George T. Grossberg, MD

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

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

Drug Brand Name

Curcumin • Theracurmin

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

Drug Brand Name

Curcumin • Theracurmin

Clinicians have devoted strenuous efforts to secondary prevention of Alzheimer’s disease (AD) by diagnosing and treating patients as early as possible. Unfortunately, there is no cure for AD, and the field has witnessed recurrent failures of several pharmacotherapy candidates with either symptomatic or disease-modifying properties.¹ An estimated one-third of AD cases can be attributed to modifiable risk factors.² Thus, implementing primary prevention measures by addressing modifiable risk factors thought to contribute to the disease, with the goal of reducing the risk of developing AD, or at least delaying its onset, is a crucial public health strategy.

Cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes, hyperhomocysteinemia, obesity, and smoking, have emerged as substantive risk factors for AD.³ Optimal management of these major risk factors, especially in mid-life, may be a preventive approach against AD. Although detailing the evidence on the impact of managing cardiovascular risk factors to delay or prevent AD is beyond the scope of this article, it is becoming clear that “what is good for the heart is good for the brain.”

Additional modifiable risk factors are related to lifestyle habits, such as physical exercise, mental and social activity, meditation/spiritual activity, and diet. This article reviews the importance of pursuing a healthy lifestyle in delaying AD, with the corresponding levels of evidence that support each specific lifestyle modification. The levels of evidence are defined in Table 1.⁴

Physical exercise

Twenty-one percent of AD cases in the United States are attributable to physical inactivity.⁵ In addition to its beneficial effect on metabolic syndrome, in animal and human research, regular exercise has been shown to have direct neuroprotective effects. High levels of physical activity increase hippocampal neurogenesis and neuroplasticity, increase vascular circulation in the brain regions implicated in AD, and modulate inflammatory mediators as well as brain growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1).⁶

The definition of regular physical exercise varies across the literature, but usually implies aerobic exercise—an ongoing activity sufficient to increase the heart rate and the need for oxygen, sustained for 20 to 30 minutes per session.⁷ Modalities include household activities and leisure-time activities. In a large prospective cohort study, Scarmeas et al⁸ categorized leisure-time activities into 3 types:

• light (walking, dancing, calisthenics, golfing, bowling, gardening, horseback riding)
• moderate (bicycling, swimming, hiking, playing tennis)
• vigorous (aerobic dancing, jogging, playing handball).

These types of physical exercise were weighed by the frequency of participation per week. Compared with being physically inactive, low levels of weekly physical activity (0.1 hours of vigorous, 0.8 hours of moderate, or 1.3 hours of light exercise) were associated with a 29% to 41% lower risk of developing AD, while higher weekly physical activity (1.3 hours of vigorous, 2.3 hours of moderate, or 3.8 hours of light exercise) were associated with a 37% to 50% lower risk (level III).⁸

In another 20-year cohort study, engaging in leisure-time physical activity at least twice a week in mid-life was significantly associated with a reduced risk of AD, after adjusting for age, sex, education, follow-up time, locomotor disorders, apolipoprotein E (ApoE) genotype, vascular disorders, smoking, and alcohol intake (level III).⁹ Moreover, a systematic review of 29 randomized controlled trials (RCTs) showed that aerobic exercise training, such as brisk walking, jogging, and biking, was associated with improvements in attention, processing speed, executive function, and memory among healthy older adults and those with mild cognitive impairment (MCI; level IA).¹⁰

Continue to: From a pathophysiological standpoint...

From a pathophysiological standpoint, higher levels of physical exercise in cognitively intact older adults have been associated with reduced brain amyloid beta deposits, especially in ApoE4 carriers.¹¹ This inverse relationship also has been demonstrated in patients who are presymptomatic who carry 1 of the 3 known autosomal dominant mutations for the familial forms of AD.¹²

Overall, physicians should recommend that patients—especially those with cardiovascular risk factors that increase their risk for AD—exercise regularly by following the guidelines of the American Heart Association or the American College of Sports Medicine.¹³ These include muscle-strengthening activities (legs, hips, back, abdomen, shoulders, and arms) at least 2 days/week, in addition to either 30 minutes/day of moderate-intensity aerobic activity such as brisk walking, 5 days/week; or 25 minutes of vigorous aerobic activity such as jogging and running, 3 days/week¹⁴ (level IA evidence for overall improvement in cognitive function; level III evidence for AD delay/risk reduction). Neuromotor exercise, such as yoga and tai chi, and flexibility exercise such as muscle stretching, especially after a hot bath, 2 to 3 days/week are also recommended (level III).¹⁵

Mental activity

Nineteen percent of AD cases worldwide and 7% in the United States. can be attributed to low educational attainment, which is associated with low brain cognitive reserve.⁵ Cognitive resilience in later life may be enhanced by building brain reserves through intellectual stimulation, which affects neuronal branching and plasticity.¹⁶ Higher levels of complex mental activities measured across the lifespan, such as education, occupation, reading, and writing, are correlated with significantly less hippocampal volume shrinkage over time.¹⁷ Frequent participation in mentally stimulating activities—such as listening to the radio; reading newspapers, magazines, or books; playing games (cards, checkers, crosswords or other puzzles); and visiting museums—was associated with an up to 64% reduction in the odds of developing AD in a cohort of cognitively intact older adults followed for 4 years.¹⁸ The correlation between mental activity and AD was found to be independent of physical activity, social activity, or baseline cognitive function.¹⁹

