 mg/d, plus OROS-MPH. OROS-MPH was started at 36 mg/d and titrated to optimal response. The primary endpoint was change in score from baseline on the Adult ADHD Investigator Symptom Report scale. Although it was well tolerated, L-methylfolate was not associated with a significant change in measures of ADHD or mental health function.³ However, researchers noticed that patients who received L-methylfolate needed to receive higher doses of methylphenidate over time. This suggests that supplementation with L-methylfolate could reduce the effectiveness of methylphenidate in adult patients with ADHD.³

While more research is needed, the contradictory results of these studies suggests that the relationship between L-methylfolate and ADHD could be impacted by dosing, as well as by differences in adult and childhood ADHD that are not yet fully understood.

Continue to: An area warranting future research

An area warranting future research

The growth of pharmacogenomics represents an important opportunity to bridge the gap between our understanding of psychiatric illnesses and new ways to treat them. Using L-methylfolate to treat ADHD might help bridge this gap. For this to occur, psychiatrists need to use evidence-based pharmacogenetic research to inform their decision-making. The differing results in studies evaluating the use of L-methylfolate in adult and pediatric patients pose interesting questions that will require more robust research to answer. Clinicians should be cautious in the use of L-methylfolate and recognize the importance of evaluating every patient with ADHD for MTHFR deficiency. This could help personalize care in ways that may improve the quality of life for patients and their families.

In 2009, the Health Information Technology for Economic and Clinical Health Act (HITECH Act), which is part of the American Recovery and Reinvestment Act, provided several billion dollars of grants and incentives to stimulate the implementation of electronic health records (EHRs) and supporting technology in the United States.¹ Since then, almost all health care organizations have employed EHRs and supporting technologies. Unfortunately, this has created new liability risks. One potential risk is that in malpractice claims, there is more discoverable evidence, including metadata, with which to prove the claims.² In this article, I explain what metadata is and how it can be used in medical malpractice cases. In addition, because we cannot change metadata, I provide guidance on making corrections in your EHR documentation to minimize liability in medical malpractice cases.

What is metadata?

Metadata—commonly described as data about data—lurk behind the words and images we can see on our computer screens. Metadata can be conceptualized as data that provides details about the information we enter into a computer system, creating a permanent electronic footprint that can be used to track our activity.^2,3 Examples of metadata include (but are not limited to) the user’s name, date and time of a record entry, changes or deletions made to the record, the date an entry was created or modified, annotations that the user added over a period of time, and any other data that the software captures without the user manually entering the information.³ Metadata is typically stored on a server or file that users cannot access, which ensures data integrity because a user cannot alter a patient’s medical record without those changes being captured.³

How metadata is used in malpractice claims

When a psychiatrist is sued for medical negligence, the integrity of the EHR is an important aspect of defending against the lawsuit. A plaintiff’s (patient’s) attorney can more readily discover changes to the patient’s medical record by requesting the metadata and having it analyzed by an information technology specialist. Because the computer system captures everything a user does, it is difficult to alter a patient’s record without being detected. Consequently, plaintiff attorneys frequently request metadata during discovery in the hopes of learning whether the defendant psychiatrist altered or attempted to hide information that was contained or missing from the original version of the medical record.³ If the medical record was revised at a time unrelated to the treatment, metadata can raise suspicion of deception, even in the absence of wrongdoing.² Alternatively, metadata can be used to validate that the EHR was changed when treatment occurred, which can bolster a defendant psychiatrist’s ability to rely on the EHR against a claim of medical negligence.²

Depending on the jurisdiction, metadata may or may not be discoverable. The Federal Rules of Civil Procedure emphasize producing documents in their original format.⁴ For federal cases, these rules suggest that the parties discuss discovery of this material when they are initially conferring; however, the rules do not specify whether a party must produce metadata, which leaves the courts to refine these rules through case law.^4,5 In one case, a federal court ruled that a party had to produce documents with metadata intact.⁵ Without an agreement between both parties to exclude metadata from produced documents, the parties must produce the metadata.⁵ State laws differ in regards to the discoverability of metadata.

Corrections vs alterations

A patient’s medical record is the best evidence of the care we provided, should that care ever be challenged in court. We can preserve the medical record’s effectiveness through appropriate changes to it. Appropriately executed corrections are a normal part of documentation, whereas alterations to the medical record can cast doubt on our credibility and lead an otherwise defensible case to require a settlement.⁶

Corrections are changes to a patient’s medical record during the normal course of treatment.⁶ These are acceptable, provided the changes are made appropriately. Health care facilities and practices have their own policies for making appropriate corrections and addendums to the medical record. Once a correction and/or addendum is made, do not remove or delete the erroneous entry, because health care colleagues may have relied on it, and deleting an erroneous entry also would alter the integrity of the medical record.⁶ When done appropriately, corrections will not be misconstrued as alterations.

Alterations are changes to a patient’s medical record after a psychiatrist receives notice of a lawsuit and “clarifies” certain points in the medical record to aid the defense against the claim.⁶ Alterations are considered deliberate misrepresentations of facts and, if discovered during litigation, can significantly impact the ability to defend against a claim.⁶ In addition, many medical liability policies exclude coverage for claims in which the medical record was altered, which might result in a psychiatrist having to pay for the judgment and defense costs out of pocket.⁶ Psychiatrists facing litigation who have a legitimate need to change an EHR entry after a claim is filed should consult with legal counsel or a risk management professional for guidance before making any changes.³ If they concur with updating the patient’s record to correct an error (including an addendum or a late entry; see below), the original entry, date, and time stamp must be accessible.³ This should also include the current date/time of the amended entry, the name of the person making the change, and the reasons for the change.³

Continue to: How to handle corrections and late entries

 

 

How to handle corrections and late entries

Sometimes situations occur that require us to make late entries, enter addendums, or add clarification notes to patient information in the EHRs. Regardless of your work environment (ie, hospital, your own practice), there should be clear procedures in place for correcting patients’ EHRs that are in accordance with applicable federal and state laws. Correcting an error in the EHR should follow the same basic principles of correcting paper records: do not obscure the original entry, make timely corrections, sign all entries, ensure the person making the change is identified, and document the reason(s) for the correction.⁷ The EHR must be able to track corrections or changes to an entry once they are entered or authenticated. Any physical copies of documentation must also have the same corrections or changes if they have been previously printed from the EHR.

You may need to make an entry that is late (out of sequence) or provides additional documentation to supplement previously written entries.⁷ A late entry should be used to record information when a pertinent entry was missed or not written in a timely manner.⁷ Label the new entry as a “late entry,” enter the current date and time (do not give the appearance that the entry was made on a previous date or at an earlier time), and identify or refer to the date and incident for which the late entry is written.⁷ If the late entry is used to document an omission, validate the source of additional information as best you can (ie, details of where you obtained the information to write the late entry).⁷ Make late entries as soon as possible after the original entry; although there is no time limit on writing a late entry, delays in corrections might diminish the credibility of the changes.

Addendums are used to provide additional information in conjunction with a previous entry.⁷ They also provide additional information to address a specific situation or incident referenced in a previous note. Addendums should not be used to document information that was forgotten or written in error.⁷ A clarification note is used to avoid incorrect interpretation of previously documented information.⁷ When writing an addendum or a clarification note, you should label it as an “addendum” or a “clarification note”; document the current date and time; state the reason for the addendum (referring back to the original entry) or clarification note (referring back to the entry being clarified); and identify any sources of information used to support an addendum or a clarification note.⁷

In 2009, the Health Information Technology for Economic and Clinical Health Act (HITECH Act), which is part of the American Recovery and Reinvestment Act, provided several billion dollars of grants and incentives to stimulate the implementation of electronic health records (EHRs) and supporting technology in the United States.¹ Since then, almost all health care organizations have employed EHRs and supporting technologies. Unfortunately, this has created new liability risks. One potential risk is that in malpractice claims, there is more discoverable evidence, including metadata, with which to prove the claims.² In this article, I explain what metadata is and how it can be used in medical malpractice cases. In addition, because we cannot change metadata, I provide guidance on making corrections in your EHR documentation to minimize liability in medical malpractice cases.

