Red blood cells

In a first-in-human trial, sutimlimab rapidly halted hemolysis, corrected anemia, precluded the need for transfusion, and caused no serious adverse effects in patients with cold agglutinin disease.

Sutimlimab also “induced clinically meaningful increases in hemoglobin levels, even in patients with multiple previous lines of therapy,” according to investigators.

The European Medicines Agency and the U.S. Food and Drug Administration (FDA) awarded sutimlimab orphan drug status based on these results. The FDA also granted sutimlimab breakthrough therapy designation.

Sutimlimab is a humanized anti-C1s IgG4 monoclonal antibody that blocks the classical complement pathway–specific protease C1s and prevents further hemolysis in patients with cold agglutinin disease.

Cold agglutinin disease is a rare, acquired chronic autoimmune hemolytic condition that destroys red blood cells. It leads to chronic anemia, severe fatigue, and potentially fatal thrombotic events. No drug has yet been approved to treat cold agglutinin disease.

The phase 1 trial of sutimlimab (formerly BIVV009 and TNT009) in cold agglutinin disease was conducted at the Medical University of Vienna in Austria and reported in Blood.

The study (NCT02502903) involved 10 patients, ages 56 to 76, who were previously treated with multiple lines of therapy, including two patients who failed treatment with eculizumab.

Of the 10 patients, eight were female, eight were Caucasian, one was Asian, and one was Hispanic. Patients had cold agglutinin disease for a median of 5 years (range, 1 – 20).

At baseline, the median hemoglobin level was 7.8 g/dL, the median number of reticulocytes was 133 x 10⁹/L, the median bilirubin was 2.0 mg/dL, and the median haptoglobin was less than 12 mg/dL.

The patients received an initial dose of 10 mg/kg intravenous sutimlimab as a test dose to allow rapid wash-out of the drug if unforeseen adverse effects occurred with the first infusion.

One to 4 days later, they received the full dose of 60 mg/kg, followed by three additional weekly doses.

Investigators observed the patients for 49 to 53 days.

Results

Within the first week, patients’ median hemoglobin levels increased by 1.6 g/dL (P=0.007), and the median best response was an increase of 3.9 g/dL (P=0.005) after 6 weeks.

Seven patients had increased hemoglobin levels by more than 2 g/dL, and this included those who recently failed to respond or relapsed after rituximab, rituximab plus bendamustine, or eculizumab.

In five patients, hemoglobin increased by 4 g/dL or more. In four patients, it completely normalized to 12 g/dL.

In the first 24 hours after sutimlimab infusion, reticulocyte counts increased by a median of 41% and then gradually declined as hemoglobin levels rose.

In four patients, haptoglobin levels normalized within 1 to 2 weeks. In eight patients who had abnormal bilirubin levels at baseline, sutimlimab decreased the median bilirubin levels by 61%, normalizing levels in most patients within 24 hours of the first infusion (P=0.007).

When sutimlimab was washed out, bilirubin levels increased again, which demonstrated the recurrence of hemolysis.

Approximately 3 to 4 weeks after the last dose of sutimlimab, hemolysis and anemia recurred in all responders.

When patients were re-exposed to sutimlimab, rapid and complete inhibition of hemolysis occurred once again.

None of the patients required packed red blood cell transfusions during treatment.

Safety

The investigators reported that all infusions were well tolerated without premedication and without relevant drug-related adverse effects.

They reported few adverse events during the trial. All were mild or moderate in severity, and most were considered unrelated or unlikely related to sutimlimab.

Two adverse events—one mild purpural rash on both hands and one case of moderate hair loss (each occurring in one patient)—were possibly related to sutimlimab.

While the investigators considered the safety data encouraging, they recommended interpreting the data “cautiously in light of the limited duration of the trial.”

“Provided that safety results remain positive, sutimlimab could become the first approved treatment for cold agglutinin disease,” said corresponding author Bernd Jilma, MD, of the Medical University of Vienna in Austria.

“The drug clearly addresses an unmet medical need, as we have seen rapid, strong responses in patients for whom multiple prior therapies have failed.”

This study was funded by True North Therapeutics, Inc, now part of Bioverativ, a Sanofi company.

Some of the authors disclosed financial relationships, including employment, with True North Therapeutics and Bioverativ.

A phase 3 trial of sutimlimab is underway with top-line results due in 2019. 

Red blood cells

In a first-in-human trial, sutimlimab rapidly halted hemolysis, corrected anemia, precluded the need for transfusion, and caused no serious adverse effects in patients with cold agglutinin disease.

Sutimlimab also “induced clinically meaningful increases in hemoglobin levels, even in patients with multiple previous lines of therapy,” according to investigators.

The European Medicines Agency and the U.S. Food and Drug Administration (FDA) awarded sutimlimab orphan drug status based on these results. The FDA also granted sutimlimab breakthrough therapy designation.

Sutimlimab is a humanized anti-C1s IgG4 monoclonal antibody that blocks the classical complement pathway–specific protease C1s and prevents further hemolysis in patients with cold agglutinin disease.

Cold agglutinin disease is a rare, acquired chronic autoimmune hemolytic condition that destroys red blood cells. It leads to chronic anemia, severe fatigue, and potentially fatal thrombotic events. No drug has yet been approved to treat cold agglutinin disease.

The phase 1 trial of sutimlimab (formerly BIVV009 and TNT009) in cold agglutinin disease was conducted at the Medical University of Vienna in Austria and reported in Blood.

