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

 

 

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

 

 

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

 

 

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

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

 

 

Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

 

 

Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

 

 

Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

Primary intestinal lymphangiectasia

Histologic examination shows chronic inflammation of the ileum characterized by increased lymphoplasma cell infiltration of lamina propria without malignancy. Moreover, marked dilatation of lymphatic ducts that involved the mucosa was identified (Figure F, arrows; stain: hematoxylin and eosin; original magnification, ×100). On the basis of pathologic examinations, a diagnosis of primary intestinal lymphangiectasia (PIL) was made.

AGA Institute

PIL is an extremely rare cause of protein-losing enteropathy characterized by the presence of dilated lymphatic channels in the mucosa, submucosa, or subserosa leading to protein-losing enteropathy.¹ The true incidence and prevalence of this disease remains unclear. The disease affects males and females equally, and usually occurs in children and young adults. To date, less than 200 cases of PIL have been reported in the literature. The clinical manifestations of PIL may be asymptomatic or symptomatic such as abdominal pain, edema, diarrhea, and dyspnea. The diagnosis is based on the typical endoscopic findings of diffuse scattered mucosal white blebs with characteristic histologic findings of abnormal lymphatic dilatation. Double-balloon enteroscopy and capsule endoscopy are powerful modalities to evaluate the entire affected area of PIL.² Although diet modification is a major treatment of PIL, several medicines have been reported to be useful such as corticosteroids, octreotide, and antiplasmin.³ Moreover, in patients with segmental lesions, surgery with local bowel resection is a useful treatment.³ In addition, PIL had a 5% risk of malignant transformation into lymphoma.³
 

References

1. Waldmann TA, Steinfeld JL, Dutcher TF, et al. The role of the gastrointestinal system in “idiopathic hypoproteinemia.” Gastroenterology. 1961;41:197-207.

2. Oh TG, Chung JW, Kim HM, et al. Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy. World J Gastrointest Endosc. 2011;3:235-40.

3. Wen J, Tang Q, Wu, J. Primary intestinal lymphangiectasia: four case reports and a review of the literature. Dig Dis Sci. 2010;55:3466-72.

Primary intestinal lymphangiectasia

Histologic examination shows chronic inflammation of the ileum characterized by increased lymphoplasma cell infiltration of lamina propria without malignancy. Moreover, marked dilatation of lymphatic ducts that involved the mucosa was identified (Figure F, arrows; stain: hematoxylin and eosin; original magnification, ×100). On the basis of pathologic examinations, a diagnosis of primary intestinal lymphangiectasia (PIL) was made.

AGA Institute

PIL is an extremely rare cause of protein-losing enteropathy characterized by the presence of dilated lymphatic channels in the mucosa, submucosa, or subserosa leading to protein-losing enteropathy.¹ The true incidence and prevalence of this disease remains unclear. The disease affects males and females equally, and usually occurs in children and young adults. To date, less than 200 cases of PIL have been reported in the literature. The clinical manifestations of PIL may be asymptomatic or symptomatic such as abdominal pain, edema, diarrhea, and dyspnea. The diagnosis is based on the typical endoscopic findings of diffuse scattered mucosal white blebs with characteristic histologic findings of abnormal lymphatic dilatation. Double-balloon enteroscopy and capsule endoscopy are powerful modalities to evaluate the entire affected area of PIL.² Although diet modification is a major treatment of PIL, several medicines have been reported to be useful such as corticosteroids, octreotide, and antiplasmin.³ Moreover, in patients with segmental lesions, surgery with local bowel resection is a useful treatment.³ In addition, PIL had a 5% risk of malignant transformation into lymphoma.³
 

References

1. Waldmann TA, Steinfeld JL, Dutcher TF, et al. The role of the gastrointestinal system in “idiopathic hypoproteinemia.” Gastroenterology. 1961;41:197-207.

2. Oh TG, Chung JW, Kim HM, et al. Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy. World J Gastrointest Endosc. 2011;3:235-40.

3. Wen J, Tang Q, Wu, J. Primary intestinal lymphangiectasia: four case reports and a review of the literature. Dig Dis Sci. 2010;55:3466-72.

Primary intestinal lymphangiectasia

Histologic examination shows chronic inflammation of the ileum characterized by increased lymphoplasma cell infiltration of lamina propria without malignancy. Moreover, marked dilatation of lymphatic ducts that involved the mucosa was identified (Figure F, arrows; stain: hematoxylin and eosin; original magnification, ×100). On the basis of pathologic examinations, a diagnosis of primary intestinal lymphangiectasia (PIL) was made.

AGA Institute

PIL is an extremely rare cause of protein-losing enteropathy characterized by the presence of dilated lymphatic channels in the mucosa, submucosa, or subserosa leading to protein-losing enteropathy.¹ The true incidence and prevalence of this disease remains unclear. The disease affects males and females equally, and usually occurs in children and young adults. To date, less than 200 cases of PIL have been reported in the literature. The clinical manifestations of PIL may be asymptomatic or symptomatic such as abdominal pain, edema, diarrhea, and dyspnea. The diagnosis is based on the typical endoscopic findings of diffuse scattered mucosal white blebs with characteristic histologic findings of abnormal lymphatic dilatation. Double-balloon enteroscopy and capsule endoscopy are powerful modalities to evaluate the entire affected area of PIL.² Although diet modification is a major treatment of PIL, several medicines have been reported to be useful such as corticosteroids, octreotide, and antiplasmin.³ Moreover, in patients with segmental lesions, surgery with local bowel resection is a useful treatment.³ In addition, PIL had a 5% risk of malignant transformation into lymphoma.³
 

References

1. Waldmann TA, Steinfeld JL, Dutcher TF, et al. The role of the gastrointestinal system in “idiopathic hypoproteinemia.” Gastroenterology. 1961;41:197-207.

2. Oh TG, Chung JW, Kim HM, et al. Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy. World J Gastrointest Endosc. 2011;3:235-40.

3. Wen J, Tang Q, Wu, J. Primary intestinal lymphangiectasia: four case reports and a review of the literature. Dig Dis Sci. 2010;55:3466-72.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

A new clinical practice update recommends combination therapy with tumor necrosis factor (TNF) inhibitors and thiopurines, as opposed to either therapy alone, for the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). The commentary was published in Gastroenterology.