In a large cohort of cognitively intact older adults (mean age 70), engaging in a mentally stimulating activity (craft activities, computer use, or going to the theater/movies) once to twice a week was significantly associated with a reduced incidence of amnestic MCI.²⁰ Another prospective 21-year study demonstrated a significant reduction in AD risk in community-dwelling cognitively intact older adults (age 75 to 85) who participated in cognitively stimulating activities, such as reading books or newspapers, writing for pleasure, doing crossword puzzles, playing board games or cards, or playing musical instruments, several times/week.²¹

Growing scientific evidence also suggests that lifelong multilingualism can delay AD onset by 4 to 5 years.²² Multilingualism is associated with greater cognitive reserve, gray matter volume, functional connectivity and white matter density.²³

Continue to: Physicians should encourage their patients...

Physicians should encourage their patients to engage in intellectually stimulating activities and creative leisure-time activities several times/week to enhance their cognitive reserves and delay AD onset (level III evidence with respect to AD risk reduction/delay).

Social activity

Social engagement may be an additional protective factor against AD. In a large 4-year prospective study, increased loneliness in cognitively intact older adults doubled the risk of AD.²⁴ Data from the large French cohort PAQUID (Personnes Agées QUID) emphasized the importance of a patient’s social network as a protective factor against AD. In this cohort, the perception of reciprocity in relationships with others (the perception that a person had received more than he or she had given) was associated with a 53% reduction in AD risk (level III).²⁵ In another longitudinal cohort study, social activity was found to decrease the incidence of subjective cognitive decline, which is a prodromal syndrome for MCI and AD (level III).²⁶

A major confounder in studies assessing for social activity is the uncertainty if social withdrawal is a modifiable risk factor or an early manifestation of AD, since apathetic patients with AD tend to be socially withdrawn.²⁷ Another limitation of measuring the impact of social activity relative to AD risk is the difficulty in isolating social activities from activities that have physical and mental activity components, such as leisure-time activities.²⁸

Meditation/spiritual activity

Chronic psychological stress is believed to compromise limbic structures that regulate stress-related behaviors and the memory network, which might explain how being prone to psychological distress may be associated with MCI or AD.²⁹ Cognitive stress may increase the oxidative stress and telomere shortening implicated in the neuro­degenerative processes of AD.³⁰ In one study, participants who were highly prone to psychological distress were found to be at 3 times increased risk for developing AD, after adjusting for depression symptoms and physical and mental activities (level III).³¹ By reducing chronic psychological stress, meditation techniques offer a promising preventive option against AD.

Mindfulness-based interventions (MBI) have gained increased attention in the past decade. They entail directing one’s attention towards the present moment, thereby decreasing ruminative thoughts and stress arousal.³² Recent RCTs have shown that MBI may promote brain health in older adults not only by improving psychological well-being but also by improving attentional control³³ and functional connectivity in brain regions implicated in executive functioning,³⁴ as well as by modulating inflammatory processes implicated in AD.³⁵ Furthermore, an RCT of patients diagnosed with MCI found that compared with memory enhancement training, a weekly 60-minute yoga session improved memory and executive functioning.³⁶

Continue to: Kirtan Kriya is a medication technique...

Kirtan Kriya is a meditation technique that is easy to learn and practice by older adults and can improve memory in patients at risk for developing AD.³⁷ However, more rigorous RCTs conducted in larger samples of older adults are needed to better evaluate the effect of all meditation techniques for delaying or preventing AD (level IB with respect to improvement in cognitive functioning/level III for AD delay/risk reduction).³⁸

Spiritual activities, such as going to places of worship or religious meditation, have been associated with a lower prevalence of AD. Attending religious services, gatherings, or retreats involves a social component because these activities often are practiced in groups. They also confer a method of dealing with psychological distress and depression. Additionally, frequent readings of religious texts represents a mentally stimulating activity that may also contribute to delaying/preventing AD (level III).³⁹

Diet

In the past decade, a growing body of evidence has linked diet to cognition. Individuals with a higher intake of calories and fat are at higher risk for developing AD.⁴⁰ The incidence of AD rose in Japan after the country transitioned to a more Westernized diet.⁴¹ A modern Western diet rich in saturated fatty acids and simple carbohydrates may negatively impact hippocampus-mediated functions such as memory and learning, and is associated with an increased risk of AD.⁴² In contrast with high-glycemic and fatty diets, a “healthy diet” is associated with a decrease in beta-amyloid burden, inflammation, and oxidative stress.^43,44

Studies focusing on dietary patterns rather than a single nutrient for delaying or preventing AD have yielded more robust and consistent results.⁴⁵ In a recent meta-analysis, adhering to a Mediterranean diet—which is rich in fruits and vegetables, whole grains, olive oil, and fish; moderate in some dairy products and wine; and low in red meat—was associated with a decreased risk of AD; this evidence was derived mostly from epidemiologic studies.⁴⁶ Scarmeas et al⁸ found that high adherence to the Mediterranean diet was associated with 32% to 40% reduced risk of AD. Combining this diet with physical exercise was associated with an up to 67% reduced risk (level III). The Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in total grains, fruits, vegetables, and dairy products, but low in sodium and sweets, correlated with neuro­cognitive improvement in patients with hypertension.⁴⁷ Both the Mediterranean and DASH diets have been associated with better cognitive function⁴⁸ and slower cognitive decline.⁴⁹ Thus, an attempt to combine the neuroprotective components from both diets led to the creation of the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet, which also has been associated with a lower incidence of AD.⁵⁰