The study (NCT02502903) involved 10 patients, ages 56 to 76, who were previously treated with multiple lines of therapy, including two patients who failed treatment with eculizumab.

Of the 10 patients, eight were female, eight were Caucasian, one was Asian, and one was Hispanic. Patients had cold agglutinin disease for a median of 5 years (range, 1 – 20).

At baseline, the median hemoglobin level was 7.8 g/dL, the median number of reticulocytes was 133 x 10⁹/L, the median bilirubin was 2.0 mg/dL, and the median haptoglobin was less than 12 mg/dL.

The patients received an initial dose of 10 mg/kg intravenous sutimlimab as a test dose to allow rapid wash-out of the drug if unforeseen adverse effects occurred with the first infusion.

One to 4 days later, they received the full dose of 60 mg/kg, followed by three additional weekly doses.

Investigators observed the patients for 49 to 53 days.

Results

Within the first week, patients’ median hemoglobin levels increased by 1.6 g/dL (P=0.007), and the median best response was an increase of 3.9 g/dL (P=0.005) after 6 weeks.

Seven patients had increased hemoglobin levels by more than 2 g/dL, and this included those who recently failed to respond or relapsed after rituximab, rituximab plus bendamustine, or eculizumab.

In five patients, hemoglobin increased by 4 g/dL or more. In four patients, it completely normalized to 12 g/dL.

In the first 24 hours after sutimlimab infusion, reticulocyte counts increased by a median of 41% and then gradually declined as hemoglobin levels rose.

In four patients, haptoglobin levels normalized within 1 to 2 weeks. In eight patients who had abnormal bilirubin levels at baseline, sutimlimab decreased the median bilirubin levels by 61%, normalizing levels in most patients within 24 hours of the first infusion (P=0.007).

When sutimlimab was washed out, bilirubin levels increased again, which demonstrated the recurrence of hemolysis.

Approximately 3 to 4 weeks after the last dose of sutimlimab, hemolysis and anemia recurred in all responders.

When patients were re-exposed to sutimlimab, rapid and complete inhibition of hemolysis occurred once again.

None of the patients required packed red blood cell transfusions during treatment.

Safety

The investigators reported that all infusions were well tolerated without premedication and without relevant drug-related adverse effects.

They reported few adverse events during the trial. All were mild or moderate in severity, and most were considered unrelated or unlikely related to sutimlimab.

Two adverse events—one mild purpural rash on both hands and one case of moderate hair loss (each occurring in one patient)—were possibly related to sutimlimab.

While the investigators considered the safety data encouraging, they recommended interpreting the data “cautiously in light of the limited duration of the trial.”

“Provided that safety results remain positive, sutimlimab could become the first approved treatment for cold agglutinin disease,” said corresponding author Bernd Jilma, MD, of the Medical University of Vienna in Austria.

“The drug clearly addresses an unmet medical need, as we have seen rapid, strong responses in patients for whom multiple prior therapies have failed.”

This study was funded by True North Therapeutics, Inc, now part of Bioverativ, a Sanofi company.

Some of the authors disclosed financial relationships, including employment, with True North Therapeutics and Bioverativ.

A phase 3 trial of sutimlimab is underway with top-line results due in 2019. 

Red blood cells

In a first-in-human trial, sutimlimab rapidly halted hemolysis, corrected anemia, precluded the need for transfusion, and caused no serious adverse effects in patients with cold agglutinin disease.

Sutimlimab also “induced clinically meaningful increases in hemoglobin levels, even in patients with multiple previous lines of therapy,” according to investigators.

The European Medicines Agency and the U.S. Food and Drug Administration (FDA) awarded sutimlimab orphan drug status based on these results. The FDA also granted sutimlimab breakthrough therapy designation.

Sutimlimab is a humanized anti-C1s IgG4 monoclonal antibody that blocks the classical complement pathway–specific protease C1s and prevents further hemolysis in patients with cold agglutinin disease.

Cold agglutinin disease is a rare, acquired chronic autoimmune hemolytic condition that destroys red blood cells. It leads to chronic anemia, severe fatigue, and potentially fatal thrombotic events. No drug has yet been approved to treat cold agglutinin disease.

The phase 1 trial of sutimlimab (formerly BIVV009 and TNT009) in cold agglutinin disease was conducted at the Medical University of Vienna in Austria and reported in Blood.

The study (NCT02502903) involved 10 patients, ages 56 to 76, who were previously treated with multiple lines of therapy, including two patients who failed treatment with eculizumab.

Of the 10 patients, eight were female, eight were Caucasian, one was Asian, and one was Hispanic. Patients had cold agglutinin disease for a median of 5 years (range, 1 – 20).

At baseline, the median hemoglobin level was 7.8 g/dL, the median number of reticulocytes was 133 x 10⁹/L, the median bilirubin was 2.0 mg/dL, and the median haptoglobin was less than 12 mg/dL.

The patients received an initial dose of 10 mg/kg intravenous sutimlimab as a test dose to allow rapid wash-out of the drug if unforeseen adverse effects occurred with the first infusion.

One to 4 days later, they received the full dose of 60 mg/kg, followed by three additional weekly doses.

Investigators observed the patients for 49 to 53 days.

Results

Within the first week, patients’ median hemoglobin levels increased by 1.6 g/dL (P=0.007), and the median best response was an increase of 3.9 g/dL (P=0.005) after 6 weeks.