Clinicians should also note that while several clinical trials use weight-based dosing to monitor clinical response following thiopurine therapy, 6-thioguanine levels have inevitably shown to better predict prognosis, wrote Stephen B. Hanauer, MD, AGAF, of Northwestern University in Chicago and his colleagues.

The thiopurine drug class is composed of many different agents, including thioguanine, azathioprine, and mercaptopurine. Methotrexate, a folate antagonist affecting thymidylate production, is commonly used alongside thiopurines as steroid-sparing agents for patients with UC and CD. Among these therapies, various different dosing strategies and routes of administration are used to manage active disease.

Initially, thiopurines were studied exclusively as monotherapy for the treatment of patients with steroid-intractable CD; however, results showed only marginal benefit when using these agents alone. As a result, combination trials were performed subsequently, and these revealed modest efficacy for use as maintenance therapies in both UC and CD. Further studies reported that methotrexate is beneficial only as a maintenance therapy for CD given that trial evidence confirmed treatment limitations in patients with UC.

“Thiopurines also have the potential to reduce postoperative recurrence of Crohn’s disease, in particular when administered with imidazole antibiotics,” the experts wrote. “There is currently no controlled data regarding the efficacy of methotrexate as maintenance therapy in ulcerative colitis,” they added.

Despite its limitations in UC, 25 mg of methotrexate administered intramuscularly once weekly in combination with oral steroids has shown benefits for inducing disease remission and limiting steroid use in the management of active CD. Comparatively, other trials have failed to show the same benefits with oral methotrexate. In addition, a number of clinical case series have reported benefit for use of methotrexate as a maintenance therapy for CD in patients who initially responded to methotrexate induction therapy.

Consequently, Dr. Hanauer and his colleagues recommended that methotrexate only be given in combination with biologics if being used for the treatment of UC.

“Thiopurines and methotrexate can be used in combination with anti-TNF biologics, in particular infliximab, to reduce immunogenicity and increase blood levels,” they stated.

One agent in particular, thioguanine, exhibits unique therapeutic efficacy in patients allergic to azathioprine or mercaptopurine. Despite this benefit, thioguanine use has been linked with an increased risk of developing hepatic nodular regenerative hyperplasia, as well as venoocclusive disease. Given these limitations, long-term use of thioguanine was not recommended by the authors.

With respect to safety, routine laboratory monitoring for both liver and hematologic adverse effects is recommended. In rare cases, patients may develop secondary lymphomas in response to thiopurine treatment. Moreover, regular follow-up is essential because of the higher prevalence of nonmelanoma skin cancers seen with thiopurines use.

“Patients using thiopurines for the treatment of IBD, particularly Caucasian patients, should avoid excessive sun exposure and use high-strength sun block,” the experts wrote. “Health care deliverers should ensure patients undergo appropriate dermatologic evaluations and investigate suspicious skin lesions in these patients,” they further reported.

Another important monitoring consideration is ongoing infection risk, in particular with opportunistic and viral pathogens. Because of the immunosuppressive effects of therapy, both methotrexate and thiopurine use are linked with a greater chance of developing these infections. Accordingly, Dr. Hanauer and his colleagues recommended that, before initiation of these therapies, applicable preventative measures should be taken, including administration of influenza, human papillomavirus, varicella zoster virus, pneumococcus, and hepatitis B vaccines.

“Live vaccines are contraindicated once therapy has begun; however, zoster vaccination can be given while patients are receiving azathioprine at less than 2 mg/kg,” they stated.

The experts went on to report that withdrawal of thiopurine agents, when used in combination therapy, has the potential to reduce therapeutic levels of infliximab and promote development of antidrug antibodies. However, the experts did not suggest a method to manage these complications. Further studies are needed to answer these and other remaining questions regarding thiopurine use in the setting of IBD.

SOURCE: Hanauer SB et al. Gastroenterology. 2018 Sep 6. doi: 10.1053/j.gastro.2018.08.043.

*This story was updated on January 4, 2019.

The surgical technique endoscopic submucosal dissection (ESD) is a safe and appropriate option for the complete resection of large, early-stage, malignant gastric lesions, according to a new clinical practice update from the American Gastroenterological Association published in Clinical Gastroenterology and Hepatology.

Clinicians should recognize ESD as one of the main treatment modalities for GI cancer enclosed within the superficial esophageal mucosa, which includes squamous cell dysplasia, wrote Peter V. Draganov, MD, of the University of Florida in Gainesville with his fellow experts.

Endoscopic resection is a surgical method used to treat both malignant and nonmalignant GI lesions. Over the past several years, the technique has advanced significantly, progressing from snare polypectomy to endoscopic mucosal resection, with current practice now ESD. The minimally invasive technique is considered first-line therapy in patients with colorectal lesions lacking invasive cancer.

While the technique is widely used in Asian countries, and as practice continues to rise throughout Europe, uptake in the United States has been slow. Several factors may be responsible for this delay, including a lack of ESD experts and training centers, underestimation of the benefits associated with ESD, and a likely bias of American oncologists toward treatment with surgical resection. In recent years, extensive improvements have occurred in ESD technique, such as incorporation of pocket and tunnel strategies, which have significantly contributed to the overall safety and efficacy of the procedure.

“With low thresholds for performing endoscopy for upper GI symptoms and the promotion of screening colonoscopy for colon cancer prevention, more precancerous lesions and early cancers are being detected that may be amenable to endoscopic resection by ESD,” the experts wrote.

For mucosal lesions too large to be removed by standard endoscopic resection, or lesions at high risk of being deemed malignant, the guidelines recommend using ESD to remove these lesions. Dr. Draganov and his colleagues acknowledged that the probability of lymph node metastasis is marginally higher when the procedure is used for these widened indications; however, the risk of metastasis remains sufficiently low. Along those lines, several additional recommendations were made related to the expanded indications for ESD, including use in certain patients with Barrett’s esophagus, colorectal neoplasia, and other forms of superficial gastric cancer.

“Expanded indications for gastric ESD include moderately and well-differentiated superficial cancers that are [more than] 2 cm, lesions [up to] 3 cm with ulceration or that contain early submucosal invasion, and poorly differentiated superficial cancers [up to] 2 cm in size,” the experts stated.

With respect to cost, endoscopic resection was found to provide significant savings in comparison to surgical techniques for the removal of colorectal lesions. The economic analysis revealed that using a lesion-specific ESD model for high-risk patients could allow for notable cost reductions.