What is metadata?

Metadata—commonly described as data about data—lurk behind the words and images we can see on our computer screens. Metadata can be conceptualized as data that provides details about the information we enter into a computer system, creating a permanent electronic footprint that can be used to track our activity.^2,3 Examples of metadata include (but are not limited to) the user’s name, date and time of a record entry, changes or deletions made to the record, the date an entry was created or modified, annotations that the user added over a period of time, and any other data that the software captures without the user manually entering the information.³ Metadata is typically stored on a server or file that users cannot access, which ensures data integrity because a user cannot alter a patient’s medical record without those changes being captured.³

How metadata is used in malpractice claims

When a psychiatrist is sued for medical negligence, the integrity of the EHR is an important aspect of defending against the lawsuit. A plaintiff’s (patient’s) attorney can more readily discover changes to the patient’s medical record by requesting the metadata and having it analyzed by an information technology specialist. Because the computer system captures everything a user does, it is difficult to alter a patient’s record without being detected. Consequently, plaintiff attorneys frequently request metadata during discovery in the hopes of learning whether the defendant psychiatrist altered or attempted to hide information that was contained or missing from the original version of the medical record.³ If the medical record was revised at a time unrelated to the treatment, metadata can raise suspicion of deception, even in the absence of wrongdoing.² Alternatively, metadata can be used to validate that the EHR was changed when treatment occurred, which can bolster a defendant psychiatrist’s ability to rely on the EHR against a claim of medical negligence.²

Depending on the jurisdiction, metadata may or may not be discoverable. The Federal Rules of Civil Procedure emphasize producing documents in their original format.⁴ For federal cases, these rules suggest that the parties discuss discovery of this material when they are initially conferring; however, the rules do not specify whether a party must produce metadata, which leaves the courts to refine these rules through case law.^4,5 In one case, a federal court ruled that a party had to produce documents with metadata intact.⁵ Without an agreement between both parties to exclude metadata from produced documents, the parties must produce the metadata.⁵ State laws differ in regards to the discoverability of metadata.

Corrections vs alterations

A patient’s medical record is the best evidence of the care we provided, should that care ever be challenged in court. We can preserve the medical record’s effectiveness through appropriate changes to it. Appropriately executed corrections are a normal part of documentation, whereas alterations to the medical record can cast doubt on our credibility and lead an otherwise defensible case to require a settlement.⁶

Corrections are changes to a patient’s medical record during the normal course of treatment.⁶ These are acceptable, provided the changes are made appropriately. Health care facilities and practices have their own policies for making appropriate corrections and addendums to the medical record. Once a correction and/or addendum is made, do not remove or delete the erroneous entry, because health care colleagues may have relied on it, and deleting an erroneous entry also would alter the integrity of the medical record.⁶ When done appropriately, corrections will not be misconstrued as alterations.

Alterations are changes to a patient’s medical record after a psychiatrist receives notice of a lawsuit and “clarifies” certain points in the medical record to aid the defense against the claim.⁶ Alterations are considered deliberate misrepresentations of facts and, if discovered during litigation, can significantly impact the ability to defend against a claim.⁶ In addition, many medical liability policies exclude coverage for claims in which the medical record was altered, which might result in a psychiatrist having to pay for the judgment and defense costs out of pocket.⁶ Psychiatrists facing litigation who have a legitimate need to change an EHR entry after a claim is filed should consult with legal counsel or a risk management professional for guidance before making any changes.³ If they concur with updating the patient’s record to correct an error (including an addendum or a late entry; see below), the original entry, date, and time stamp must be accessible.³ This should also include the current date/time of the amended entry, the name of the person making the change, and the reasons for the change.³

Continue to: How to handle corrections and late entries

 

 

How to handle corrections and late entries

Sometimes situations occur that require us to make late entries, enter addendums, or add clarification notes to patient information in the EHRs. Regardless of your work environment (ie, hospital, your own practice), there should be clear procedures in place for correcting patients’ EHRs that are in accordance with applicable federal and state laws. Correcting an error in the EHR should follow the same basic principles of correcting paper records: do not obscure the original entry, make timely corrections, sign all entries, ensure the person making the change is identified, and document the reason(s) for the correction.⁷ The EHR must be able to track corrections or changes to an entry once they are entered or authenticated. Any physical copies of documentation must also have the same corrections or changes if they have been previously printed from the EHR.

You may need to make an entry that is late (out of sequence) or provides additional documentation to supplement previously written entries.⁷ A late entry should be used to record information when a pertinent entry was missed or not written in a timely manner.⁷ Label the new entry as a “late entry,” enter the current date and time (do not give the appearance that the entry was made on a previous date or at an earlier time), and identify or refer to the date and incident for which the late entry is written.⁷ If the late entry is used to document an omission, validate the source of additional information as best you can (ie, details of where you obtained the information to write the late entry).⁷ Make late entries as soon as possible after the original entry; although there is no time limit on writing a late entry, delays in corrections might diminish the credibility of the changes.

Addendums are used to provide additional information in conjunction with a previous entry.⁷ They also provide additional information to address a specific situation or incident referenced in a previous note. Addendums should not be used to document information that was forgotten or written in error.⁷ A clarification note is used to avoid incorrect interpretation of previously documented information.⁷ When writing an addendum or a clarification note, you should label it as an “addendum” or a “clarification note”; document the current date and time; state the reason for the addendum (referring back to the original entry) or clarification note (referring back to the entry being clarified); and identify any sources of information used to support an addendum or a clarification note.⁷

In 2009, the Health Information Technology for Economic and Clinical Health Act (HITECH Act), which is part of the American Recovery and Reinvestment Act, provided several billion dollars of grants and incentives to stimulate the implementation of electronic health records (EHRs) and supporting technology in the United States.¹ Since then, almost all health care organizations have employed EHRs and supporting technologies. Unfortunately, this has created new liability risks. One potential risk is that in malpractice claims, there is more discoverable evidence, including metadata, with which to prove the claims.² In this article, I explain what metadata is and how it can be used in medical malpractice cases. In addition, because we cannot change metadata, I provide guidance on making corrections in your EHR documentation to minimize liability in medical malpractice cases.

What is metadata?

Metadata—commonly described as data about data—lurk behind the words and images we can see on our computer screens. Metadata can be conceptualized as data that provides details about the information we enter into a computer system, creating a permanent electronic footprint that can be used to track our activity.^2,3 Examples of metadata include (but are not limited to) the user’s name, date and time of a record entry, changes or deletions made to the record, the date an entry was created or modified, annotations that the user added over a period of time, and any other data that the software captures without the user manually entering the information.³ Metadata is typically stored on a server or file that users cannot access, which ensures data integrity because a user cannot alter a patient’s medical record without those changes being captured.³

How metadata is used in malpractice claims

When a psychiatrist is sued for medical negligence, the integrity of the EHR is an important aspect of defending against the lawsuit. A plaintiff’s (patient’s) attorney can more readily discover changes to the patient’s medical record by requesting the metadata and having it analyzed by an information technology specialist. Because the computer system captures everything a user does, it is difficult to alter a patient’s record without being detected. Consequently, plaintiff attorneys frequently request metadata during discovery in the hopes of learning whether the defendant psychiatrist altered or attempted to hide information that was contained or missing from the original version of the medical record.³ If the medical record was revised at a time unrelated to the treatment, metadata can raise suspicion of deception, even in the absence of wrongdoing.² Alternatively, metadata can be used to validate that the EHR was changed when treatment occurred, which can bolster a defendant psychiatrist’s ability to rely on the EHR against a claim of medical negligence.²

Depending on the jurisdiction, metadata may or may not be discoverable. The Federal Rules of Civil Procedure emphasize producing documents in their original format.⁴ For federal cases, these rules suggest that the parties discuss discovery of this material when they are initially conferring; however, the rules do not specify whether a party must produce metadata, which leaves the courts to refine these rules through case law.^4,5 In one case, a federal court ruled that a party had to produce documents with metadata intact.⁵ Without an agreement between both parties to exclude metadata from produced documents, the parties must produce the metadata.⁵ State laws differ in regards to the discoverability of metadata.