Besides specific diets, some food groups have also been found to promote brain health and may help delay or prevent AD. Berries have the highest amount of antioxidants of all fruit. Among vegetables, tomatoes and green leafy vegetables have the highest amount of nutrients for the brain. Nuts, such as walnuts, which are rich in omega-3 fatty acids, are also considered “power foods” for the brain; however, they should be consumed in moderation because they are also rich in fat. Monounsaturated fatty acids, which are found in olives and olive oil, are also beneficial for the brain. Among the 3 types of omega-3 fatty acids, the most important for cognition is docosahexaenoic acid (DHA) because it constitutes 40% of all fatty acids in the brain. Mainly found in oily fish, DHA has antioxidant and anti-inflammatory properties that may delay or prevent AD. Low levels of DHA have been found in patients with AD.⁵¹

Continue to: Curcumin, which is derived from...

Curcumin, which is derived from the curry spice turmeric, is a polyphenol with anti-inflammatory, antioxidant, and anti-amyloid properties that may have a promising role in preventing AD in cognitively intact individuals. Initial trials with curcumin have yielded mixed results on cognition, which was partly related to the low solubility and bioavailability of its formulation.⁵² However, a recent 18-month double-blind randomized placebo-controlled trial found positive effects on memory and attention, as well as reduction of amyloid plaques and tau tangles deposition in the brain, in non-demented older adults age 51 to 84 who took Theracumin, a highly absorptive oral form of curcumin dispersed with colloidal nanoparticles.⁵³ A longer follow-up is required to determine if curcumin can delay or prevent AD.

Alcohol

The role of alcohol in AD prevention is controversial. Overall, data from prospective studies has shown that low to moderate alcohol consumption may be associated with a reduced risk of AD (level III).⁵⁴ Alcohol drinking in mid-life showed a U-shaped relationship with cognitive impairment; both abstainers and heavy drinkers had an increased risk of cognitive decline compared with light to moderate drinkers (level III).⁵⁵ Binge drinking significantly increased the odds of cognitive decline, even after controlling for total alcohol consumption per week.⁵⁵

The definition of low-to-moderate drinking varies substantially among countries. In addition, the size and amount of alcohol contained in a standard drink may differ.⁵⁶ According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA),⁵⁷ moderate drinking is defined as up to 1 drink daily for women and 2 drinks daily for men. Binge drinking involves drinking >4 drinks for women and >5 drinks for men, in approximately 2 hours, at least monthly. In the United States, one standard drink contains 14 grams of pure alcohol, which is usually found in 12 ounces of regular beer, 5 ounces of wine, and 1.5 ounces of distilled spirits (vodka or whiskey).⁵⁸

In a 5-year prospective Canadian study, having 1 drink weekly (especially wine) was associated with an up to 50% reduced risk of AD (level III).⁵⁹ In the French cohort PAQUID, mild drinkers (<1 to 2 drinks/day) and moderate drinkers (3 to 4 drinks daily) had a reduced incidence of AD compared with non-drinkers. Wine was the most frequently consumed beverage in this study.⁶⁰ Other studies have found cognitive benefits from mild to moderate drinking regardless of beverage type.⁵⁴ However, a recent study that included a 30-year follow-up failed to find a significant protective effect of light drinking over abstinence in terms of hippocampal atrophy.⁶¹ Atrophy of the hippocampus was correlated with increasing alcohol amounts in a dose-dependent manner, starting at 7 to 14 drinks/week (level III).⁶¹

Research has shown that moderate and heavy alcohol use or misuse can directly induce microglial activation and inflammatory mediators’ release, which induce amyloid beta pathology and leads to brain atrophy.⁶² Hence, non-drinkers should not be advised to begin drinking, because of the lack of RCTs and the concern that beginning to drink may lead to heavy drinking. All drinkers should be advised to adhere to the NIAAA recommendations.¹³

Continue to: Coffee/tea

Although studies of caffeinated coffee have been heterogeneous and yielded mixed results (beneficial effect vs no effect on delaying cognitive decline), systematic reviews and meta-analyses of cross-sectional, case-control, and longitudinal cohort studies have found a general trend towards a favorable preventive role (level III).^63-65 Caffeine exhibits its neuroprotective effect by increasing brain serotonin and acetylcholine, and by stabilizing blood-brain-barrier integrity.⁶⁶ Moreover, in an animal study, mice given caffeine in their drinking water from young adulthood into older age had lower amyloid beta plasma levels compared with those given decaffeinated water.⁶⁷ These findings suggest that in humans, 5 cups of regular caffeinated coffee daily, equivalent to 500 mg of caffeine, could be protective against cognitive impairment. Other caffeinated beverages, such as tea or soft drinks, contain up to 4 times less caffeine per serving; many more servings would therefore be required to reach the target amount of 500 mg/d of caffeine.⁶⁷ Data from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study demonstrate a 65% reduced risk of dementia/AD in individuals who consumed 3 to 5 cups of regular coffee daily in mid-life.⁶⁸