“Although some insurers have begun preapproving and covering their members who might benefit from ESD, the hurdles preventing other patients from being covered for this innovative and potentially cost-saving procedure should be removed,” they added.

Other recommendations were made in regards to effective implementation of a stepwise ESD educational model to train American endoscopists on how to properly perform the procedure. The proposed strategy involves completion of a formal training program, independent study, self-practice using animal models, and live viewing of cases by ESD experts. In addition, they recommend that newly trained endoscopists complete their first procedures on patients with absolute indications for ESD.

“At present, there is no standardized approach for ESD training in the United States,” the experts wrote. They further explained that “the usual starting point is to attend an ESD course or series of courses that provide increasingly more in-depth exposure.” And they concluded, “a guiding principle should be that our patients’ interests and welfare stand above all else and that patients must not be used as an opportunity for practice or skills acquisition.”

The practice update also recommends that endoscopists avoid the use of techniques that have the ability to produce submucosal fibrosis. Dr. Draganov and his colleagues warn that these practices, such as “tattooing in close proximity to or beneath a lesion for marking” and “partial snare resection of a portion of a lesion for histopathology,” can impede subsequent endoscopic procedures.

Dr. Draganov and several coauthors disclosed financial affiliations with AbbVie, Boston Scientific Corporation, Cook Medical, Olympus America, and others.

SOURCE: Draganov PV et al. Clin Gastroenterol Hepatol. 2018 Aug 2. doi: 10.1016/j.cgh.2018.07.041.

The surgical technique endoscopic submucosal dissection (ESD) is a safe and appropriate option for the complete resection of large, early-stage, malignant gastric lesions, according to a new clinical practice update from the American Gastroenterological Association published in Clinical Gastroenterology and Hepatology.

Clinicians should recognize ESD as one of the main treatment modalities for GI cancer enclosed within the superficial esophageal mucosa, which includes squamous cell dysplasia, wrote Peter V. Draganov, MD, of the University of Florida in Gainesville with his fellow experts.

Endoscopic resection is a surgical method used to treat both malignant and nonmalignant GI lesions. Over the past several years, the technique has advanced significantly, progressing from snare polypectomy to endoscopic mucosal resection, with current practice now ESD. The minimally invasive technique is considered first-line therapy in patients with colorectal lesions lacking invasive cancer.

While the technique is widely used in Asian countries, and as practice continues to rise throughout Europe, uptake in the United States has been slow. Several factors may be responsible for this delay, including a lack of ESD experts and training centers, underestimation of the benefits associated with ESD, and a likely bias of American oncologists toward treatment with surgical resection. In recent years, extensive improvements have occurred in ESD technique, such as incorporation of pocket and tunnel strategies, which have significantly contributed to the overall safety and efficacy of the procedure.

“With low thresholds for performing endoscopy for upper GI symptoms and the promotion of screening colonoscopy for colon cancer prevention, more precancerous lesions and early cancers are being detected that may be amenable to endoscopic resection by ESD,” the experts wrote.

For mucosal lesions too large to be removed by standard endoscopic resection, or lesions at high risk of being deemed malignant, the guidelines recommend using ESD to remove these lesions. Dr. Draganov and his colleagues acknowledged that the probability of lymph node metastasis is marginally higher when the procedure is used for these widened indications; however, the risk of metastasis remains sufficiently low. Along those lines, several additional recommendations were made related to the expanded indications for ESD, including use in certain patients with Barrett’s esophagus, colorectal neoplasia, and other forms of superficial gastric cancer.

“Expanded indications for gastric ESD include moderately and well-differentiated superficial cancers that are [more than] 2 cm, lesions [up to] 3 cm with ulceration or that contain early submucosal invasion, and poorly differentiated superficial cancers [up to] 2 cm in size,” the experts stated.

With respect to cost, endoscopic resection was found to provide significant savings in comparison to surgical techniques for the removal of colorectal lesions. The economic analysis revealed that using a lesion-specific ESD model for high-risk patients could allow for notable cost reductions.

“Although some insurers have begun preapproving and covering their members who might benefit from ESD, the hurdles preventing other patients from being covered for this innovative and potentially cost-saving procedure should be removed,” they added.

Other recommendations were made in regards to effective implementation of a stepwise ESD educational model to train American endoscopists on how to properly perform the procedure. The proposed strategy involves completion of a formal training program, independent study, self-practice using animal models, and live viewing of cases by ESD experts. In addition, they recommend that newly trained endoscopists complete their first procedures on patients with absolute indications for ESD.

“At present, there is no standardized approach for ESD training in the United States,” the experts wrote. They further explained that “the usual starting point is to attend an ESD course or series of courses that provide increasingly more in-depth exposure.” And they concluded, “a guiding principle should be that our patients’ interests and welfare stand above all else and that patients must not be used as an opportunity for practice or skills acquisition.”

The practice update also recommends that endoscopists avoid the use of techniques that have the ability to produce submucosal fibrosis. Dr. Draganov and his colleagues warn that these practices, such as “tattooing in close proximity to or beneath a lesion for marking” and “partial snare resection of a portion of a lesion for histopathology,” can impede subsequent endoscopic procedures.

Dr. Draganov and several coauthors disclosed financial affiliations with AbbVie, Boston Scientific Corporation, Cook Medical, Olympus America, and others.

SOURCE: Draganov PV et al. Clin Gastroenterol Hepatol. 2018 Aug 2. doi: 10.1016/j.cgh.2018.07.041.

The surgical technique endoscopic submucosal dissection (ESD) is a safe and appropriate option for the complete resection of large, early-stage, malignant gastric lesions, according to a new clinical practice update from the American Gastroenterological Association published in Clinical Gastroenterology and Hepatology.

Clinicians should recognize ESD as one of the main treatment modalities for GI cancer enclosed within the superficial esophageal mucosa, which includes squamous cell dysplasia, wrote Peter V. Draganov, MD, of the University of Florida in Gainesville with his fellow experts.

Endoscopic resection is a surgical method used to treat both malignant and nonmalignant GI lesions. Over the past several years, the technique has advanced significantly, progressing from snare polypectomy to endoscopic mucosal resection, with current practice now ESD. The minimally invasive technique is considered first-line therapy in patients with colorectal lesions lacking invasive cancer.