Corrections vs alterations

A patient’s medical record is the best evidence of the care we provided, should that care ever be challenged in court. We can preserve the medical record’s effectiveness through appropriate changes to it. Appropriately executed corrections are a normal part of documentation, whereas alterations to the medical record can cast doubt on our credibility and lead an otherwise defensible case to require a settlement.⁶

Corrections are changes to a patient’s medical record during the normal course of treatment.⁶ These are acceptable, provided the changes are made appropriately. Health care facilities and practices have their own policies for making appropriate corrections and addendums to the medical record. Once a correction and/or addendum is made, do not remove or delete the erroneous entry, because health care colleagues may have relied on it, and deleting an erroneous entry also would alter the integrity of the medical record.⁶ When done appropriately, corrections will not be misconstrued as alterations.

Alterations are changes to a patient’s medical record after a psychiatrist receives notice of a lawsuit and “clarifies” certain points in the medical record to aid the defense against the claim.⁶ Alterations are considered deliberate misrepresentations of facts and, if discovered during litigation, can significantly impact the ability to defend against a claim.⁶ In addition, many medical liability policies exclude coverage for claims in which the medical record was altered, which might result in a psychiatrist having to pay for the judgment and defense costs out of pocket.⁶ Psychiatrists facing litigation who have a legitimate need to change an EHR entry after a claim is filed should consult with legal counsel or a risk management professional for guidance before making any changes.³ If they concur with updating the patient’s record to correct an error (including an addendum or a late entry; see below), the original entry, date, and time stamp must be accessible.³ This should also include the current date/time of the amended entry, the name of the person making the change, and the reasons for the change.³

Continue to: How to handle corrections and late entries

 

 

How to handle corrections and late entries

Sometimes situations occur that require us to make late entries, enter addendums, or add clarification notes to patient information in the EHRs. Regardless of your work environment (ie, hospital, your own practice), there should be clear procedures in place for correcting patients’ EHRs that are in accordance with applicable federal and state laws. Correcting an error in the EHR should follow the same basic principles of correcting paper records: do not obscure the original entry, make timely corrections, sign all entries, ensure the person making the change is identified, and document the reason(s) for the correction.⁷ The EHR must be able to track corrections or changes to an entry once they are entered or authenticated. Any physical copies of documentation must also have the same corrections or changes if they have been previously printed from the EHR.

You may need to make an entry that is late (out of sequence) or provides additional documentation to supplement previously written entries.⁷ A late entry should be used to record information when a pertinent entry was missed or not written in a timely manner.⁷ Label the new entry as a “late entry,” enter the current date and time (do not give the appearance that the entry was made on a previous date or at an earlier time), and identify or refer to the date and incident for which the late entry is written.⁷ If the late entry is used to document an omission, validate the source of additional information as best you can (ie, details of where you obtained the information to write the late entry).⁷ Make late entries as soon as possible after the original entry; although there is no time limit on writing a late entry, delays in corrections might diminish the credibility of the changes.

Addendums are used to provide additional information in conjunction with a previous entry.⁷ They also provide additional information to address a specific situation or incident referenced in a previous note. Addendums should not be used to document information that was forgotten or written in error.⁷ A clarification note is used to avoid incorrect interpretation of previously documented information.⁷ When writing an addendum or a clarification note, you should label it as an “addendum” or a “clarification note”; document the current date and time; state the reason for the addendum (referring back to the original entry) or clarification note (referring back to the entry being clarified); and identify any sources of information used to support an addendum or a clarification note.⁷

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

And then there were three. The U.S. Food and Drug Administration (FDA) on Feb. 27 granted emergency use authorization (EUA) to the Ad26.COV2.S vaccine from Janssen/Johnson & Johnson (J&J) for people 18 and older after reviewing its safety and efficacy data.

More vaccine availability at a time of high demand and limited supply could help officials vaccinate more Americans, more quickly. In addition, the J&J vaccine offers one-dose convenience and storage at conventional refrigeration temperatures.

Initial reactions to the EUA for the J&J vaccine have been positive.

“The advantages of having a third vaccine, especially one that is a single shot and can be stored without special refrigeration requirements, will be a major contribution in getting the general public vaccinated sooner, both in the U.S. and around the world,” Phyllis Tien, MD, professor of medicine in the division of infectious diseases at the University of California, San Francisco, told Medscape Medical News.

“It’s great news. We have yet a third vaccine that is highly effective at preventing COVID, and even more effective at preventing severe COVID,” said Paul Goepfert, MD. It’s a “tremendous boon for our country and other countries as well.”

“This vaccine has also been shown to be effective against the B.1.351 strain that was first described in South Africa,” added Dr. Goepfert, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama at Birmingham.

The EUA “is indeed exciting news,” Colleen Kraft, MD, associate chief medical officer at Emory University Hospital and associate professor at Emory University School of Medicine in Atlanta, said during a February 25 media briefing.

One recent concern centers on people aged 60 years and older. Documents the FDA released earlier this week suggest a lower efficacy, 42%, for the J&J immunization among people in this age group with certain relevant comorbidities. In contrast, without underlying conditions like heart disease or diabetes, efficacy in this cohort was 72%.

The more the merrier

The scope and urgency of the COVID-19 pandemic necessitates as many protective measures as possible, said Raj Shah, MD, geriatrician, and associate professor of family medicine and codirector of the Center for Community Health Equity at Rush University in Chicago.

“Trying to vaccinate as many individuals living in the United States to prevent the spread of COVID is such a big project that no one company or one vaccine was going to be able to ramp up fast enough on its own,” Dr. Shah told Medscape Medical News.“This has been the hope for us,” he added, “to get to multiple vaccines with slightly different properties that will provide more options.”

Experience with the J&J vaccine so far suggests reactions are less severe. “The nice thing about the Johnson and Johnson [vaccine] is that it definitely has less side effects,” Dr. Kraft said.

On the other hand, low-grade fever, chills, or fatigue after vaccination can be considered a positive because they can reflect how well the immune system is responding, she added.

One and done?

Single-dose administration could be more than a convenience — it could also help clinicians vaccinate members of underserved communities and rural locations, where returning for a second dose could be more difficult for some people.

“In a controlled setting, in a clinical trial, we do a lot to make sure people get all the treatment they need,” Dr. Shah said. “We’re not seeing it right now, but we’re always worried when we have more than one dose that has to be administered, that some people will drop off and not come back for the second vaccine.”

This group could include the needle-phobic, he added. “For them, having it done once alleviates a lot of the anxiety.”

Looking beyond the numbers

The phase 3 ENSEMBLE study of the J&J vaccine revealed a 72% efficacy for preventing moderate-to-severe COVID-19 among U.S. participants. In contrast, researchers reported 94% to 95% efficacy for the Pfizer/BioNTech and Moderna vaccines.

However, experts agreed that focusing solely on these numbers can miss more important points. For example, no participants who received the J&J vaccine in the phase 3 trial died from COVID-19-related illness. There were five such deaths in the placebo cohort.

“One of the things that these vaccines do very well is they minimize severe disease,” Dr. Kraft said. “As somebody that has spent an inordinate time in the hospital taking care of patients with severe disease from COVID, this is very much a welcome addition to our armamentarium to fight this virus.”