An Italian study showed that older adults who don’t or rarely drink coffee (<1 cup daily) and those who recently increased their consumption pattern to >1 cup daily had a higher incidence of MCI than those who habitually consumed 1 to 2 cups daily.⁶⁹ Therefore, it is not recommended to advise a change in coffee drinking pattern in old age. Older adults who are coffee drinkers should, however, be educated about the association between heavier caffeine intake and anxiety, insomnia, and cardiac arrhythmias.⁷⁰

Despite its more modest caffeine levels, green tea is rich in polyphenols, which belong to the family of catechins and are characterized by antioxidant and anti-inflammatory properties.⁷¹ In a Japanese cohort, higher green tea consumption (up to 1 cup daily) was associated with a decreased incidence of MCI in older adults.⁷² More studies are needed to confirm its potential preventative role in AD.

Which lifestyle change is the most important?

Focusing on a single lifestyle change may be insufficient, especially because the bulk of evidence for individual interventions comes from population-based cohort studies (level III), rather than strong RCTs with a long follow-up. There is increasing evidence that combining multiple lifestyle modifications may yield better outcomes in maintaining or improving cognition.⁷³

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a large, 2-year RCT that included community-dwelling older adults (age 60 to 77) with no diagnosis of major neurocognitive disorder, found that compared with regular health advice, multi-domain interventions reduced cognitive decline and improved overall cognition, executive functioning, and processing speed. The interventions evaluated in this study combined the following 4 modalities⁷⁴:

• a healthy diet according to the Finnish nutrition recommendations (eating vegetables, fruits, and berries [minimum: 500 g/d], whole grain cereals [several times a day], and fish [2 to 3 times/week]; using low-salt products; consuming fat-free or low-fat milk products; and limiting red meat consumption to <500 g/week
• regular physical exercise tailored for improving muscle strength (1 to 3 times/week) coupled with aerobic exercise (2 to 5 times/week)
• cognitive training, including group sessions that have a social activity component and computer-based individual sessions 3 times/week that target episodic and working memory and executive functioning
• optimal management of cardiovascular risk factors.

Continue to: This multi-domain approach...

This multi-domain approach for lifestyle modification should be strongly recommended to cognitively intact older patients (level IB).

Modeled after the FINGER study, the Alzheimer’s Association U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is a 2-year, multicenter, controlled clinical trial aimed at testing the ability of a multi­dimensional lifestyle intervention to prevent AD in at-risk older adults (age 60 to 79, with established metabolic and cardiovascular risk factors). Interventions include a combination of physical exercise, nutritional counseling and management, cognitive and social stimulation, and improved management of cardiovascular risk factors. Recruitment for this large-scale trial was estimated to begin in January 2019 (NCT03688126).⁷⁵

On a practical basis, Desai et al¹³ have proposed a checklist (Table 2¹³) that physicians can use in their routine consultations to improve primary prevention of AD among their older patients.

Bottom Line

Advise patients that pursuing a healthy lifestyle is a key to delaying or preventing Alzheimer’s disease. This involves managing cardiovascular risk factors and a combination of staying physically, mentally, socially, and spiritually active, in addition to adhering to a healthy diet such as the Mediterranean diet.

Related Resources

• Anderson K, Grossberg GT. Brain games to slow cognitive decline in Alzheimer’s disease. J Am Med Dir Assoc. 2014;15(8):536-537.
• Small G, Vorgan G. The memory prescription: Dr. Garry Small’s 14-day plan to keep your brain and body young. New York, NY: Hyperion; 2004.
• Small G, Vorgan G. The Alzheimer’s prevention program; keep your brain healthy for the rest of your life. New York, NY: Workman Publishing Company, Inc.; 2012.

Drug Brand Name

Curcumin • Theracurmin

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

Long-term care (LTC) services provide health care to >8 million people in approximately 30,000 nursing homes and assisted living/residential care communities in the United States.¹ One-half of older adults in LTC have neurocognitive disorders (NCDs), and one-third have depressive syndromes.² Common reasons for psychiatric consultation include these 2 major diagnoses, as well as delirium, behavioral and psychological symptoms of dementia (BPSD), bipolar disorder, anxiety, sleep disorders, and pain management.

Psychiatric assessment of individuals in LTC can be challenging because of atypical presentations, cognitive impairment, and multiple comorbidities. Establishing a management plan involves eliciting a careful history from both the patient and caretakers, examining previous records and medications, and selecting appropriate screening tools and laboratory tests (Table 1 and Table 2).

• assessment tools for psychiatric symptoms in LTC
• potentially inappropriate medication use in older adults
• antipsychotic use for agitation and psychosis with dementia
• nonpharmacologic interventions to help prevent cognitive decline
• antipsychotic review in reducing antipsychotic use and mortality.