While the technique is widely used in Asian countries, and as practice continues to rise throughout Europe, uptake in the United States has been slow. Several factors may be responsible for this delay, including a lack of ESD experts and training centers, underestimation of the benefits associated with ESD, and a likely bias of American oncologists toward treatment with surgical resection. In recent years, extensive improvements have occurred in ESD technique, such as incorporation of pocket and tunnel strategies, which have significantly contributed to the overall safety and efficacy of the procedure.

“With low thresholds for performing endoscopy for upper GI symptoms and the promotion of screening colonoscopy for colon cancer prevention, more precancerous lesions and early cancers are being detected that may be amenable to endoscopic resection by ESD,” the experts wrote.

For mucosal lesions too large to be removed by standard endoscopic resection, or lesions at high risk of being deemed malignant, the guidelines recommend using ESD to remove these lesions. Dr. Draganov and his colleagues acknowledged that the probability of lymph node metastasis is marginally higher when the procedure is used for these widened indications; however, the risk of metastasis remains sufficiently low. Along those lines, several additional recommendations were made related to the expanded indications for ESD, including use in certain patients with Barrett’s esophagus, colorectal neoplasia, and other forms of superficial gastric cancer.

“Expanded indications for gastric ESD include moderately and well-differentiated superficial cancers that are [more than] 2 cm, lesions [up to] 3 cm with ulceration or that contain early submucosal invasion, and poorly differentiated superficial cancers [up to] 2 cm in size,” the experts stated.

With respect to cost, endoscopic resection was found to provide significant savings in comparison to surgical techniques for the removal of colorectal lesions. The economic analysis revealed that using a lesion-specific ESD model for high-risk patients could allow for notable cost reductions.

“Although some insurers have begun preapproving and covering their members who might benefit from ESD, the hurdles preventing other patients from being covered for this innovative and potentially cost-saving procedure should be removed,” they added.

Other recommendations were made in regards to effective implementation of a stepwise ESD educational model to train American endoscopists on how to properly perform the procedure. The proposed strategy involves completion of a formal training program, independent study, self-practice using animal models, and live viewing of cases by ESD experts. In addition, they recommend that newly trained endoscopists complete their first procedures on patients with absolute indications for ESD.

“At present, there is no standardized approach for ESD training in the United States,” the experts wrote. They further explained that “the usual starting point is to attend an ESD course or series of courses that provide increasingly more in-depth exposure.” And they concluded, “a guiding principle should be that our patients’ interests and welfare stand above all else and that patients must not be used as an opportunity for practice or skills acquisition.”

The practice update also recommends that endoscopists avoid the use of techniques that have the ability to produce submucosal fibrosis. Dr. Draganov and his colleagues warn that these practices, such as “tattooing in close proximity to or beneath a lesion for marking” and “partial snare resection of a portion of a lesion for histopathology,” can impede subsequent endoscopic procedures.

Dr. Draganov and several coauthors disclosed financial affiliations with AbbVie, Boston Scientific Corporation, Cook Medical, Olympus America, and others.

SOURCE: Draganov PV et al. Clin Gastroenterol Hepatol. 2018 Aug 2. doi: 10.1016/j.cgh.2018.07.041.

Two months ago I met Ed, still working at age 71. “My life’s ambition,” he said, “has been to help high school science teachers do their jobs better.”

“How’s it going?” I asked.

Ed sighed. “I’m still at it,” he said. “Let’s just say we’re not there yet.”

I too, dear colleagues, have had a life’s ambition, secret until right now: I wanted to eliminate erroneous fungal diagnosis. Or, to put it more pungently, to help nondermatologists stop treating every roundish scaly rash as ringworm.

Alas, like Ed’s, my work is not yet done.

I get reminders of this all the time, but last week the evidence got so overwhelming that I had to take a breath to settle down. And a nip. Ten cases. In 24 hours.

1. A 66-year-old woman energetically smeared econazole cream twice daily for weeks for an itchy, lichenified rash on both dorsal feet and ankles. Switched to betamethasone. Cleared in 5 days.

2. A 48-year-old woman with scaly patches on both legs. No response to terbinafine cream, then to ketoconazole cream, then to oral fluconazole. Cleared promptly on triamcinolone.

3. A 26-year-old with an erosive vulvar rash lasting month, unresponsive to Nystatin. After 5 days on a steroid, it was gone.

4. A 45-year-old man with lots of dermatoheliosis and idiopathic guttate hypomelanosis on arms and legs. No luck with topical selenium sulfide for tinea versicolor.

5. A 42-year-old nurse treated for weeks with topical antifungals. She came in with globs of fungus cream sealed in with Tegaderm (to prevent spread). Her roommates wanted to cancel her lease. Cleared of both rash and Tegaderm in 1 week. Now allowed to touch doorknobs.

6. A 27-year-old man with 8 weeks of lichenified patches all over his torso. Antifungal creams not working. Steroids do!

7. A 25-year-old recent émigré from India, where he was treated for his itchy groin rash with a succession of antifungal creams. He cannot sleep. (Imagine the plane trip from Delhi!) Has lichenified inguinal folds and scrotum. Cleared in 1 week with a topical steroid.

8. A 22-year-old woman with widespread atopic dermatitis. No response to antifungals. She had a rash at age 2 that was called “allergy to shampoo.” Clears promptly on a steroid.

9. A 22-year-old man being treated for a scaly, bilateral periocular rash with oral cephalexin. Clears promptly on a weak topical steroid.

10. A 29-year-old woman who has been suffering for months with “sensitivity” of her vulvar skin that has been diagnosed and treated as “a yeast infection,” in the absence of any rash or discharge. Her only visible finding is inverse psoriasis in the gluteal cleft. Guess what clears her up?

And so it goes, and so it has gone, week after week, year after year, decade after decade. Medicine scales Olympus: genomics, immunotherapy, stereotactic surgery. Meantime, the it’s-not-a-fungus problem seems impervious to both education and even to daily observation as obvious as it is ineffective: If a supposed fungus does not respond to antifungal treatment, then it must be a very bad fungus. If it doesn’t respond to yet another antifungal cream, then it must be terrible fungus. Reconsidering that it may not be a fungus at all seems to demand a mental paradigm shift whose achievement will have to await a more discerning generation.