Seven patients had increased hemoglobin levels by more than 2 g/dL, and this included those who recently failed to respond or relapsed after rituximab, rituximab plus bendamustine, or eculizumab.

In five patients, hemoglobin increased by 4 g/dL or more. In four patients, it completely normalized to 12 g/dL.

In the first 24 hours after sutimlimab infusion, reticulocyte counts increased by a median of 41% and then gradually declined as hemoglobin levels rose.

In four patients, haptoglobin levels normalized within 1 to 2 weeks. In eight patients who had abnormal bilirubin levels at baseline, sutimlimab decreased the median bilirubin levels by 61%, normalizing levels in most patients within 24 hours of the first infusion (P=0.007).

When sutimlimab was washed out, bilirubin levels increased again, which demonstrated the recurrence of hemolysis.

Approximately 3 to 4 weeks after the last dose of sutimlimab, hemolysis and anemia recurred in all responders.

When patients were re-exposed to sutimlimab, rapid and complete inhibition of hemolysis occurred once again.

None of the patients required packed red blood cell transfusions during treatment.

Safety

The investigators reported that all infusions were well tolerated without premedication and without relevant drug-related adverse effects.

They reported few adverse events during the trial. All were mild or moderate in severity, and most were considered unrelated or unlikely related to sutimlimab.

Two adverse events—one mild purpural rash on both hands and one case of moderate hair loss (each occurring in one patient)—were possibly related to sutimlimab.

While the investigators considered the safety data encouraging, they recommended interpreting the data “cautiously in light of the limited duration of the trial.”

“Provided that safety results remain positive, sutimlimab could become the first approved treatment for cold agglutinin disease,” said corresponding author Bernd Jilma, MD, of the Medical University of Vienna in Austria.

“The drug clearly addresses an unmet medical need, as we have seen rapid, strong responses in patients for whom multiple prior therapies have failed.”

This study was funded by True North Therapeutics, Inc, now part of Bioverativ, a Sanofi company.

Some of the authors disclosed financial relationships, including employment, with True North Therapeutics and Bioverativ.

A phase 3 trial of sutimlimab is underway with top-line results due in 2019. 

On the first day of my psychiatry clerkship, I sat at a table with another student, 2 residents, and our attending physician. This wasn’t my first clinical rotation, but it was my first formal exposure to psychiatry, and I was excited and a bit anxious because I was considering psychiatry as an area of specialty training for myself. I’d been assigned 1 patient that morning: a 42-year-old man admitted for alcohol withdrawal. Our team, the psychiatry consultation-liaison team, was asked to evaluate the patient’s depressed mood in the context of withdrawal. As I began to present the patient’s story, I spoke of how terrible this man’s life had been, and how depressed he had recently become; this depression, I said, was likely exacerbated by alcohol use, but he was dealing with his depression by drinking more. He now wanted to quit for good. My attending, whom I had just met, interrupted me: “Misery,” she said with an intense look, “is a gift to an addicted person.”

I have ruminated on those surprising words ever since, and in that time I have begun to understand something about misery through the eyes of my patients. Sick people often are miserable; physical ailments can wreck hopes and plans and suck the joy from seemingly everything. Individuals who are ill or in pain often are suffering psychologically as well as physically. This suffering has been especially apparent to me in patients withdrawing from addictive substances: alcohol, cocaine, heroin, nicotine. I have been begged, cursed, praised, thanked, and more based on my ability or inability to relieve someone’s suffering caused by the lack of a certain substance: Please, just one cigarette. Please, something for this pain. Please, something to drink. As a medical student, I did one of 2 things: stood there helpless, or promised I would do the best I could, knowing my resident or attending would likely tell them no.

Withdrawal from addictive substances is, unsurprisingly, not pleasant. Alcohol withdrawal is one of the few that can be fatal, due to its ability to cause autonomic instability and seizures. Withdrawing from alcohol is also unpleasant due to hallucinosis and tremors, on top of the very real cravings for the substance itself. My patient knew this; he had withdrawn from alcohol in the past. As he talked to me, though, it became clear he had finally decided this was the end. In the past, others encouraged him to stop drinking; this time he was doing it for himself. His life had become so dismal that he was willing to undergo the agony of withdrawal to be free from his addiction.

Was his suffering, then, his misery, a gift? As I came to know my attending better, I also came to understand what these jarring words meant to her. They were her version of the old adage: It’s only when you hit rock bottom that you can start climbing back out. It isn’t the misery of withdrawing, but the misery inflicted by the substance that might provide an unexpected opportunity to start fixing things. For my patient, this particular trip to the hospital—which happened to intersect in space and time with me, a third-year medical student keen to learn and to help—was rock bottom, and he knew it. His life had been destroyed by his addiction, and here, at this intersection, the destruction was so great that he was finally willing to make a change for the better.

It is counterintuitive to think of misery as a gift, but then again, this patient—and more broadly, all patients whose lives are tormented by addiction and substance abuse—are often on the receiving end of counterintuitive advice, and it is frequently the only way to enact lasting change. Consider, for example, Alcoholics’ Anonymous, which works for far more individuals than one might expect. It does not seem possible that a small group without formal training could keep people sober simply by talking openly about their struggles; yet every day throughout the world, it does just that.