Delirium

Delirium is an important topic in LTC because it is highly prevalent, poorly recognized, and can be difficult to manage. Common causes of delirium in LTC include infection (often urinary), dehydration, medications, long-standing constipation, and urinary retention (Table 3).³ Early recognition is key because delirium has been associated with cognitive decline, decreased functional status, increased caregiver burden, and increased mortality.^4,5

The Confusion Assessment Method (CAM) is a quick tool with 4 features to differentiate delirium from other forms of cognitive impairment.⁶ The 2 core features are an acute change or fluctuating course of mental status and inattention. Family members or caregivers can provide information about an acute change. To assess inattention, ask the patient to say the days of the week backward or spell the word “world” backward. The 2 other features of delirium—one of which must be present when using the CAM—are disorganized thinking and altered level of consciousness.

Individuals with delirium may present with hyperactive or hypoactive psychomotor activity. Hypoactive delirium’s features, such as sluggishness and lethargy, could be confused with depression.⁷ A careful history to determine symptom onset and fluctuation in course can help differentiate between the 2.

Management. Delirium management always should begin by addressing underlying causes and implementing psychosocial and environmental interventions. Pharmacologic interventions have not demonstrated consistent benefit for delirium in well-designed trials and are not recommended as first-line treatment.⁸ The American Geriatrics Society (AGS) Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines in this population.⁹ Antipsychotics could be used in patients with severe agitation who pose harm to themselves or others. Nonpharmacologic approaches to delirium in LTC include:

• frequent reorientation (clocks, daily schedule)
• one-on-one monitoring by staff or family members
• use of hearing aids and eye-glasses, if needed
• maintaining an appropriate sleep-wake cycle by encouraging exposure to bright light during the day and avoiding night-time interruptions.

Restraints should not be used; they appear to worsen delirium severity, and their removal does not increase the rate of falls or fall-related injury.¹⁰

Various methods for managing a patient with delirium have been proposed, such as the TADA approach (tolerate, anticipate, and don’t agitate).^5,11,12 For example, if a patient’s agitation worsens with attempted reorientation, distraction or playing along with the disorientation could be more beneficial.¹²

Keep in mind delirium’s overlapping presentation with Lewy body dementia (LBD). Patients with LBD demonstrate a progressive decline in cognitive functioning associated with fluctuating cognition, visual hallucinations, and parkinsonism features. Consider LBD when no cause for delirium-like symptoms is found. These patients may show increased sensitivity to neuroleptics and extrapyramidal side effects.

Neurocognitive disorders

Reversible causes. Although most individuals with major NCDs are diagnosed before entering LTC, the consulting psychiatrist’s review of potentially reversible causes of neurocognitive symptoms can lead to dramatically different treatment regimens (Table 4³). For example, anticholinergic medications can harm the aging brain and have been linked to delirium, increased brain atrophy, and lower scores on tests of cognitive functioning.¹³ Given the prevalence of polypharmacy in older adults, be aware of unexpected anticholinergic properties of many common drugs, as rated by the Aging Brain Care initiative.¹⁴

The randomized, double-blind Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability provides convincing data that a nonpharmacologic approach could benefit older adults at risk for a major NCD. A 2-year intervention of nutritional advice, aerobic and strength training, cognitive training, social activities, and blood pressure and weight monitoring was more effective in improving or maintaining cognitive function in individuals age 60 to 77, compared with general health advice given to a control group.¹⁵

Behavioral and psychological symptoms. Psychiatrists are likely to be consulted in LTC when a person with a major NCD presents with an acute episode of increased confusion and cognitive worsening, often accompanied by behavioral symptoms. BPSD may include agitation, aggression, apathy, depression, sleep problems, socially inappropriate behaviors, and psychosis. One study of patients with Alzheimer’s disease (AD) reported a cumulative 51% incidence of new-onset hallucinations and delusions at 4 years.¹⁶

Increased vulnerability to stressors, unmet needs, over- or under-stimulation, or lack of routines may predispose individuals with major NCDs to developing BPSD.¹⁷ Nonpharmacologic approaches usually are tried first, although supporting evidence is not substantial.¹⁸ Changes in environment, behavioral redirection, sensory interventions, or music therapy may reduce disruptive behaviors.¹⁹ Patients with increased confusion and agitation in late afternoon and evening (“sundowning”) may benefit from short naps after lunch, light therapy, calming activities in late afternoon, and reduced noise (such as from dishes, loud speakers, staff conversations).²⁰

Antipsychotics. The drugs most commonly used to manage BPSD are antipsychotics, antidepressants, mood stabilizers/anticonvulsants, ChEIs, and the N-methyl-d-aspartate receptor antagonist memantine. Antipsychotics often are used despite their uncertain efficacy²¹ and serious safety concerns. Atypical antipsychotics are generally preferred for their side effect profiles, but both atypical and typical classes carry a “black-box” warning of increased risk of mortality in older patients with major NCDs. Other potential adverse events include anticholinergic effects, orthostatic hypotension, prolonged QT interval, and extrapyramidal symptoms (EPS).