“If you can give something that prevents people from dying, that is a true path to normalcy,” Dr. Goepfert added.

More work to do

“The demand is strong from all groups right now. We just have to work on getting more vaccines out there,” Dr. Shah said.

“We are at a point in this country where we are getting better with the distribution of the vaccine,” he added, “but we are nowhere close to achieving that distribution of vaccines to get to everybody.”

Dr. Goepfert, Dr. Shah, and Dr. Kraft disclosed no relevant financial relationships. Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the San Francisco VA Health Care System.

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

And then there were three. The U.S. Food and Drug Administration (FDA) on Feb. 27 granted emergency use authorization (EUA) to the Ad26.COV2.S vaccine from Janssen/Johnson & Johnson (J&J) for people 18 and older after reviewing its safety and efficacy data.

More vaccine availability at a time of high demand and limited supply could help officials vaccinate more Americans, more quickly. In addition, the J&J vaccine offers one-dose convenience and storage at conventional refrigeration temperatures.

Initial reactions to the EUA for the J&J vaccine have been positive.

“The advantages of having a third vaccine, especially one that is a single shot and can be stored without special refrigeration requirements, will be a major contribution in getting the general public vaccinated sooner, both in the U.S. and around the world,” Phyllis Tien, MD, professor of medicine in the division of infectious diseases at the University of California, San Francisco, told Medscape Medical News.

“It’s great news. We have yet a third vaccine that is highly effective at preventing COVID, and even more effective at preventing severe COVID,” said Paul Goepfert, MD. It’s a “tremendous boon for our country and other countries as well.”

“This vaccine has also been shown to be effective against the B.1.351 strain that was first described in South Africa,” added Dr. Goepfert, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama at Birmingham.

The EUA “is indeed exciting news,” Colleen Kraft, MD, associate chief medical officer at Emory University Hospital and associate professor at Emory University School of Medicine in Atlanta, said during a February 25 media briefing.

One recent concern centers on people aged 60 years and older. Documents the FDA released earlier this week suggest a lower efficacy, 42%, for the J&J immunization among people in this age group with certain relevant comorbidities. In contrast, without underlying conditions like heart disease or diabetes, efficacy in this cohort was 72%.

The more the merrier

The scope and urgency of the COVID-19 pandemic necessitates as many protective measures as possible, said Raj Shah, MD, geriatrician, and associate professor of family medicine and codirector of the Center for Community Health Equity at Rush University in Chicago.

“Trying to vaccinate as many individuals living in the United States to prevent the spread of COVID is such a big project that no one company or one vaccine was going to be able to ramp up fast enough on its own,” Dr. Shah told Medscape Medical News.“This has been the hope for us,” he added, “to get to multiple vaccines with slightly different properties that will provide more options.”

Experience with the J&J vaccine so far suggests reactions are less severe. “The nice thing about the Johnson and Johnson [vaccine] is that it definitely has less side effects,” Dr. Kraft said.

On the other hand, low-grade fever, chills, or fatigue after vaccination can be considered a positive because they can reflect how well the immune system is responding, she added.

One and done?

Single-dose administration could be more than a convenience — it could also help clinicians vaccinate members of underserved communities and rural locations, where returning for a second dose could be more difficult for some people.

“In a controlled setting, in a clinical trial, we do a lot to make sure people get all the treatment they need,” Dr. Shah said. “We’re not seeing it right now, but we’re always worried when we have more than one dose that has to be administered, that some people will drop off and not come back for the second vaccine.”

This group could include the needle-phobic, he added. “For them, having it done once alleviates a lot of the anxiety.”

Looking beyond the numbers

The phase 3 ENSEMBLE study of the J&J vaccine revealed a 72% efficacy for preventing moderate-to-severe COVID-19 among U.S. participants. In contrast, researchers reported 94% to 95% efficacy for the Pfizer/BioNTech and Moderna vaccines.

However, experts agreed that focusing solely on these numbers can miss more important points. For example, no participants who received the J&J vaccine in the phase 3 trial died from COVID-19-related illness. There were five such deaths in the placebo cohort.

“One of the things that these vaccines do very well is they minimize severe disease,” Dr. Kraft said. “As somebody that has spent an inordinate time in the hospital taking care of patients with severe disease from COVID, this is very much a welcome addition to our armamentarium to fight this virus.”

“If you can give something that prevents people from dying, that is a true path to normalcy,” Dr. Goepfert added.

More work to do

“The demand is strong from all groups right now. We just have to work on getting more vaccines out there,” Dr. Shah said.

“We are at a point in this country where we are getting better with the distribution of the vaccine,” he added, “but we are nowhere close to achieving that distribution of vaccines to get to everybody.”

Dr. Goepfert, Dr. Shah, and Dr. Kraft disclosed no relevant financial relationships. Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the San Francisco VA Health Care System.

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

And then there were three. The U.S. Food and Drug Administration (FDA) on Feb. 27 granted emergency use authorization (EUA) to the Ad26.COV2.S vaccine from Janssen/Johnson & Johnson (J&J) for people 18 and older after reviewing its safety and efficacy data.

More vaccine availability at a time of high demand and limited supply could help officials vaccinate more Americans, more quickly. In addition, the J&J vaccine offers one-dose convenience and storage at conventional refrigeration temperatures.

Initial reactions to the EUA for the J&J vaccine have been positive.

“The advantages of having a third vaccine, especially one that is a single shot and can be stored without special refrigeration requirements, will be a major contribution in getting the general public vaccinated sooner, both in the U.S. and around the world,” Phyllis Tien, MD, professor of medicine in the division of infectious diseases at the University of California, San Francisco, told Medscape Medical News.

“It’s great news. We have yet a third vaccine that is highly effective at preventing COVID, and even more effective at preventing severe COVID,” said Paul Goepfert, MD. It’s a “tremendous boon for our country and other countries as well.”

“This vaccine has also been shown to be effective against the B.1.351 strain that was first described in South Africa,” added Dr. Goepfert, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama at Birmingham.

The EUA “is indeed exciting news,” Colleen Kraft, MD, associate chief medical officer at Emory University Hospital and associate professor at Emory University School of Medicine in Atlanta, said during a February 25 media briefing.

One recent concern centers on people aged 60 years and older. Documents the FDA released earlier this week suggest a lower efficacy, 42%, for the J&J immunization among people in this age group with certain relevant comorbidities. In contrast, without underlying conditions like heart disease or diabetes, efficacy in this cohort was 72%.

The more the merrier

The scope and urgency of the COVID-19 pandemic necessitates as many protective measures as possible, said Raj Shah, MD, geriatrician, and associate professor of family medicine and codirector of the Center for Community Health Equity at Rush University in Chicago.

“Trying to vaccinate as many individuals living in the United States to prevent the spread of COVID is such a big project that no one company or one vaccine was going to be able to ramp up fast enough on its own,” Dr. Shah told Medscape Medical News.“This has been the hope for us,” he added, “to get to multiple vaccines with slightly different properties that will provide more options.”

Experience with the J&J vaccine so far suggests reactions are less severe. “The nice thing about the Johnson and Johnson [vaccine] is that it definitely has less side effects,” Dr. Kraft said.

On the other hand, low-grade fever, chills, or fatigue after vaccination can be considered a positive because they can reflect how well the immune system is responding, she added.

One and done?

Single-dose administration could be more than a convenience — it could also help clinicians vaccinate members of underserved communities and rural locations, where returning for a second dose could be more difficult for some people.

“In a controlled setting, in a clinical trial, we do a lot to make sure people get all the treatment they need,” Dr. Shah said. “We’re not seeing it right now, but we’re always worried when we have more than one dose that has to be administered, that some people will drop off and not come back for the second vaccine.”

This group could include the needle-phobic, he added. “For them, having it done once alleviates a lot of the anxiety.”