Patients struggling with addiction—labeled as addicts and drug-seekers by most of the world—are often written off as “difficult patients.” Perhaps because of my inexperience, I didn’t see this man as difficult, or as just another case of alcohol withdrawal. Although it may often be easier to define someone by his or her disease, I believe in choosing to see the human underneath the label. To me, these patients are not difficult; they are broken and miserable, and they desperately need help. Knowing this, I am forced to consider just how bad things have gotten for them, and how hard it must be to make a change. Their brokenness may be an opportunity to start down a new path, but only if we extend that invitation. Such an invitation may be the first step to turning genuine misery into a gift.

When I’m asked why I have chosen psychiatry, willingly entering such a “difficult field,” I think about my experience on that consult service and this patient. I know that I’m still just beginning my journey, and that even more difficult moments and patients lie ahead. But difficulty depends on one’s perspective; certainly that patient, trying to free himself from addiction’s grasp, was “going through a difficult time.” This is of course a platitude; the word “misery” gets much closer to the truth. I usually answer with some variation of the following: Medicine, especially psychiatry, is about caring for those who need it most: hurting, vulnerable people rejected by friends, family, and society. Our business is misery; sometimes we track in the broken, the beat down, the rock bottom. We get down in the depths with our patients to offer comfort and hope. We look at an addict, but we see a human being. We try to see the world from his or her perspective. This isn’t always pleasant—sometimes, it’s downright miserable—but to see the world through the eyes of another is, always, a gift.

On the first day of my psychiatry clerkship, I sat at a table with another student, 2 residents, and our attending physician. This wasn’t my first clinical rotation, but it was my first formal exposure to psychiatry, and I was excited and a bit anxious because I was considering psychiatry as an area of specialty training for myself. I’d been assigned 1 patient that morning: a 42-year-old man admitted for alcohol withdrawal. Our team, the psychiatry consultation-liaison team, was asked to evaluate the patient’s depressed mood in the context of withdrawal. As I began to present the patient’s story, I spoke of how terrible this man’s life had been, and how depressed he had recently become; this depression, I said, was likely exacerbated by alcohol use, but he was dealing with his depression by drinking more. He now wanted to quit for good. My attending, whom I had just met, interrupted me: “Misery,” she said with an intense look, “is a gift to an addicted person.”

I have ruminated on those surprising words ever since, and in that time I have begun to understand something about misery through the eyes of my patients. Sick people often are miserable; physical ailments can wreck hopes and plans and suck the joy from seemingly everything. Individuals who are ill or in pain often are suffering psychologically as well as physically. This suffering has been especially apparent to me in patients withdrawing from addictive substances: alcohol, cocaine, heroin, nicotine. I have been begged, cursed, praised, thanked, and more based on my ability or inability to relieve someone’s suffering caused by the lack of a certain substance: Please, just one cigarette. Please, something for this pain. Please, something to drink. As a medical student, I did one of 2 things: stood there helpless, or promised I would do the best I could, knowing my resident or attending would likely tell them no.

Withdrawal from addictive substances is, unsurprisingly, not pleasant. Alcohol withdrawal is one of the few that can be fatal, due to its ability to cause autonomic instability and seizures. Withdrawing from alcohol is also unpleasant due to hallucinosis and tremors, on top of the very real cravings for the substance itself. My patient knew this; he had withdrawn from alcohol in the past. As he talked to me, though, it became clear he had finally decided this was the end. In the past, others encouraged him to stop drinking; this time he was doing it for himself. His life had become so dismal that he was willing to undergo the agony of withdrawal to be free from his addiction.

Was his suffering, then, his misery, a gift? As I came to know my attending better, I also came to understand what these jarring words meant to her. They were her version of the old adage: It’s only when you hit rock bottom that you can start climbing back out. It isn’t the misery of withdrawing, but the misery inflicted by the substance that might provide an unexpected opportunity to start fixing things. For my patient, this particular trip to the hospital—which happened to intersect in space and time with me, a third-year medical student keen to learn and to help—was rock bottom, and he knew it. His life had been destroyed by his addiction, and here, at this intersection, the destruction was so great that he was finally willing to make a change for the better.

It is counterintuitive to think of misery as a gift, but then again, this patient—and more broadly, all patients whose lives are tormented by addiction and substance abuse—are often on the receiving end of counterintuitive advice, and it is frequently the only way to enact lasting change. Consider, for example, Alcoholics’ Anonymous, which works for far more individuals than one might expect. It does not seem possible that a small group without formal training could keep people sober simply by talking openly about their struggles; yet every day throughout the world, it does just that.

Patients struggling with addiction—labeled as addicts and drug-seekers by most of the world—are often written off as “difficult patients.” Perhaps because of my inexperience, I didn’t see this man as difficult, or as just another case of alcohol withdrawal. Although it may often be easier to define someone by his or her disease, I believe in choosing to see the human underneath the label. To me, these patients are not difficult; they are broken and miserable, and they desperately need help. Knowing this, I am forced to consider just how bad things have gotten for them, and how hard it must be to make a change. Their brokenness may be an opportunity to start down a new path, but only if we extend that invitation. Such an invitation may be the first step to turning genuine misery into a gift.