In the meantime, patients not only don’t get better, but they feel defiled and dirty. They avoid human contact, intimate and otherwise, and do a lot of superfluous and expensive cleaning of house and wardrobe. If you doubt this, ask them. If you think I overstate, spend a day with me.

Early in my career I inherited the once-yearly dermatology slot at Medical Grand Rounds at the local community hospital. I spoke about cutaneous fungus, with emphasis on the fact that lots of round rashes are nummular eczema rather than fungus, as well as what it means to patients to be told they are “fungal.”

I didn’t get much direct feedback, but the chief of medicine sprang into action. He canceled the dermatology slot. Not medical enough, I guess.

Ed tells me that many high school science teachers don’t know much science. They teach it because they thought they might like to, or because there was an opening. After Ed hangs up his cleats, there will be plenty of his work left to be done.

But then, there always is.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Two months ago I met Ed, still working at age 71. “My life’s ambition,” he said, “has been to help high school science teachers do their jobs better.”

“How’s it going?” I asked.

Ed sighed. “I’m still at it,” he said. “Let’s just say we’re not there yet.”

I too, dear colleagues, have had a life’s ambition, secret until right now: I wanted to eliminate erroneous fungal diagnosis. Or, to put it more pungently, to help nondermatologists stop treating every roundish scaly rash as ringworm.

Alas, like Ed’s, my work is not yet done.

I get reminders of this all the time, but last week the evidence got so overwhelming that I had to take a breath to settle down. And a nip. Ten cases. In 24 hours.

1. A 66-year-old woman energetically smeared econazole cream twice daily for weeks for an itchy, lichenified rash on both dorsal feet and ankles. Switched to betamethasone. Cleared in 5 days.

2. A 48-year-old woman with scaly patches on both legs. No response to terbinafine cream, then to ketoconazole cream, then to oral fluconazole. Cleared promptly on triamcinolone.

3. A 26-year-old with an erosive vulvar rash lasting month, unresponsive to Nystatin. After 5 days on a steroid, it was gone.

4. A 45-year-old man with lots of dermatoheliosis and idiopathic guttate hypomelanosis on arms and legs. No luck with topical selenium sulfide for tinea versicolor.

5. A 42-year-old nurse treated for weeks with topical antifungals. She came in with globs of fungus cream sealed in with Tegaderm (to prevent spread). Her roommates wanted to cancel her lease. Cleared of both rash and Tegaderm in 1 week. Now allowed to touch doorknobs.

6. A 27-year-old man with 8 weeks of lichenified patches all over his torso. Antifungal creams not working. Steroids do!

7. A 25-year-old recent émigré from India, where he was treated for his itchy groin rash with a succession of antifungal creams. He cannot sleep. (Imagine the plane trip from Delhi!) Has lichenified inguinal folds and scrotum. Cleared in 1 week with a topical steroid.

8. A 22-year-old woman with widespread atopic dermatitis. No response to antifungals. She had a rash at age 2 that was called “allergy to shampoo.” Clears promptly on a steroid.

9. A 22-year-old man being treated for a scaly, bilateral periocular rash with oral cephalexin. Clears promptly on a weak topical steroid.

10. A 29-year-old woman who has been suffering for months with “sensitivity” of her vulvar skin that has been diagnosed and treated as “a yeast infection,” in the absence of any rash or discharge. Her only visible finding is inverse psoriasis in the gluteal cleft. Guess what clears her up?

And so it goes, and so it has gone, week after week, year after year, decade after decade. Medicine scales Olympus: genomics, immunotherapy, stereotactic surgery. Meantime, the it’s-not-a-fungus problem seems impervious to both education and even to daily observation as obvious as it is ineffective: If a supposed fungus does not respond to antifungal treatment, then it must be a very bad fungus. If it doesn’t respond to yet another antifungal cream, then it must be terrible fungus. Reconsidering that it may not be a fungus at all seems to demand a mental paradigm shift whose achievement will have to await a more discerning generation.

In the meantime, patients not only don’t get better, but they feel defiled and dirty. They avoid human contact, intimate and otherwise, and do a lot of superfluous and expensive cleaning of house and wardrobe. If you doubt this, ask them. If you think I overstate, spend a day with me.

Early in my career I inherited the once-yearly dermatology slot at Medical Grand Rounds at the local community hospital. I spoke about cutaneous fungus, with emphasis on the fact that lots of round rashes are nummular eczema rather than fungus, as well as what it means to patients to be told they are “fungal.”

I didn’t get much direct feedback, but the chief of medicine sprang into action. He canceled the dermatology slot. Not medical enough, I guess.

Ed tells me that many high school science teachers don’t know much science. They teach it because they thought they might like to, or because there was an opening. After Ed hangs up his cleats, there will be plenty of his work left to be done.

But then, there always is.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Two months ago I met Ed, still working at age 71. “My life’s ambition,” he said, “has been to help high school science teachers do their jobs better.”

“How’s it going?” I asked.

Ed sighed. “I’m still at it,” he said. “Let’s just say we’re not there yet.”

I too, dear colleagues, have had a life’s ambition, secret until right now: I wanted to eliminate erroneous fungal diagnosis. Or, to put it more pungently, to help nondermatologists stop treating every roundish scaly rash as ringworm.

Alas, like Ed’s, my work is not yet done.

I get reminders of this all the time, but last week the evidence got so overwhelming that I had to take a breath to settle down. And a nip. Ten cases. In 24 hours.

1. A 66-year-old woman energetically smeared econazole cream twice daily for weeks for an itchy, lichenified rash on both dorsal feet and ankles. Switched to betamethasone. Cleared in 5 days.

2. A 48-year-old woman with scaly patches on both legs. No response to terbinafine cream, then to ketoconazole cream, then to oral fluconazole. Cleared promptly on triamcinolone.

3. A 26-year-old with an erosive vulvar rash lasting month, unresponsive to Nystatin. After 5 days on a steroid, it was gone.

4. A 45-year-old man with lots of dermatoheliosis and idiopathic guttate hypomelanosis on arms and legs. No luck with topical selenium sulfide for tinea versicolor.

5. A 42-year-old nurse treated for weeks with topical antifungals. She came in with globs of fungus cream sealed in with Tegaderm (to prevent spread). Her roommates wanted to cancel her lease. Cleared of both rash and Tegaderm in 1 week. Now allowed to touch doorknobs.