Looking beyond the numbers

The phase 3 ENSEMBLE study of the J&J vaccine revealed a 72% efficacy for preventing moderate-to-severe COVID-19 among U.S. participants. In contrast, researchers reported 94% to 95% efficacy for the Pfizer/BioNTech and Moderna vaccines.

However, experts agreed that focusing solely on these numbers can miss more important points. For example, no participants who received the J&J vaccine in the phase 3 trial died from COVID-19-related illness. There were five such deaths in the placebo cohort.

“One of the things that these vaccines do very well is they minimize severe disease,” Dr. Kraft said. “As somebody that has spent an inordinate time in the hospital taking care of patients with severe disease from COVID, this is very much a welcome addition to our armamentarium to fight this virus.”

“If you can give something that prevents people from dying, that is a true path to normalcy,” Dr. Goepfert added.

More work to do

“The demand is strong from all groups right now. We just have to work on getting more vaccines out there,” Dr. Shah said.

“We are at a point in this country where we are getting better with the distribution of the vaccine,” he added, “but we are nowhere close to achieving that distribution of vaccines to get to everybody.”

Dr. Goepfert, Dr. Shah, and Dr. Kraft disclosed no relevant financial relationships. Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the San Francisco VA Health Care System.

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

An FDA advisory panel lent their support Feb. 26 to a rapid clearance for Janssen/Johnson & Johnson’s COVID-19 vaccine.

The Food and Drug Administration (FDA) is expected to quickly provide an emergency use authorization (EUA) for the vaccine following the recommendation by the panel. The FDA’s Vaccines and Related Biological Products Advisory Committee voted 22-0 on this question: Based on the totality of scientific evidence available, do the benefits of the Johnson & Johnson COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?

The Johnson & Johnson vaccine is expected to offer more convenient dosing and be easier to distribute than the two rival products already available in the United States. Janssen’s vaccine is intended to be given in a single dose. In December, the FDA granted EUAs for the Pfizer/BioNTech and Moderna COVID-19 vaccines, which are each two-dose regimens.

Johnson & Johnson’s vaccine can be stored for at least 3 months at normal refrigerator temperatures of 2°C to 8°C (36°F to 46°F). Its shipping and storage fits into the existing medical supply infrastructure, the company said in its briefing materials for the FDA advisory committee meeting. In contrast, Pfizer’s vaccine is stored in ultracold freezers at temperatures between -80°C and -60°C (-112°F and -76°F), according to the Centers for Disease Control and Prevention. Moderna’s vaccine may be stored in a freezer between -25°C and -15°C (-13°F and 5°F).

But FDA advisers focused more in their deliberations on concerns about Janssen’s vaccine, including emerging reports of allergic reactions.

The advisers also discussed how patients might respond to the widely reported gap between Johnson & Johnson’s topline efficacy rates compared with rivals. The company’s initial unveiling last month of key results for its vaccine caused an initial wave of disappointment, with its overall efficacy against moderate-to-severe COVID-19 28 days postvaccination first reported at about 66% globally. By contrast, results for the Pfizer and Moderna vaccines suggest they have efficacy rates of 95% and 94%.

But in concluding, the advisers spoke of the Janssen vaccine as a much-needed tool to address the COVID-19 pandemic. The death toll in the United States attributed to the virus has reached 501,414, according to the World Health Organization.

“Despite the concerns that were raised during the discussion. I think what we have to keep in mind is that we’re still in the midst of this deadly pandemic,” said FDA adviser Archana Chatterjee, MD, PhD, from Rosalind Franklin University. “There is a shortage of vaccines that are currently authorized, and I think authorization of this vaccine will help meet the needs at the moment.”

The FDA is not bound to accept the recommendations of its advisers, but it often does so.

Anaphylaxis case

FDA advisers raised only a few questions for Johnson & Johnson and FDA staff ahead of their vote. The committee’s deliberations were less contentious and heated than had been during its December reviews of the Pfizer and Moderna vaccines. In those meetings, the panel voted 17-4, with one abstention, in favor of Pfizer’s vaccine and  20-0, with one abstention, on the Moderna vaccine.

“We are very comfortable now with the procedure, as well as the vaccines,” said Arnold Monto, MD, after the Feb. 26 vote on the Janssen vaccine. Dr. Monto, from the University of Michigan School of Public Health in Ann Arbor, has served as the chairman of the FDA panel through its review of all three COVID-19 vaccines.

Among the issues noted in the deliberations was the emergence of a concern about anaphylaxis with the vaccine.

This serious allergic reaction has been seen in people who have taken the Pfizer and Moderna vaccines. Before the week of the panel meeting, though, there had not been reports of anaphylaxis with the Johnson & Johnson vaccine, said Macaya Douoguih, MD, MPH, head of clinical development and medical affairs for Janssen/ Johnson & Johnson’s vaccines division.

However, on February 24, Johnson & Johnson received preliminary reports about two cases of severe allergic reaction from an open-label study in South Africa, with one of these being anaphylaxis, Dr. Douoguih said. The company will continue to closely monitor for these events as outlined in their pharmacovigilance plan, Dr. Douoguih said.

Federal health officials have sought to make clinicians aware of the rare risk for anaphylaxis with COVID vaccines, while reminding the public that this reaction can be managed.

The FDA had Tom Shimabukuro, MD, MPH, MBA, from the CDC, give an update on postmarketing surveillance for the Pfizer and Moderna vaccines as part of the review of the Johnson & Johnson application. Dr. Shimabukuro and CDC colleagues published a report in JAMA on February 14 that looked at an anaphylaxis case reported connected with COVID vaccines between December 14, 2020, and January 18, 2021.

The CDC identified 66 case reports received that met Brighton Collaboration case definition criteria for anaphylaxis (levels 1, 2, or 3): 47 following Pfizer/BioNTech vaccine, for a reporting rate of 4.7 cases/million doses administered, and 19 following Moderna vaccine, for a reporting rate of 2.5 cases/million doses administered, Dr. Shimabukuro and CDC colleagues wrote.

The CDC has published materials to help clinicians prepare for the possibility of this rare event, Dr. Shimabukuro told the FDA advisers.

“The take-home message here is that these are rare events and anaphylaxis, although clinically serious, is treatable,” Dr. Shimabukuro said.

At the conclusion of the meeting, FDA panelist Patrick Moore, MD, MPH, from the University of Pittsburgh in Pennsylvania, stressed the need to convey to the public that the COVID vaccines appear so far to be safe. Many people earlier had doubts about how the FDA could both safely and quickly review the applications for EUAs for these products.

“As of February 26, things are looking good. That could change tomorrow,” Dr. Moore said. But “this whole EUA process does seem to have worked, despite my own personal concerns about it.”

No second-class vaccines

The Johnson & Johnson vaccine, known as Ad26.COV2.S, is composed of a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector. It’s intended to encode a stabilized form of SARS-CoV-2 spike (S) protein. The Pfizer and Moderna vaccines use a different mechanism. They rely on mRNA.

The FDA advisers also discussed how patients might respond to the widely reported gap between Janssen’s topline efficacy rates compared with rivals. They urged against people parsing study details too finely and seeking to pick and choose their shots.

“It’s important that people do not think that one vaccine is better than another,” said FDA adviser H. Cody Meissner, MD, from Tufts University School of Medicine in Boston.

Dr. Monto agreed, noting that many people in the United States are still waiting for their turn to get COVID vaccines because of the limited early supply.

Trying to game the system to get one vaccine instead of another would not be wise. “In this environment, whatever you can get, get,” Dr. Monto said.

During an open public hearing, Sarah Christopherson, policy advocacy director of the National Women’s Health Network, said that press reports are fueling a damaging impression in the public that there are “first and second-class” vaccines.

“That has the potential to exacerbate existing mistrust” in vaccines, she said. “Public health authorities must address these perceptions head on.”