When nonpharmacotherapeutic interventions are not successful, most guidelines agree that using an atypical antipsychotic is warranted in AD patients with severe agitation and/or psychosis that pose a risk to the patient or others or severely impair their quality of life.^9,22,23

Antipsychotic review. Recent guidelines from the American Psychiatric Association (APA) recommend that attempts to taper and withdraw antipsychotic drugs be made within 4 months of initiating treatment in patients with dementia who display an adequate response.²³ In a recent nursing home study, antipsychotic review was found to reduce antipsychotic use by 50% and, when combined with a social intervention, to reduce mortality compared with a group receiving neither intervention.²⁴

Interestingly, patients receiving antipsychotic review alone showed an increase in overall neuropsychiatric symptoms.²⁴ A previous study of patients with AD whose psychosis or agitation responded to risperidone also found an increased risk of relapse when risperidone was discontinued.²⁵ These results highlight the importance of making patient-centered decisions, frequent re-assessments, and adding non-pharmacologic interventions (eg, positive social interactions or exercise) when attempting to discontinue antipsychotics.

Other treatment options. Because patients with LBD often display increased sensitivity to neuroleptics, agents such as quetiapine or aripiprazole (with a lower risk of EPS) are preferred when managing severe psychosis/aggression. ChEIs may show some benefit for behavioral disturbances in patients with LBD.²⁶

In patients with AD, ChEIs have shown inconsistent results in benefiting neuropsychiatric symptoms. Preliminary data suggest some benefit with citalopram (also associated with prolonged QTc)²⁷ and the dextromethorphan/quinidine combination FDA-approved for pseudobulbar affect, but more studies are needed.²⁸ Pimavanserin, a 5-HT2A receptor inverse agonist, recently was approved for treating hallucinations and delusions associated with Parkinson’s disease psychosis and currently is in clinical trials for Alzheimer’s disease psychosis.

Electroconvulsive therapy (ECT) may be a therapeutic option for agitation and aggression in people with dementia.²⁹ ECT has no absolute contraindications and can be safely performed in individuals with pacemakers or implantable cardioverter defibrillators. Common adverse effects include transient changes in blood pressure or heart rate, headache, and nausea. Cognitive adverse effects from ECT may include:

• anterograde amnesia, which typically resolves after a few weeks
• retrograde amnesia, which typically manifests as loss of impersonal memories occurring in the past few months.

Depression

The prevalence of depression in nursing home residents is an estimated 3 to 4 times that of community-dwelling older adults.³⁰ Assessing for depression is particularly important in people with mild cognitive impairment, as depressive symptoms have been associated with progression to AD.³¹ Quick screening tools (Table 2) include short forms of the Patient Health Questionnaire (PHQ-2 or PHQ-9)³² or the Saint Louis University Appetite, Mood, Sleep, Activity, and thoughts of Death (SLU “AM SAD”) scale.³³ The Cornell Scale for Depression in Dementia is useful for individuals with major NCDs because it relies on interviews with the patient and nursing staff or family.³⁴

To test for other causes of depression, order a complete blood count for anemia, serum glucose, thyroid-stimulating hormone for hypothyroidism or hyperthyroidism, B12 and folate levels, and a cognitive screen such as the Saint Louis University Mental Status examination.³⁵

Treatment. Antidepressants are generally considered effective in older patients with depression. Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments because of safety concerns with tricyclic antidepressants. All 3 classes have shown similar efficacy in comparison trials in geriatric populations.

When initiating these agents, take care in the first few days and weeks to monitor for potential serious adverse effects, such as nausea and vomiting, which may be associated with substantial morbidity in patients with comorbidities. For monitoring treatment response, the PHQ-9 can effectively distinguish patients with persistent major depression, partial remission, or full remission.³⁶

The optimal duration of a short-term antidepressant trial before switching to a different agent is unclear, although a good therapeutic trial typically is 4 to 12 weeks. In one study of older adults with depression, 4 weeks was enough to reliably identify those likely to benefit from a change in treatment plan.³⁷

Cognitive-behavioral therapy (CBT) can be used in older adults not wishing to pursue pharmacotherapy or as an adjunct to antidepressants. Randomized controlled trials have shown some benefit for those with depression, anxiety, and insomnia.³⁸ Individuals with significant cognitive deficits or those not motivated to apply CBT strategies might not benefit.

ECT may be appropriate for treating depression in older adults with:

• urgent need of a therapeutic response (eg, suicidal ideation or nutritional compromise)
• lack of response to antidepressant medication
• major depressive disorder with psychotic or catatonic features.

Evidence regarding ECT’s efficacy for late-life depression is derived primarily from clinical experience and open-label trials.³⁹

Bipolar disorder

Most individuals with bipolar disorder present before age 50, although 9% of first manic episodes occur after age 60.⁴⁰ Earlier age of onset appears to predict poor outcomes, and early-onset bipolar disorder may worsen with advanced age related to increased comorbidities and difficulty in medical management.⁴¹ Compared with younger patients, features of bipolar disorder in older adults include increased prominence of rapid cycling, more time spent in a depressed state than in manic state, and less severe manic and psychotic symptoms.⁴²

When older patients present with depression, always evaluate for clinical features more consistent with late-onset bipolar disorder than with major depressive disorder: hypomania, family history of bipolar disorder, higher number of prior depressive episodes, and higher levels of fear and inner tension.⁴³ The differential diagnosis for new-onset manic symptoms in older adults includes:

• general medical conditions (stroke, brain tumors, hyperthyroidism, neurosyphilis)
• medications (corticosteroids, dopaminergic drugs, St. John’s wort)
• substance use.