6. A 27-year-old man with 8 weeks of lichenified patches all over his torso. Antifungal creams not working. Steroids do!

7. A 25-year-old recent émigré from India, where he was treated for his itchy groin rash with a succession of antifungal creams. He cannot sleep. (Imagine the plane trip from Delhi!) Has lichenified inguinal folds and scrotum. Cleared in 1 week with a topical steroid.

8. A 22-year-old woman with widespread atopic dermatitis. No response to antifungals. She had a rash at age 2 that was called “allergy to shampoo.” Clears promptly on a steroid.

9. A 22-year-old man being treated for a scaly, bilateral periocular rash with oral cephalexin. Clears promptly on a weak topical steroid.

10. A 29-year-old woman who has been suffering for months with “sensitivity” of her vulvar skin that has been diagnosed and treated as “a yeast infection,” in the absence of any rash or discharge. Her only visible finding is inverse psoriasis in the gluteal cleft. Guess what clears her up?

And so it goes, and so it has gone, week after week, year after year, decade after decade. Medicine scales Olympus: genomics, immunotherapy, stereotactic surgery. Meantime, the it’s-not-a-fungus problem seems impervious to both education and even to daily observation as obvious as it is ineffective: If a supposed fungus does not respond to antifungal treatment, then it must be a very bad fungus. If it doesn’t respond to yet another antifungal cream, then it must be terrible fungus. Reconsidering that it may not be a fungus at all seems to demand a mental paradigm shift whose achievement will have to await a more discerning generation.

In the meantime, patients not only don’t get better, but they feel defiled and dirty. They avoid human contact, intimate and otherwise, and do a lot of superfluous and expensive cleaning of house and wardrobe. If you doubt this, ask them. If you think I overstate, spend a day with me.

Early in my career I inherited the once-yearly dermatology slot at Medical Grand Rounds at the local community hospital. I spoke about cutaneous fungus, with emphasis on the fact that lots of round rashes are nummular eczema rather than fungus, as well as what it means to patients to be told they are “fungal.”

I didn’t get much direct feedback, but the chief of medicine sprang into action. He canceled the dermatology slot. Not medical enough, I guess.

Ed tells me that many high school science teachers don’t know much science. They teach it because they thought they might like to, or because there was an opening. After Ed hangs up his cleats, there will be plenty of his work left to be done.

But then, there always is.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Dermatology News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years. His second book, “Act Like a Doctor, Think Like a Patient,” is available at amazon.com and barnesandnoble.com. Write to him at dermnews@mdedge.com.

Photo by Elise Amendola

An initiative that reduced red blood cell (RBC) transfusions and increased moderate anemia in hospital did not adversely impact patients long-term, according to an analysis.

Researchers found that an increase in moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months.

However, authors of a related editorial argued that additional factors must be assessed to truly determine the effects of moderate anemia on patient outcomes.

The study and the editorial were published in the Annals of Internal Medicine.

Study: Long-term outcomes

Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland, and colleagues sought to evaluate the impact of blood management programs—starting in 2010—that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their new report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014.

In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings. In parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P<0.001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P<0.001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P=0.004) over that time period among patients with moderate anemia.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” the researchers wrote.

However, they also said additional studies are needed to guide anemia management, particularly since persistent anemia has impacts on quality of life that are “likely to be substantial” and linked to the severity of that anemia.

This study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants from the National Institutes of Health.

Editorial: Aim to treat anemia, not tolerate it

Dr. Roubinian and his colleagues’ findings warrant some scrutiny, according to Aryeh Shander, MD, of Englewood Hospital and Medical Center in New Jersey, and Lawrence Tim Goodnough, MD, of Stanford University in California.

“Missing here is a wide spectrum of morbidity outcomes and issues related to diminished quality of life that do not reach the level of severity that would necessitate admission but nonetheless detract from patients’ health and well-being,” Drs. Shander and Goodnough wrote in a related editorial.

They also noted that transfusion rate is not a clinical outcome, adding that readmission and mortality are important outcomes, but they do not accurately or fully reflect patient well-being.

While blood management initiatives may be a safe practice, as the study suggests, proper management of anemia after discharge may actually improve outcomes, given the many consequences of anemia, Drs. Shander and Goodnough wrote.

The pair suggested that, instead of again testing whether restricting transfusions is acceptable because of lack of impact on outcomes, future studies could evaluate a “more sensible” hypothesis that proper anemia management, especially post-discharge, could improve outcomes.

“Let’s increase efforts to prevent and treat anemia properly, rather than requiring patients to tolerate it,” Drs. Shander and Goodnough wrote.

Dr. Shander reported consulting fees from Vifor and AMAG. Dr. Goodnough reported having no relevant financial disclosures.

Photo by Elise Amendola

An initiative that reduced red blood cell (RBC) transfusions and increased moderate anemia in hospital did not adversely impact patients long-term, according to an analysis.

Researchers found that an increase in moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months.

However, authors of a related editorial argued that additional factors must be assessed to truly determine the effects of moderate anemia on patient outcomes.

The study and the editorial were published in the Annals of Internal Medicine.

Study: Long-term outcomes

Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland, and colleagues sought to evaluate the impact of blood management programs—starting in 2010—that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their new report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014.

In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings. In parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P<0.001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P<0.001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P=0.004) over that time period among patients with moderate anemia.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” the researchers wrote.

However, they also said additional studies are needed to guide anemia management, particularly since persistent anemia has impacts on quality of life that are “likely to be substantial” and linked to the severity of that anemia.

This study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants from the National Institutes of Health.

Editorial: Aim to treat anemia, not tolerate it

Dr. Roubinian and his colleagues’ findings warrant some scrutiny, according to Aryeh Shander, MD, of Englewood Hospital and Medical Center in New Jersey, and Lawrence Tim Goodnough, MD, of Stanford University in California.

“Missing here is a wide spectrum of morbidity outcomes and issues related to diminished quality of life that do not reach the level of severity that would necessitate admission but nonetheless detract from patients’ health and well-being,” Drs. Shander and Goodnough wrote in a related editorial.

They also noted that transfusion rate is not a clinical outcome, adding that readmission and mortality are important outcomes, but they do not accurately or fully reflect patient well-being.

While blood management initiatives may be a safe practice, as the study suggests, proper management of anemia after discharge may actually improve outcomes, given the many consequences of anemia, Drs. Shander and Goodnough wrote.