She urged against attempts to compare the Janssen vaccine to others, noting the potential effects of emerging variants of the virus.

“It’s difficult to make an apples-to-apples comparison between vaccines,” she said.

Johnson & Johnson’s efficacy results, which are lower than those of the mRNA vaccines, may be a reflection of the ways in which SARS-Co-V-2 is mutating and thus becoming more of a threat, according to the company. A key study of the new vaccine, involving about 44,000 people, coincided with the emergence of new SARS-CoV-2 variants, which were emerging in some of the countries where the pivotal COV3001 study was being conducted, the company said.

At least 14 days after vaccination, the Johnson & Johnson COVID vaccine efficacy (95% confidence interval) was 72.0% (58.2, 81.7) in the United States, 68.1% (48.8, 80.7) in Brazil, and 64.0% (41.2, 78.7) in South Africa.

Weakened standards?

Several researchers called on the FDA to maintain a critical attitude when assessing Johnson & Johnson’s application for the EUA, warning of a potential for a permanent erosion of agency rules due to hasty action on COVID vaccines.

They raised concerns about the FDA demanding too little in terms of follow-up studies on COVID vaccines and with persisting murkiness resulting in attempts to determine how well these treatments work beyond the initial study period.

“I worry about FDA lowering its approval standards,” said Peter Doshi, PhD, from The BMJ and a faculty member at the University of Maryland School of Medicine in Baltimore, during an open public hearing at the meeting.

“There’s a real urgency to stand back right now and look at the forest here, as well as the trees, and I urge the committee to consider the effects FDA decisions may have on the entire regulatory approval process,” Dr. Doshi said.

Dr. Doshi asked why Johnson & Johnson did not seek a standard full approval — a biologics license application (BLA) — instead of aiming for the lower bar of an EUA. The FDA already has allowed wide distribution of the Pfizer/BioNTech and Moderna vaccines through EUAs. That removes the sense of urgency that FDA faced last year in his view.

The FDA’s June 2020 guidance on the development of COVID vaccines had asked drugmakers to plan on following participants in COVID vaccine trials for “ideally at least one to two years.” Yet people who got placebo in Moderna and Pfizer trials already are being vaccinated, Dr. Doshi said. And Johnson & Johnson said in its presentation to the FDA that if the Ad26.COV2.S vaccine were granted an EUA, the COV3001 study design would be amended to “facilitate cross-over of placebo participants in all participating countries to receive one dose of active study vaccine as fast as operationally feasible.”

“I’m nervous about the prospect of there never being a COVID vaccine that meets the FDA’s approval standard” for a BLA instead of the more limited EUA, Dr. Doshi said.

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, noted that the FDA’s subsequent guidance tailored for EUAs for COVID vaccines “drastically shortened” the follow-up time to a median of 2 months. Dr. Zuckerman said that a crossover design would be “a reasonable compromise, but only if the placebo group has at least 6 months of data.” Dr. Zuckerman opened her remarks in the open public hearing by saying she had inherited Johnson & Johnson stock, so was speaking at the meeting against her own financial interest.

“As soon as a vaccine is authorized, we start losing the placebo group. If FDA lets that happen, that’s a huge loss for public health and a huge loss of information about how we can all stay safe,” Dr. Zuckerman said.



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

An FDA advisory panel lent their support Feb. 26 to a rapid clearance for Janssen/Johnson & Johnson’s COVID-19 vaccine.

The Food and Drug Administration (FDA) is expected to quickly provide an emergency use authorization (EUA) for the vaccine following the recommendation by the panel. The FDA’s Vaccines and Related Biological Products Advisory Committee voted 22-0 on this question: Based on the totality of scientific evidence available, do the benefits of the Johnson & Johnson COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?

The Johnson & Johnson vaccine is expected to offer more convenient dosing and be easier to distribute than the two rival products already available in the United States. Janssen’s vaccine is intended to be given in a single dose. In December, the FDA granted EUAs for the Pfizer/BioNTech and Moderna COVID-19 vaccines, which are each two-dose regimens.

Johnson & Johnson’s vaccine can be stored for at least 3 months at normal refrigerator temperatures of 2°C to 8°C (36°F to 46°F). Its shipping and storage fits into the existing medical supply infrastructure, the company said in its briefing materials for the FDA advisory committee meeting. In contrast, Pfizer’s vaccine is stored in ultracold freezers at temperatures between -80°C and -60°C (-112°F and -76°F), according to the Centers for Disease Control and Prevention. Moderna’s vaccine may be stored in a freezer between -25°C and -15°C (-13°F and 5°F).

But FDA advisers focused more in their deliberations on concerns about Janssen’s vaccine, including emerging reports of allergic reactions.

The advisers also discussed how patients might respond to the widely reported gap between Johnson & Johnson’s topline efficacy rates compared with rivals. The company’s initial unveiling last month of key results for its vaccine caused an initial wave of disappointment, with its overall efficacy against moderate-to-severe COVID-19 28 days postvaccination first reported at about 66% globally. By contrast, results for the Pfizer and Moderna vaccines suggest they have efficacy rates of 95% and 94%.

But in concluding, the advisers spoke of the Janssen vaccine as a much-needed tool to address the COVID-19 pandemic. The death toll in the United States attributed to the virus has reached 501,414, according to the World Health Organization.

“Despite the concerns that were raised during the discussion. I think what we have to keep in mind is that we’re still in the midst of this deadly pandemic,” said FDA adviser Archana Chatterjee, MD, PhD, from Rosalind Franklin University. “There is a shortage of vaccines that are currently authorized, and I think authorization of this vaccine will help meet the needs at the moment.”

The FDA is not bound to accept the recommendations of its advisers, but it often does so.

Anaphylaxis case

FDA advisers raised only a few questions for Johnson & Johnson and FDA staff ahead of their vote. The committee’s deliberations were less contentious and heated than had been during its December reviews of the Pfizer and Moderna vaccines. In those meetings, the panel voted 17-4, with one abstention, in favor of Pfizer’s vaccine and  20-0, with one abstention, on the Moderna vaccine.

“We are very comfortable now with the procedure, as well as the vaccines,” said Arnold Monto, MD, after the Feb. 26 vote on the Janssen vaccine. Dr. Monto, from the University of Michigan School of Public Health in Ann Arbor, has served as the chairman of the FDA panel through its review of all three COVID-19 vaccines.

Among the issues noted in the deliberations was the emergence of a concern about anaphylaxis with the vaccine.

This serious allergic reaction has been seen in people who have taken the Pfizer and Moderna vaccines. Before the week of the panel meeting, though, there had not been reports of anaphylaxis with the Johnson & Johnson vaccine, said Macaya Douoguih, MD, MPH, head of clinical development and medical affairs for Janssen/ Johnson & Johnson’s vaccines division.

However, on February 24, Johnson & Johnson received preliminary reports about two cases of severe allergic reaction from an open-label study in South Africa, with one of these being anaphylaxis, Dr. Douoguih said. The company will continue to closely monitor for these events as outlined in their pharmacovigilance plan, Dr. Douoguih said.

Federal health officials have sought to make clinicians aware of the rare risk for anaphylaxis with COVID vaccines, while reminding the public that this reaction can be managed.

The FDA had Tom Shimabukuro, MD, MPH, MBA, from the CDC, give an update on postmarketing surveillance for the Pfizer and Moderna vaccines as part of the review of the Johnson & Johnson application. Dr. Shimabukuro and CDC colleagues published a report in JAMA on February 14 that looked at an anaphylaxis case reported connected with COVID vaccines between December 14, 2020, and January 18, 2021.

The CDC identified 66 case reports received that met Brighton Collaboration case definition criteria for anaphylaxis (levels 1, 2, or 3): 47 following Pfizer/BioNTech vaccine, for a reporting rate of 4.7 cases/million doses administered, and 19 following Moderna vaccine, for a reporting rate of 2.5 cases/million doses administered, Dr. Shimabukuro and CDC colleagues wrote.