When I’m asked why I have chosen psychiatry, willingly entering such a “difficult field,” I think about my experience on that consult service and this patient. I know that I’m still just beginning my journey, and that even more difficult moments and patients lie ahead. But difficulty depends on one’s perspective; certainly that patient, trying to free himself from addiction’s grasp, was “going through a difficult time.” This is of course a platitude; the word “misery” gets much closer to the truth. I usually answer with some variation of the following: Medicine, especially psychiatry, is about caring for those who need it most: hurting, vulnerable people rejected by friends, family, and society. Our business is misery; sometimes we track in the broken, the beat down, the rock bottom. We get down in the depths with our patients to offer comfort and hope. We look at an addict, but we see a human being. We try to see the world from his or her perspective. This isn’t always pleasant—sometimes, it’s downright miserable—but to see the world through the eyes of another is, always, a gift.

On the first day of my psychiatry clerkship, I sat at a table with another student, 2 residents, and our attending physician. This wasn’t my first clinical rotation, but it was my first formal exposure to psychiatry, and I was excited and a bit anxious because I was considering psychiatry as an area of specialty training for myself. I’d been assigned 1 patient that morning: a 42-year-old man admitted for alcohol withdrawal. Our team, the psychiatry consultation-liaison team, was asked to evaluate the patient’s depressed mood in the context of withdrawal. As I began to present the patient’s story, I spoke of how terrible this man’s life had been, and how depressed he had recently become; this depression, I said, was likely exacerbated by alcohol use, but he was dealing with his depression by drinking more. He now wanted to quit for good. My attending, whom I had just met, interrupted me: “Misery,” she said with an intense look, “is a gift to an addicted person.”

I have ruminated on those surprising words ever since, and in that time I have begun to understand something about misery through the eyes of my patients. Sick people often are miserable; physical ailments can wreck hopes and plans and suck the joy from seemingly everything. Individuals who are ill or in pain often are suffering psychologically as well as physically. This suffering has been especially apparent to me in patients withdrawing from addictive substances: alcohol, cocaine, heroin, nicotine. I have been begged, cursed, praised, thanked, and more based on my ability or inability to relieve someone’s suffering caused by the lack of a certain substance: Please, just one cigarette. Please, something for this pain. Please, something to drink. As a medical student, I did one of 2 things: stood there helpless, or promised I would do the best I could, knowing my resident or attending would likely tell them no.

Withdrawal from addictive substances is, unsurprisingly, not pleasant. Alcohol withdrawal is one of the few that can be fatal, due to its ability to cause autonomic instability and seizures. Withdrawing from alcohol is also unpleasant due to hallucinosis and tremors, on top of the very real cravings for the substance itself. My patient knew this; he had withdrawn from alcohol in the past. As he talked to me, though, it became clear he had finally decided this was the end. In the past, others encouraged him to stop drinking; this time he was doing it for himself. His life had become so dismal that he was willing to undergo the agony of withdrawal to be free from his addiction.

Was his suffering, then, his misery, a gift? As I came to know my attending better, I also came to understand what these jarring words meant to her. They were her version of the old adage: It’s only when you hit rock bottom that you can start climbing back out. It isn’t the misery of withdrawing, but the misery inflicted by the substance that might provide an unexpected opportunity to start fixing things. For my patient, this particular trip to the hospital—which happened to intersect in space and time with me, a third-year medical student keen to learn and to help—was rock bottom, and he knew it. His life had been destroyed by his addiction, and here, at this intersection, the destruction was so great that he was finally willing to make a change for the better.

It is counterintuitive to think of misery as a gift, but then again, this patient—and more broadly, all patients whose lives are tormented by addiction and substance abuse—are often on the receiving end of counterintuitive advice, and it is frequently the only way to enact lasting change. Consider, for example, Alcoholics’ Anonymous, which works for far more individuals than one might expect. It does not seem possible that a small group without formal training could keep people sober simply by talking openly about their struggles; yet every day throughout the world, it does just that.

Patients struggling with addiction—labeled as addicts and drug-seekers by most of the world—are often written off as “difficult patients.” Perhaps because of my inexperience, I didn’t see this man as difficult, or as just another case of alcohol withdrawal. Although it may often be easier to define someone by his or her disease, I believe in choosing to see the human underneath the label. To me, these patients are not difficult; they are broken and miserable, and they desperately need help. Knowing this, I am forced to consider just how bad things have gotten for them, and how hard it must be to make a change. Their brokenness may be an opportunity to start down a new path, but only if we extend that invitation. Such an invitation may be the first step to turning genuine misery into a gift.

When I’m asked why I have chosen psychiatry, willingly entering such a “difficult field,” I think about my experience on that consult service and this patient. I know that I’m still just beginning my journey, and that even more difficult moments and patients lie ahead. But difficulty depends on one’s perspective; certainly that patient, trying to free himself from addiction’s grasp, was “going through a difficult time.” This is of course a platitude; the word “misery” gets much closer to the truth. I usually answer with some variation of the following: Medicine, especially psychiatry, is about caring for those who need it most: hurting, vulnerable people rejected by friends, family, and society. Our business is misery; sometimes we track in the broken, the beat down, the rock bottom. We get down in the depths with our patients to offer comfort and hope. We look at an addict, but we see a human being. We try to see the world from his or her perspective. This isn’t always pleasant—sometimes, it’s downright miserable—but to see the world through the eyes of another is, always, a gift.