The pair suggested that, instead of again testing whether restricting transfusions is acceptable because of lack of impact on outcomes, future studies could evaluate a “more sensible” hypothesis that proper anemia management, especially post-discharge, could improve outcomes.

“Let’s increase efforts to prevent and treat anemia properly, rather than requiring patients to tolerate it,” Drs. Shander and Goodnough wrote.

Dr. Shander reported consulting fees from Vifor and AMAG. Dr. Goodnough reported having no relevant financial disclosures.

Photo by Elise Amendola

An initiative that reduced red blood cell (RBC) transfusions and increased moderate anemia in hospital did not adversely impact patients long-term, according to an analysis.

Researchers found that an increase in moderate in-hospital anemia did not increase subsequent RBC use, readmission, or mortality over the next 6 months.

However, authors of a related editorial argued that additional factors must be assessed to truly determine the effects of moderate anemia on patient outcomes.

The study and the editorial were published in the Annals of Internal Medicine.

Study: Long-term outcomes

Nareg H. Roubinian, MD, of Kaiser Permanente Northern California in Oakland, and colleagues sought to evaluate the impact of blood management programs—starting in 2010—that included blood-sparing surgical and medical techniques, increased use of hemostatic and cell salvage agents, and treatment of suboptimal iron stores before surgery.

In previous retrospective cohort studies, the researchers had found that blood conservation strategies did not impact in-hospital or 30-day mortality rates, which was consistent with short-term safety data from clinical trials and other observational studies.

Their new report on longer-term outcomes was based on data from Kaiser Permanente Northern California for 445,371 adults who had 801,261 hospitalizations with discharges between 2010 and 2014.

In this cohort, moderate anemia (hemoglobin between 7 g/dL and 10 g/dL) at discharge occurred in 119,489 patients (27%) and 187,440 hospitalizations overall (23%).

Over the 2010-2014 period, RBC transfusions decreased by more than 25% in the inpatient and outpatient settings. In parallel, the prevalence of moderate anemia at hospital discharge increased from 20% to 25%.

However, the risks of subsequent RBC transfusions and rehospitalization after discharge with anemia decreased during the study period, and mortality rates stayed steady or decreased slightly.

Among patients with moderate anemia, the proportion with subsequent RBC transfusions within 6 months decreased from 18.9% in 2010 to 16.8% in 2014 (P<0.001), while the rate of rehospitalization within 6 months decreased from 36.5% to 32.8% over that same time period (P<0.001).

The adjusted 6-month mortality rate likewise decreased from 16.1% to 15.6% (P=0.004) over that time period among patients with moderate anemia.

“These data support the efficacy and safety of practice recommendations to limit red blood cell transfusion in patients with anemia during and after hospitalization,” the researchers wrote.

However, they also said additional studies are needed to guide anemia management, particularly since persistent anemia has impacts on quality of life that are “likely to be substantial” and linked to the severity of that anemia.

This study was supported by a grant from the National Heart, Lung, and Blood Institute. Dr. Roubinian and several coauthors reported grants from the National Institutes of Health.

Editorial: Aim to treat anemia, not tolerate it

Dr. Roubinian and his colleagues’ findings warrant some scrutiny, according to Aryeh Shander, MD, of Englewood Hospital and Medical Center in New Jersey, and Lawrence Tim Goodnough, MD, of Stanford University in California.

“Missing here is a wide spectrum of morbidity outcomes and issues related to diminished quality of life that do not reach the level of severity that would necessitate admission but nonetheless detract from patients’ health and well-being,” Drs. Shander and Goodnough wrote in a related editorial.

They also noted that transfusion rate is not a clinical outcome, adding that readmission and mortality are important outcomes, but they do not accurately or fully reflect patient well-being.

While blood management initiatives may be a safe practice, as the study suggests, proper management of anemia after discharge may actually improve outcomes, given the many consequences of anemia, Drs. Shander and Goodnough wrote.

The pair suggested that, instead of again testing whether restricting transfusions is acceptable because of lack of impact on outcomes, future studies could evaluate a “more sensible” hypothesis that proper anemia management, especially post-discharge, could improve outcomes.

“Let’s increase efforts to prevent and treat anemia properly, rather than requiring patients to tolerate it,” Drs. Shander and Goodnough wrote.

Dr. Shander reported consulting fees from Vifor and AMAG. Dr. Goodnough reported having no relevant financial disclosures.

The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.¹ Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.² New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).³

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.⁴ The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.⁵ The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.^6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.⁸ Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.⁹ In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.¹⁰

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.¹¹
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).¹² In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.¹³ Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.¹⁴ One twin study showed that increased levels of Gordonia correlated with rosacea severity.¹⁵ A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.¹⁶

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.¹⁷ In my favorite recent study,¹⁸ complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.¹⁴ I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.

The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.¹ Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.² New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).³

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.⁴ The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.⁵ The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.^6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.⁸ Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.⁹ In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.¹⁰

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.¹¹
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).¹² In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.¹³ Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.¹⁴ One twin study showed that increased levels of Gordonia correlated with rosacea severity.¹⁵ A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.¹⁶

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.¹⁷ In my favorite recent study,¹⁸ complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.¹⁴ I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.

The microbiome of the gut and skin can impact one another in health and disease. Numerous dermatologic disorders can be traced to gastrointestinal etiologic origins.¹ Incorporating discussion of the latest findings on the cutaneous and gut microbiome expands our understanding of the origin of dermatologic disease. In this column, the focus is on the most common cutaneous conditions in which the skin microbiome is believed to play an important role, but the gut microbiome also has effects on the skin microbiome that are just being elucidated. Although we do not yet know enough to give our patients definitive advice about probiotics, the knowledge in this field is rapidly expanding and is an exciting area to watch. Certainly, everything applied to the skin or ingested in the diet plays a role in the skin and gut microbiome. Therefore, the savvy dermatologist understands that personal care products, including cosmeceuticals, will affect the microbiome. At this point, we do not yet know what is beneficial, but we do know that diversity of organisms is important and is the preferred state as compared to having fewer types of organisms on the skin.