The CDC has published materials to help clinicians prepare for the possibility of this rare event, Dr. Shimabukuro told the FDA advisers.

“The take-home message here is that these are rare events and anaphylaxis, although clinically serious, is treatable,” Dr. Shimabukuro said.

At the conclusion of the meeting, FDA panelist Patrick Moore, MD, MPH, from the University of Pittsburgh in Pennsylvania, stressed the need to convey to the public that the COVID vaccines appear so far to be safe. Many people earlier had doubts about how the FDA could both safely and quickly review the applications for EUAs for these products.

“As of February 26, things are looking good. That could change tomorrow,” Dr. Moore said. But “this whole EUA process does seem to have worked, despite my own personal concerns about it.”

No second-class vaccines

The Johnson & Johnson vaccine, known as Ad26.COV2.S, is composed of a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector. It’s intended to encode a stabilized form of SARS-CoV-2 spike (S) protein. The Pfizer and Moderna vaccines use a different mechanism. They rely on mRNA.

The FDA advisers also discussed how patients might respond to the widely reported gap between Janssen’s topline efficacy rates compared with rivals. They urged against people parsing study details too finely and seeking to pick and choose their shots.

“It’s important that people do not think that one vaccine is better than another,” said FDA adviser H. Cody Meissner, MD, from Tufts University School of Medicine in Boston.

Dr. Monto agreed, noting that many people in the United States are still waiting for their turn to get COVID vaccines because of the limited early supply.

Trying to game the system to get one vaccine instead of another would not be wise. “In this environment, whatever you can get, get,” Dr. Monto said.

During an open public hearing, Sarah Christopherson, policy advocacy director of the National Women’s Health Network, said that press reports are fueling a damaging impression in the public that there are “first and second-class” vaccines.

“That has the potential to exacerbate existing mistrust” in vaccines, she said. “Public health authorities must address these perceptions head on.”

She urged against attempts to compare the Janssen vaccine to others, noting the potential effects of emerging variants of the virus.

“It’s difficult to make an apples-to-apples comparison between vaccines,” she said.

Johnson & Johnson’s efficacy results, which are lower than those of the mRNA vaccines, may be a reflection of the ways in which SARS-Co-V-2 is mutating and thus becoming more of a threat, according to the company. A key study of the new vaccine, involving about 44,000 people, coincided with the emergence of new SARS-CoV-2 variants, which were emerging in some of the countries where the pivotal COV3001 study was being conducted, the company said.

At least 14 days after vaccination, the Johnson & Johnson COVID vaccine efficacy (95% confidence interval) was 72.0% (58.2, 81.7) in the United States, 68.1% (48.8, 80.7) in Brazil, and 64.0% (41.2, 78.7) in South Africa.

Weakened standards?

Several researchers called on the FDA to maintain a critical attitude when assessing Johnson & Johnson’s application for the EUA, warning of a potential for a permanent erosion of agency rules due to hasty action on COVID vaccines.

They raised concerns about the FDA demanding too little in terms of follow-up studies on COVID vaccines and with persisting murkiness resulting in attempts to determine how well these treatments work beyond the initial study period.

“I worry about FDA lowering its approval standards,” said Peter Doshi, PhD, from The BMJ and a faculty member at the University of Maryland School of Medicine in Baltimore, during an open public hearing at the meeting.

“There’s a real urgency to stand back right now and look at the forest here, as well as the trees, and I urge the committee to consider the effects FDA decisions may have on the entire regulatory approval process,” Dr. Doshi said.

Dr. Doshi asked why Johnson & Johnson did not seek a standard full approval — a biologics license application (BLA) — instead of aiming for the lower bar of an EUA. The FDA already has allowed wide distribution of the Pfizer/BioNTech and Moderna vaccines through EUAs. That removes the sense of urgency that FDA faced last year in his view.

The FDA’s June 2020 guidance on the development of COVID vaccines had asked drugmakers to plan on following participants in COVID vaccine trials for “ideally at least one to two years.” Yet people who got placebo in Moderna and Pfizer trials already are being vaccinated, Dr. Doshi said. And Johnson & Johnson said in its presentation to the FDA that if the Ad26.COV2.S vaccine were granted an EUA, the COV3001 study design would be amended to “facilitate cross-over of placebo participants in all participating countries to receive one dose of active study vaccine as fast as operationally feasible.”

“I’m nervous about the prospect of there never being a COVID vaccine that meets the FDA’s approval standard” for a BLA instead of the more limited EUA, Dr. Doshi said.

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, noted that the FDA’s subsequent guidance tailored for EUAs for COVID vaccines “drastically shortened” the follow-up time to a median of 2 months. Dr. Zuckerman said that a crossover design would be “a reasonable compromise, but only if the placebo group has at least 6 months of data.” Dr. Zuckerman opened her remarks in the open public hearing by saying she had inherited Johnson & Johnson stock, so was speaking at the meeting against her own financial interest.

“As soon as a vaccine is authorized, we start losing the placebo group. If FDA lets that happen, that’s a huge loss for public health and a huge loss of information about how we can all stay safe,” Dr. Zuckerman said.



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

An FDA advisory panel lent their support Feb. 26 to a rapid clearance for Janssen/Johnson & Johnson’s COVID-19 vaccine.

The Food and Drug Administration (FDA) is expected to quickly provide an emergency use authorization (EUA) for the vaccine following the recommendation by the panel. The FDA’s Vaccines and Related Biological Products Advisory Committee voted 22-0 on this question: Based on the totality of scientific evidence available, do the benefits of the Johnson & Johnson COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?

The Johnson & Johnson vaccine is expected to offer more convenient dosing and be easier to distribute than the two rival products already available in the United States. Janssen’s vaccine is intended to be given in a single dose. In December, the FDA granted EUAs for the Pfizer/BioNTech and Moderna COVID-19 vaccines, which are each two-dose regimens.

Johnson & Johnson’s vaccine can be stored for at least 3 months at normal refrigerator temperatures of 2°C to 8°C (36°F to 46°F). Its shipping and storage fits into the existing medical supply infrastructure, the company said in its briefing materials for the FDA advisory committee meeting. In contrast, Pfizer’s vaccine is stored in ultracold freezers at temperatures between -80°C and -60°C (-112°F and -76°F), according to the Centers for Disease Control and Prevention. Moderna’s vaccine may be stored in a freezer between -25°C and -15°C (-13°F and 5°F).

But FDA advisers focused more in their deliberations on concerns about Janssen’s vaccine, including emerging reports of allergic reactions.

The advisers also discussed how patients might respond to the widely reported gap between Johnson & Johnson’s topline efficacy rates compared with rivals. The company’s initial unveiling last month of key results for its vaccine caused an initial wave of disappointment, with its overall efficacy against moderate-to-severe COVID-19 28 days postvaccination first reported at about 66% globally. By contrast, results for the Pfizer and Moderna vaccines suggest they have efficacy rates of 95% and 94%.

But in concluding, the advisers spoke of the Janssen vaccine as a much-needed tool to address the COVID-19 pandemic. The death toll in the United States attributed to the virus has reached 501,414, according to the World Health Organization.

“Despite the concerns that were raised during the discussion. I think what we have to keep in mind is that we’re still in the midst of this deadly pandemic,” said FDA adviser Archana Chatterjee, MD, PhD, from Rosalind Franklin University. “There is a shortage of vaccines that are currently authorized, and I think authorization of this vaccine will help meet the needs at the moment.”

The FDA is not bound to accept the recommendations of its advisers, but it often does so.