Hyperthyroidism deserves special attention because it can present in older adults with either manic-like symptoms and hyperkinesis or features of apathy, depression, and somnolence. Given that older age and bipolar disorder both are associated with increased suicide risk, monitor these individuals for signs of hopelessness and statements of suicide.⁴⁴

Treatment. Managing bipolar disorder in older adults often requires complex medication regimens. Acute treatment options for geriatric mania and hypomania with the most supporting evidence include lithium, valproate, quetiapine, and olanzapine.^45-47 The therapeutic index of lithium is small, and older individuals are more vulnerable to adverse effects related to physiologic changes (eg, decreased glomerular filtration rate or low volume of distribution) that impair lithium clearance. Lithium also interacts with many drugs commonly used by older patients, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics. Common adverse events associated with lithium include memory impairment, diarrhea, falls, and tremors.

Maintenance treatment for bipolar disorder is generally the same medication used to induce remission. The evidence for maintenance treatment of bipolar disorder in older adults is limited mostly to subgroup analyses. In one retrospective analysis of patients age ≥55 in 2 randomized trials, lamotrigine and lithium were effective and well-tolerated in delaying time to intervention.⁴⁸

Anxiety disorders

Anxiety among LTC residents may manifest as irritability, insomnia, restlessness, and verbal and/or physical agitation/aggression.⁴⁹ Typical causes include:

• primary anxiety disorders
• anxiety symptoms during depressive episodes or bereavement
• adverse effects of medications
• complications of major NCDs or delirium.

Anxiety disorders and subsyndromal anxiety have been associated with poorer quality of life, decreased sleep, and increased distress and impairment.⁵⁰

Assessment begins with a self-report of symptoms, although this may be difficult in people with major NCDs. Factors that may differentiate true anxiety from major NCDs include restlessness, irritability, muscle tension, fears, and respiratory symptoms in addition to excessive anxiety and worry.⁵¹ The Geriatric Anxiety Inventory is a useful screening tool.⁵² The newer Brief Anxiety and Depression Scale may identify and differentiate patients with major depressive episodes and generalized anxiety disorder (GAD).⁵³ Potential instruments for patients with comorbid anxiety and major NCDs include the Neuropsychiatric Inventory, Rating Anxiety in Dementia scale,⁵⁴ and the Anxiety in Cognitive Impairment and Dementia scale.⁵⁵ Because medications can cause akathisia that may mimic anxiety symptoms, screen for the recent addition of antidepressants, antipsychotics, sympathomimetics, thyroid supplements, and corticosteroids.

Treatment of anxiety disorders—such as panic disorder, social phobia, or GAD—generally starts with SSRIs or SNRIs. Although benzodiazepines are commonly used for anxiety in older adults,⁵⁶ these drugs are associated with a high rate of adverse effects: increased risk of agitation, falls, impaired cognition, and possibly dementia.⁵⁷ In general, reserve benzodiazepines for treating acute episodes of severe anxiety in this population.

A particularly prevalent source of anxiety in LTC is fear of falling, which may affect up to 50% of residents and cause them to restrict their activities.⁵⁸ Interventions such as CBT, exercise, or tai chi may be beneficial, although supporting evidence is lacking.

Pain and sleep management

Addressing pain. Age-related changes in pain perception and difficulty in reporting pain likely contribute to under-recognition of pain in LTC residents. Two useful methods to recognize their pain are to:

• observe for pain behaviors, such as facial expressions (grimacing and brow lowering), vocalizations, and body movements (clenched fists)
• solicit reports from nurses and other caregivers.⁵⁹

Self-report may be a reliable indicator of pain for individuals with mild-to-moderate NCDs. Observational pain scales, such as the Pain Assessment Checklist for Seniors with Limited Ability to Communicate, may be useful in severe NCDs.⁶⁰

The AGS recommends acetaminophen as initial pharmacotherapy to manage persistent pain.⁶¹ NSAIDs may be another option, but caution is warranted for patients with acid-peptic disease or chronic kidney disease. Opioids may be considered for severe pain, but otherwise avoid using them.

Sleep disturbances are common in LTC because of physiologic changes associated with aging (altered circadian rhythm), comorbidities (depression), and environmental factors.⁶² A strong association appears to exist between insomnia and use of sedative-hypnotic drugs, and the AGS Beers Criteria recommend avoiding non-benzodiazepine receptor agonists and benzodiazepines when treating insomnia in older adults.⁹

Assess factors that may contribute to sleep disturbances, including medications and use of caffeine or alcohol. Have the resident or caregiver document sleep patterns in a sleep diary.

Consider administrating medications at different times (eg, switch donepezil from bedtime to morning) or replace with alternatives (switch from the more anticholinergic amitriptyline to nortriptyline). Ensure that residents engage in physical activity and have at least 30 minutes daily exposure to sunlight.

In addition to behavioral interventions and CBT, treatment in older adults can involve melatonin—which has mixed evidence—or sedating antidepressants, such as mirtazapine or trazodone, in patients with comorbid depression.

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.

The National Football League (NFL) had its highest concussion tally last year: 182 such injuries reported¹ in the 2014-2015 regular season. The true rate of concussion in the NFL is likely higher, as a result of multiple factors (fear of “letting the team [or the coach] down,” fear of retaliation from team owners,² etc.).