Our 24-hour society has made night shift work essential to people in many professions, including medical specialties. Working nights disrupts homeostatic and circadian rhythms, which leads to an accumulation of sleep debt (ie, the cumulative effect of not getting enough sleep).¹ This debt can affect performance by impairing processing speed, concentration, mood, and physical health.¹ Night shift work takes place during the period of the sleep-wake cycle that is programmed for sleep; after the shift, workers need to sleep during the period that is least conducive to sleep.¹ Research indicates that a night shift worker’s sleep can be improved by scheduling light exposure and optimizing the timing of when they start their shifts.² However, this may not be practical because night shifts usually are scheduled at particular intervals and cannot be tailored to the individual worker’s preference. Additionally, in the short term, full circadian adaptation to night shifts is impossible.¹

Because sleep and performance are complex phenomena that are difficult to control, there is no single solution to maximizing these factors when one works nights.¹ The most effective approach to combating the effects of night shift work is individualized and multimodal.¹ However, whether you are working a night shift or are caring for a patient who does, the following nonpharmacologic strategies can help improve sleep and performance until the body naturally adapts to working this type of schedule^1,3:

Minimize sleep debt before starting aseries of night shifts by not setting an alarm on the morning before the first night shift and by napping in the afternoon for approximately 45 minutes.

Take a nap during a work break (if work demands allow you to do so). However, nap for <30 minutes to avoid slow-wave sleep and subsequent grogginess when awakening.

Expose yourself to bright light immediately upon waking and for 15 minutes 2 or 3 times during a shift to promote alertness.

Drink caffeinated beverages before and during the shift to help improve concentration and reasoning (if there is no medical contraindication to consuming caffeine). However, avoid caffeine for at least 3 hours prior to going to sleep.

Add additional checks to critical tasks, such as ordering medications, during the shift, especially during the physiological nadir in the early hours of the morning.

Continue to: Create a cool, dark, quiet environment for sleep...

Create a cool, dark, quiet environment for sleep using a comfortable mattress and pillow, blackout blinds, ear plugs, and a noise machine. Also, avoid using your smartphone or tablet while trying to go to sleep. Minimize exposure to bright light on the drive home, and stick to a routine (eg, for meals and exercise).

Avoid working too many consecutive night shifts (if possible) because this can increase sleep deprivation. Also, limiting the number of night shifts and scheduling days off can speed recovery from sleep deprivation.

Our 24-hour society has made night shift work essential to people in many professions, including medical specialties. Working nights disrupts homeostatic and circadian rhythms, which leads to an accumulation of sleep debt (ie, the cumulative effect of not getting enough sleep).¹ This debt can affect performance by impairing processing speed, concentration, mood, and physical health.¹ Night shift work takes place during the period of the sleep-wake cycle that is programmed for sleep; after the shift, workers need to sleep during the period that is least conducive to sleep.¹ Research indicates that a night shift worker’s sleep can be improved by scheduling light exposure and optimizing the timing of when they start their shifts.² However, this may not be practical because night shifts usually are scheduled at particular intervals and cannot be tailored to the individual worker’s preference. Additionally, in the short term, full circadian adaptation to night shifts is impossible.¹

Because sleep and performance are complex phenomena that are difficult to control, there is no single solution to maximizing these factors when one works nights.¹ The most effective approach to combating the effects of night shift work is individualized and multimodal.¹ However, whether you are working a night shift or are caring for a patient who does, the following nonpharmacologic strategies can help improve sleep and performance until the body naturally adapts to working this type of schedule^1,3:

Minimize sleep debt before starting aseries of night shifts by not setting an alarm on the morning before the first night shift and by napping in the afternoon for approximately 45 minutes.

Take a nap during a work break (if work demands allow you to do so). However, nap for <30 minutes to avoid slow-wave sleep and subsequent grogginess when awakening.

Expose yourself to bright light immediately upon waking and for 15 minutes 2 or 3 times during a shift to promote alertness.

Drink caffeinated beverages before and during the shift to help improve concentration and reasoning (if there is no medical contraindication to consuming caffeine). However, avoid caffeine for at least 3 hours prior to going to sleep.

Add additional checks to critical tasks, such as ordering medications, during the shift, especially during the physiological nadir in the early hours of the morning.

Continue to: Create a cool, dark, quiet environment for sleep...

Create a cool, dark, quiet environment for sleep using a comfortable mattress and pillow, blackout blinds, ear plugs, and a noise machine. Also, avoid using your smartphone or tablet while trying to go to sleep. Minimize exposure to bright light on the drive home, and stick to a routine (eg, for meals and exercise).

Avoid working too many consecutive night shifts (if possible) because this can increase sleep deprivation. Also, limiting the number of night shifts and scheduling days off can speed recovery from sleep deprivation.

Our 24-hour society has made night shift work essential to people in many professions, including medical specialties. Working nights disrupts homeostatic and circadian rhythms, which leads to an accumulation of sleep debt (ie, the cumulative effect of not getting enough sleep).¹ This debt can affect performance by impairing processing speed, concentration, mood, and physical health.¹ Night shift work takes place during the period of the sleep-wake cycle that is programmed for sleep; after the shift, workers need to sleep during the period that is least conducive to sleep.¹ Research indicates that a night shift worker’s sleep can be improved by scheduling light exposure and optimizing the timing of when they start their shifts.² However, this may not be practical because night shifts usually are scheduled at particular intervals and cannot be tailored to the individual worker’s preference. Additionally, in the short term, full circadian adaptation to night shifts is impossible.¹

Because sleep and performance are complex phenomena that are difficult to control, there is no single solution to maximizing these factors when one works nights.¹ The most effective approach to combating the effects of night shift work is individualized and multimodal.¹ However, whether you are working a night shift or are caring for a patient who does, the following nonpharmacologic strategies can help improve sleep and performance until the body naturally adapts to working this type of schedule^1,3:

Minimize sleep debt before starting aseries of night shifts by not setting an alarm on the morning before the first night shift and by napping in the afternoon for approximately 45 minutes.