Anaphylaxis case

FDA advisers raised only a few questions for Johnson & Johnson and FDA staff ahead of their vote. The committee’s deliberations were less contentious and heated than had been during its December reviews of the Pfizer and Moderna vaccines. In those meetings, the panel voted 17-4, with one abstention, in favor of Pfizer’s vaccine and  20-0, with one abstention, on the Moderna vaccine.

“We are very comfortable now with the procedure, as well as the vaccines,” said Arnold Monto, MD, after the Feb. 26 vote on the Janssen vaccine. Dr. Monto, from the University of Michigan School of Public Health in Ann Arbor, has served as the chairman of the FDA panel through its review of all three COVID-19 vaccines.

Among the issues noted in the deliberations was the emergence of a concern about anaphylaxis with the vaccine.

This serious allergic reaction has been seen in people who have taken the Pfizer and Moderna vaccines. Before the week of the panel meeting, though, there had not been reports of anaphylaxis with the Johnson & Johnson vaccine, said Macaya Douoguih, MD, MPH, head of clinical development and medical affairs for Janssen/ Johnson & Johnson’s vaccines division.

However, on February 24, Johnson & Johnson received preliminary reports about two cases of severe allergic reaction from an open-label study in South Africa, with one of these being anaphylaxis, Dr. Douoguih said. The company will continue to closely monitor for these events as outlined in their pharmacovigilance plan, Dr. Douoguih said.

Federal health officials have sought to make clinicians aware of the rare risk for anaphylaxis with COVID vaccines, while reminding the public that this reaction can be managed.

The FDA had Tom Shimabukuro, MD, MPH, MBA, from the CDC, give an update on postmarketing surveillance for the Pfizer and Moderna vaccines as part of the review of the Johnson & Johnson application. Dr. Shimabukuro and CDC colleagues published a report in JAMA on February 14 that looked at an anaphylaxis case reported connected with COVID vaccines between December 14, 2020, and January 18, 2021.

The CDC identified 66 case reports received that met Brighton Collaboration case definition criteria for anaphylaxis (levels 1, 2, or 3): 47 following Pfizer/BioNTech vaccine, for a reporting rate of 4.7 cases/million doses administered, and 19 following Moderna vaccine, for a reporting rate of 2.5 cases/million doses administered, Dr. Shimabukuro and CDC colleagues wrote.

The CDC has published materials to help clinicians prepare for the possibility of this rare event, Dr. Shimabukuro told the FDA advisers.

“The take-home message here is that these are rare events and anaphylaxis, although clinically serious, is treatable,” Dr. Shimabukuro said.

At the conclusion of the meeting, FDA panelist Patrick Moore, MD, MPH, from the University of Pittsburgh in Pennsylvania, stressed the need to convey to the public that the COVID vaccines appear so far to be safe. Many people earlier had doubts about how the FDA could both safely and quickly review the applications for EUAs for these products.

“As of February 26, things are looking good. That could change tomorrow,” Dr. Moore said. But “this whole EUA process does seem to have worked, despite my own personal concerns about it.”

No second-class vaccines

The Johnson & Johnson vaccine, known as Ad26.COV2.S, is composed of a recombinant, replication-incompetent human adenovirus type 26 (Ad26) vector. It’s intended to encode a stabilized form of SARS-CoV-2 spike (S) protein. The Pfizer and Moderna vaccines use a different mechanism. They rely on mRNA.

The FDA advisers also discussed how patients might respond to the widely reported gap between Janssen’s topline efficacy rates compared with rivals. They urged against people parsing study details too finely and seeking to pick and choose their shots.

“It’s important that people do not think that one vaccine is better than another,” said FDA adviser H. Cody Meissner, MD, from Tufts University School of Medicine in Boston.

Dr. Monto agreed, noting that many people in the United States are still waiting for their turn to get COVID vaccines because of the limited early supply.

Trying to game the system to get one vaccine instead of another would not be wise. “In this environment, whatever you can get, get,” Dr. Monto said.

During an open public hearing, Sarah Christopherson, policy advocacy director of the National Women’s Health Network, said that press reports are fueling a damaging impression in the public that there are “first and second-class” vaccines.

“That has the potential to exacerbate existing mistrust” in vaccines, she said. “Public health authorities must address these perceptions head on.”

She urged against attempts to compare the Janssen vaccine to others, noting the potential effects of emerging variants of the virus.

“It’s difficult to make an apples-to-apples comparison between vaccines,” she said.

Johnson & Johnson’s efficacy results, which are lower than those of the mRNA vaccines, may be a reflection of the ways in which SARS-Co-V-2 is mutating and thus becoming more of a threat, according to the company. A key study of the new vaccine, involving about 44,000 people, coincided with the emergence of new SARS-CoV-2 variants, which were emerging in some of the countries where the pivotal COV3001 study was being conducted, the company said.

At least 14 days after vaccination, the Johnson & Johnson COVID vaccine efficacy (95% confidence interval) was 72.0% (58.2, 81.7) in the United States, 68.1% (48.8, 80.7) in Brazil, and 64.0% (41.2, 78.7) in South Africa.

Weakened standards?

Several researchers called on the FDA to maintain a critical attitude when assessing Johnson & Johnson’s application for the EUA, warning of a potential for a permanent erosion of agency rules due to hasty action on COVID vaccines.

They raised concerns about the FDA demanding too little in terms of follow-up studies on COVID vaccines and with persisting murkiness resulting in attempts to determine how well these treatments work beyond the initial study period.

“I worry about FDA lowering its approval standards,” said Peter Doshi, PhD, from The BMJ and a faculty member at the University of Maryland School of Medicine in Baltimore, during an open public hearing at the meeting.

“There’s a real urgency to stand back right now and look at the forest here, as well as the trees, and I urge the committee to consider the effects FDA decisions may have on the entire regulatory approval process,” Dr. Doshi said.

Dr. Doshi asked why Johnson & Johnson did not seek a standard full approval — a biologics license application (BLA) — instead of aiming for the lower bar of an EUA. The FDA already has allowed wide distribution of the Pfizer/BioNTech and Moderna vaccines through EUAs. That removes the sense of urgency that FDA faced last year in his view.

The FDA’s June 2020 guidance on the development of COVID vaccines had asked drugmakers to plan on following participants in COVID vaccine trials for “ideally at least one to two years.” Yet people who got placebo in Moderna and Pfizer trials already are being vaccinated, Dr. Doshi said. And Johnson & Johnson said in its presentation to the FDA that if the Ad26.COV2.S vaccine were granted an EUA, the COV3001 study design would be amended to “facilitate cross-over of placebo participants in all participating countries to receive one dose of active study vaccine as fast as operationally feasible.”

“I’m nervous about the prospect of there never being a COVID vaccine that meets the FDA’s approval standard” for a BLA instead of the more limited EUA, Dr. Doshi said.

Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, noted that the FDA’s subsequent guidance tailored for EUAs for COVID vaccines “drastically shortened” the follow-up time to a median of 2 months. Dr. Zuckerman said that a crossover design would be “a reasonable compromise, but only if the placebo group has at least 6 months of data.” Dr. Zuckerman opened her remarks in the open public hearing by saying she had inherited Johnson & Johnson stock, so was speaking at the meeting against her own financial interest.

“As soon as a vaccine is authorized, we start losing the placebo group. If FDA lets that happen, that’s a huge loss for public health and a huge loss of information about how we can all stay safe,” Dr. Zuckerman said.



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

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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

Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.

A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.

Factors linked to higher rates of PTSD included experiencing delirium or agitation during the acute COVID phase or having persistent medical symptoms after hospitalization. 

Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.

“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.

However, data focused specifically on COVID-19 have been “piecemeal,” they add.

The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
 

A traumatic event

From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.

The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.

Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:

• Depressive episodes (17.3%).
• GAD (7%).
• Hypomanic episodes (0.7%).
• Psychotic disorders (0.2%).

Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).

In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).

After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).

The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”

Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.

“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.

Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.

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