Acne

Acne has long been known to have a multifactorial etiologic pathway. It is increasingly thought that understanding the role of the skin (and possibly gut) microbiome in acne pathophysiology may lead to enhanced treatments.² New gene sequencing technologies, particularly those based on recA and tly loci, are teaching us more about the anaerobic bacterium Propionibacterium acnes (now called Cutibacterium acnes).³

In 2017, Dréno et al. studied the skin microbiota in 26 subjects with mild to moderate acne. The microflora were characterized using a high‐throughput sequencing approach that targets a portion of the bacterial 16S rRNA gene. The samples were obtained before and after 28 days of treatment with erythromycin 4% or a cosmeceutical containing lipohydroxy acid, salicylic acid, linoleic acid, niacinamide, piroctone olamine, a ceramide, and thermal spring water. Upon conclusion of the study, Actinobacteria were reduced in both groups while staphylococci were reduced only in the dermocosmetic group.⁴ The interesting point of this study was that the cosmeceutical had a greater impact on staphylococci than did topical erythromycin, demonstrating that personal care products can have profound effects on the microbiome.

Early in 2018, Kelhälä et al. compared the impact of the systemic acne treatments isotretinoin and lymecycline on cutaneous microbiota in the cheeks, back, and axillae of mild to moderate acne patients using gene sequencing. They found that acne severity positively correlated with Propionibacterium acnes levels. P. acnes levels were decreased by both treatments, but isotretinoin resulted in a greater decrease. Increased microbiome diversity was seen on the cheek and back in all treated subjects, but diversity was highest in those treated with isotretinoin.⁵ The authors postulated that the diversity resulted from a decrease in P. acnes levels. To learn more about what to tell your patients about acne and the microbiome, read my blog


 

Atopic dermatitis

Atopic dermatitis (AD) is associated with dysbiosis of cutaneous microbiota and diminished diversity in microbial communities.^6,7 There is also a robust epidemiologic relationship between the cutaneous and gut microbiomes and AD.⁸ Many studies have looked at the role of the microbiome in AD, including the role of Staphylococcus aureus, because it selectively colonizes the lesional skin of AD patients but is notably lacking on the skin of most healthy people.

In a 2017 literature review, Bjerre et al. found that while the data were not extensive, AD-affected skin was characterized by low bacterial diversity with S. aureus and Staphylococcus epidermidis more abundant. Also that year, Williams and Gallo reported on a prospective clinical trial in children that colonization by S. aureus occurred before the emergence of AD symptoms.⁹ In 2018, Clausen et al. reported on an observational case-control study of 45 adult healthy controls and 56 adult patients with AD between January and June 2015 to evaluate skin and nasal microbiome diversity and composition and to elucidate the relationship between disease severity and filaggrin gene mutations in AD patients. Next-generation sequencing targeting 16S ribosomal RNA was used to show that microbiome diversity was lower in the lesional skin, nonlesional skin, and nose in AD patients compared with controls. Such diversity was also found to be inversely correlated with disease severity, and microbiome composition in nonlesional AD skin was found to be associated with filaggrin gene mutations. The authors concluded that host genetics and skin microbiome may be connected in AD.¹⁰

However, the role of S. aureus in AD and the effect of its presence on microbiome diversity is still unclear. Marrs and Flohr note that the eradication of S. aureus does not appear to account for improvement in AD and increase in bacterial diversity after the use of antimicrobial and anti-inflammatory therapy.¹¹
 

Rosacea

Rosacea is a chronic inflammatory skin condition long associated with Demodex mites (Demodex folliculorum and Demodex brevis).¹² In rosacea-affected skin, Demodex mites are found to occur in greater density than in unaffected skin.¹³ Other microbiota-linked alterations have been detected on the skin and in the small intestines in cases of rosacea.¹⁴ One twin study showed that increased levels of Gordonia correlated with rosacea severity.¹⁵ A study in Korean women with rosacea demonstrated a reduction of Peptococcaceae, Methanobrevibacter, Slackia, Coprobacillus, Citrobacter (genus), and Desulfovibrio and an increased amount of Acidaminococcus, Megasphaera, and Lactobacillales in women with rosacea.¹⁶

Other studies have shown that treating bacterial overgrowth in the gut can improve rosacea.¹⁷ In my favorite recent study,¹⁸ complement appeared to affect microbial diversity and richness of the skin and the gut in mice, demonstrating that the immune system plays an important role in rosacea and the skin and gut microbiome. Certainly we have a lot to learn before we can make specific recommendations, but I feel certain that this area of research will unlock some of the mysteries of rosacea. To read more about what to tell your patients about the microbiome and rosacea visit the blog at STSfranchise.com.

Conclusion

In recent years, it has become increasingly clear that the cutaneous microbiome is a factor in various skin disorders. Some authors such as Egert et al. advocate the use of pre- and probiotics, including topical microbiome transplantation therapies, to treat acne, rosacea, and AD.¹⁴ I believe that we do not yet have enough data to support this approach or predict which ones may be effective. Stay tuned for more developments.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at dermnews@mededge.com.

References

1. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

2. Rocha MA et al. Arch Dermatol Res. 2018 Apr;310(3):181-5.

3. McDowell A. Microorganisms. 2017 Dec 21. doi: 10.3390/microorganisms6010001.

4. Dréno B et al. Exp Dermatol. 2017 Sep;26(9):798-803.

5. Kelhälä HL et al. Exp Dermatol. 2018 Jan;27(1):30-6.

6. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

7. Bjerre RD et al. Br J Dermatol. 2017 Nov;177(5):1272-8.

8. Knaysi G et al. Curr Allergy Asthma Rep. 2017 Jan;17(1):7.

9. Williams MR et al. J Invest Dermatol. 2017 Dec;137(12):2460-1.

10. Clausen ML et al. JAMA Dermatol. 2018 Mar 1;154(3):293-300.

11. Marrs T et al. Br J Dermatol. 2016 Oct;175 Suppl 2:13-18.

12. Patra V et al. Front Microbiol. 2016 Aug 10. doi: 10.3389/fmicb.2016.01235.

13. Igawa S et al. Transl Res. 2017 Jun;184:68-76.

14. Egert Met al. Clin Pharmacol Ther. 2017;102(1):62-9.

15. Zaidi AK et al. Exp Dermatol. 2018 Mar;27(3):295-8.

16. Nam, JH et al. Exp Dermatol. 2018 Jan;27(1):37-42.

17. Porubsky CF et al. “The Role of Probiotics in Acne and Rosacea,” IntechOpen. 2018 Nov 5. doi: 10.5772/intechopen.79044.

18. Chehoud C et al. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15061-6.