To simply call a head injury a “concussion” is a disservice to players and their family: Any blow to the head, severe or otherwise, has the potential to cause microvascular disruption in the brain; repeated blows to the head undoubtedly cause further damage.

In reality, a “concussion” is a mild traumatic brain injury (mTBI). With repeated blows, an mTBI can lead to chronic traumatic encephalopathy (CTE). In 2015, eighty-seven of 91 brains from autopsied former NFL players displayed some stage of CTE.³

Pathophysiology and presentation
CTE comprises 4 histological stages; Stage 4 is the most advanced. Alzheimer’s disease (AD) and CTE display similarities, which suggests a separate classification of CTE-AD; the presence of amyloid β plaques correlates with (1) more severe hyperphosphorylated tau (pTau) pathology and (2) advanced stages of the disease and clinical presentations. Death tends to occur 10 years earlier in CTE-AD than in AD, suggesting that repetitive mTBI might change the deposition and accumulation of amyloid β plaques, and even accelerate the aging process in the brain.⁴

Symptoms. The case series by Omalu et al⁴ (which inspired the 2015 motion picture Concussion) and the case series presented by McKee et al⁵ described severe psychiatric symptoms associated with CTE:

• decreased speed of information processing
• increase in religiosity
• lack of insight
• poor judgment
• involvement in illegal activities
• substance abuse
• indiscretion
• verbal and physical abuse
• problems with interpersonal relationships
• isolation
• restlessness and hyperactivity
• somatic complaints.

The 2 groups of researchers also noted hopelessness, social phobia, anxiety, agitation, mania, labile mood, insomnia, explosivity, and suicidal ideation, attempt, and completion.^4,5

By Stage 4, all affected patients are symptomatic. Cognitive impairment is severe; many are described as having “severe memory loss with dementia,”⁵ “profound” inattention and loss of concentration,⁵ and dysarthria. Paranoia may develop. Mood symptoms can be severe: Approximately 31% of subjects studied have contemplated suicide; of those, 26% had “suicidal tendencies” and 14% completed suicide.⁵

Two distinct types of CTE progression are apparent:

• patients who display cognitive deficits first; they progress to dementia but live longer
• patients who display mood and behavioral symptoms first; they tend to be younger, more violent, depressed, and explosive.⁶

CTE cannot be diagnosed with imaging. There are, however, a few positron emission tomography (PET) ligands for pTau that show promise:

• [F-18]FDDNP, which consistently identifies pTau deposits in brains in which CTE is clinically suspected, in the same distribution of pTau neurofibrillary tangles on autopsy.
• [11C]DPA-713, which detected TBI-related inflammation of neurons in 9 former NFL players in whom CTE was suspected based on the clinical presentation.
• PiB amyloid ligand, under investigation for use in PET neuroimaging.⁷

Casualties
In January 2016 alone, at least 3 former NFL players were found to have CTE posthumously.

Earl Morrall. Former quarterback who had a 21-year NFL career. Official cause of death in 2014 at age 79 was recorded as “complications of Parkinson’s disease.” In 2016, Stage-4 CTE was discovered on autopsy.⁸

Ken Stabler. Former quarterback for several NFL teams over 15 seasons. Died of colon cancer at age 69 in 2015. On autopsy, was found to have Stage-3 CTE.⁹

Tyler Sash. Former University of Iowa and New York Giants football player. Died in September 2015 at age 27 of an apparent drug overdose; post­humously, determined to have Stage-2 CTE. His family reported memory loss, minor fits of rage, confusion, inattention, lack of focus, and chronic pain.

Sash’s mother said, “My son knew something was wrong, but he couldn’t express it. He was such a good person, and it’s sad that he struggled so with this—not knowing where to go with it. Now it makes sense.”¹⁰ Sash played 16 years of football in all, sustaining at least 5 concussions. (“If you’ve played football, you know there are often other incidents [of head trauma],” Sash’s father said.¹⁰)

Cultural and medical mindsets about contact sports
In the United States, children as young as age 5, with a low weight limit of 35 pounds, routinely are introduced to football.¹¹ Reports of 5 high school players dying from football-related injury in the 2014 season, and 3 deaths in the 2015 season, led a St. Louis, Missouri, area school district to defund their football program entirely. The district’s 2015 homecoming game was a soccer match; students and parents seemed to embrace the change.¹²

On its face, soccer seems a good alternative to football. When children are instructed to “head” the ball, however, concern arises about CTE: Mild CTE changes have been reported in 2 young soccer players, and late-stage CTE changes were seen in a retired soccer player with dementia.¹³

Perhaps most disturbing is that players who develop symptoms of CTE, or are at risk, are unlikely to seek psychiatric help. We, as psychiatric clinicians, must be diligent about questioning young patients about their extracurricular activities. It is not enough to simply ask about a history of head trauma: Ask patients about any blow to the head, and don’t limit your questioning to whether they sustained a “concussion” during practice or play.

When speaking with adult and geriatric patients, ask about a history of playing interscholastic or collegiate contact sports, such as football, hockey, and soccer.

Is the solution to better shield the head?
That is not a solution: Helmets and other protective headgear appear to be insufficient to protect the brain from traumatic injury. Perhaps keeping children from engaging in violent sports that put them at high risk of CTE later is the preventive approach that merits the most attention.