Take a nap during a work break (if work demands allow you to do so). However, nap for <30 minutes to avoid slow-wave sleep and subsequent grogginess when awakening.

Expose yourself to bright light immediately upon waking and for 15 minutes 2 or 3 times during a shift to promote alertness.

Drink caffeinated beverages before and during the shift to help improve concentration and reasoning (if there is no medical contraindication to consuming caffeine). However, avoid caffeine for at least 3 hours prior to going to sleep.

Add additional checks to critical tasks, such as ordering medications, during the shift, especially during the physiological nadir in the early hours of the morning.

Continue to: Create a cool, dark, quiet environment for sleep...

Create a cool, dark, quiet environment for sleep using a comfortable mattress and pillow, blackout blinds, ear plugs, and a noise machine. Also, avoid using your smartphone or tablet while trying to go to sleep. Minimize exposure to bright light on the drive home, and stick to a routine (eg, for meals and exercise).

Avoid working too many consecutive night shifts (if possible) because this can increase sleep deprivation. Also, limiting the number of night shifts and scheduling days off can speed recovery from sleep deprivation.

CASE

Mr. C, a veteran in his 60s who has posttraumatic stress disorder (PTSD), presents to your clinic for a 45-minute follow-up visit. He has a remote history of depression and a 20-year history of substance use disorder (SUD); he uses heroin, at least 3 bags a day by insufflation. You review his response to his currently prescribed PTSD treatment regimen, ask if he is experiencing any adverse effects, and perform a mental status exam and a review of systems. You offer Mr. C detoxification and rehabilitation treatment for his heroin use, but he refuses. With 15 minutes left in the appointment, you consider conducting motivational interviewing (MI) to help him reconsider getting treatment for his SUD.

Even when delivered as a brief, one-time intervention, MI can be effective in getting patients to change their behavior.¹ First created in part by psychologists William Miller, PhD, and Stephen Rollnick, PhD,² MI is based on the premise that a patient’s ambivalence to change is normal and that all patients vary in their readiness to change. MI can be brief, and can be more helpful than providing only proscriptive advice, which sometimes can be counterproductitive.³

To effectively implement MI during a brief visit, it is helpful to keep in mind 3 mnemonics: RULE, PACE, and OARS.

RULE

RULE can be used to remember the core principles of MI.⁴ First, Resist the righting reflex, which means we should resist giving suggestions to our patients for their problems. While we may mean well, offering suggestions might actually make the patient less likely to make a positive change. Understand the patient’s motivation by being a curious listener and attempting to elicit the patient’s own underlying motivation for change. Listen with a patient-centered, empathic approach. Lastly, Empower the patient. He must understand that he is in control of his actions, and any change he desires will require him to take steps toward that change.

PACE

PACE is the “spirit” or mindset that clinicians should have when conducting MI.^4,5 Always work in Partnership with the patient; this allows the patient and clinician to collaborate on the same level. While the physician is a clinical expert, the patient is an expert in prior efforts at trying to change his or her circumstances for the better. Make the therapeutic environment as positive as possible so that your patient will find it comfortable to discuss change. The patient should see the clinician as a guide who offers information about paths the patient may choose, not someone who decides the destination.⁵ While as physicians we must continue to educate our patients about the harms of behaviors such as excessive drinking or substance use, we recognize that ultimately the decision is the patient’s. Make every effort to draw from the patients’ goals and values, so that the patient, and not the clinician, can argue for why change is needed. This Acceptance helps foster an attitude that we are on the patient’s side and that his past choices in life do not negatively affect our perception of him. The patient should be accepted for who he is, and not met with disapproval over any personal decisions that he made.⁵ Exercise Compassion towards the patient’s struggles and experiences,⁵ and never be punitive. Make every attempt to have discussions that can be Evocative for the patient. Strong feelings and memories can be particularly salient to discuss, especially if they could help change the patient’s attitude towards maladaptive behaviors.

OARS

OARS can be used to help remember core skills of MI.⁵ These include asking Open-ended questions to get the patient to think before responding, providing frequent Affirmations of the patient’s positive traits, using Reflective listening techniques while your patient talks about his disorder, and providing succinct Summaries of the experiences expressed by your patient throughout the encounter to invite continued exploration of his behaviors.

Getting patients to talk about change

Use RULE, PACE, and OARS to elicit “change talk,”⁴ so that your patient makes his own arguments for change. Here ambivalence is good, in that an ambivalent patient may be open to discuss reasons for making changes. It is important to remember not to use the righting reflex to give suggestions to change.

Continue to: CASE...

You use the last 15 minutes of Mr. C’s visit to conduct MI and acknowledge his ambivalence to change. Mr. C reveals that his motivation for change centers on how he perceives himself as a disappointment to his daughter because of his continuous drug use. At the end of the encounter, Mr. C is in tears but has a renewed motivation to stop using heroin. He agrees to enter substance abuse treatment.

CASE

Mr. C, a veteran in his 60s who has posttraumatic stress disorder (PTSD), presents to your clinic for a 45-minute follow-up visit. He has a remote history of depression and a 20-year history of substance use disorder (SUD); he uses heroin, at least 3 bags a day by insufflation. You review his response to his currently prescribed PTSD treatment regimen, ask if he is experiencing any adverse effects, and perform a mental status exam and a review of systems. You offer Mr. C detoxification and rehabilitation treatment for his heroin use, but he refuses. With 15 minutes left in the appointment, you consider conducting motivational interviewing (MI) to help him reconsider getting treatment for his SUD.

Even when delivered as a brief, one-time intervention, MI can be effective in getting patients to change their behavior.¹ First created in part by psychologists William Miller, PhD, and Stephen Rollnick, PhD,² MI is based on the premise that a patient’s ambivalence to change is normal and that all patients vary in their readiness to change. MI can be brief, and can be more helpful than providing only proscriptive advice, which sometimes can be counterproductitive.³

To effectively implement MI during a brief visit, it is helpful to keep in mind 3 mnemonics: RULE, PACE, and OARS.

RULE

RULE can be used to remember the core principles of MI.⁴ First, Resist the righting reflex, which means we should resist giving suggestions to our patients for their problems. While we may mean well, offering suggestions might actually make the patient less likely to make a positive change. Understand the patient’s motivation by being a curious listener and attempting to elicit the patient’s own underlying motivation for change. Listen with a patient-centered, empathic approach. Lastly, Empower the patient. He must understand that he is in control of his actions, and any change he desires will require him to take steps toward that change.

PACE

PACE is the “spirit” or mindset that clinicians should have when conducting MI.^4,5 Always work in Partnership with the patient; this allows the patient and clinician to collaborate on the same level. While the physician is a clinical expert, the patient is an expert in prior efforts at trying to change his or her circumstances for the better. Make the therapeutic environment as positive as possible so that your patient will find it comfortable to discuss change. The patient should see the clinician as a guide who offers information about paths the patient may choose, not someone who decides the destination.⁵ While as physicians we must continue to educate our patients about the harms of behaviors such as excessive drinking or substance use, we recognize that ultimately the decision is the patient’s. Make every effort to draw from the patients’ goals and values, so that the patient, and not the clinician, can argue for why change is needed. This Acceptance helps foster an attitude that we are on the patient’s side and that his past choices in life do not negatively affect our perception of him. The patient should be accepted for who he is, and not met with disapproval over any personal decisions that he made.⁵ Exercise Compassion towards the patient’s struggles and experiences,⁵ and never be punitive. Make every attempt to have discussions that can be Evocative for the patient. Strong feelings and memories can be particularly salient to discuss, especially if they could help change the patient’s attitude towards maladaptive behaviors.

OARS

OARS can be used to help remember core skills of MI.⁵ These include asking Open-ended questions to get the patient to think before responding, providing frequent Affirmations of the patient’s positive traits, using Reflective listening techniques while your patient talks about his disorder, and providing succinct Summaries of the experiences expressed by your patient throughout the encounter to invite continued exploration of his behaviors.

Getting patients to talk about change

Use RULE, PACE, and OARS to elicit “change talk,”⁴ so that your patient makes his own arguments for change. Here ambivalence is good, in that an ambivalent patient may be open to discuss reasons for making changes. It is important to remember not to use the righting reflex to give suggestions to change.

Continue to: CASE...

You use the last 15 minutes of Mr. C’s visit to conduct MI and acknowledge his ambivalence to change. Mr. C reveals that his motivation for change centers on how he perceives himself as a disappointment to his daughter because of his continuous drug use. At the end of the encounter, Mr. C is in tears but has a renewed motivation to stop using heroin. He agrees to enter substance abuse treatment.

CASE

Mr. C, a veteran in his 60s who has posttraumatic stress disorder (PTSD), presents to your clinic for a 45-minute follow-up visit. He has a remote history of depression and a 20-year history of substance use disorder (SUD); he uses heroin, at least 3 bags a day by insufflation. You review his response to his currently prescribed PTSD treatment regimen, ask if he is experiencing any adverse effects, and perform a mental status exam and a review of systems. You offer Mr. C detoxification and rehabilitation treatment for his heroin use, but he refuses. With 15 minutes left in the appointment, you consider conducting motivational interviewing (MI) to help him reconsider getting treatment for his SUD.

Even when delivered as a brief, one-time intervention, MI can be effective in getting patients to change their behavior.¹ First created in part by psychologists William Miller, PhD, and Stephen Rollnick, PhD,² MI is based on the premise that a patient’s ambivalence to change is normal and that all patients vary in their readiness to change. MI can be brief, and can be more helpful than providing only proscriptive advice, which sometimes can be counterproductitive.³

To effectively implement MI during a brief visit, it is helpful to keep in mind 3 mnemonics: RULE, PACE, and OARS.

RULE

RULE can be used to remember the core principles of MI.⁴ First, Resist the righting reflex, which means we should resist giving suggestions to our patients for their problems. While we may mean well, offering suggestions might actually make the patient less likely to make a positive change. Understand the patient’s motivation by being a curious listener and attempting to elicit the patient’s own underlying motivation for change. Listen with a patient-centered, empathic approach. Lastly, Empower the patient. He must understand that he is in control of his actions, and any change he desires will require him to take steps toward that change.

PACE

PACE is the “spirit” or mindset that clinicians should have when conducting MI.^4,5 Always work in Partnership with the patient; this allows the patient and clinician to collaborate on the same level. While the physician is a clinical expert, the patient is an expert in prior efforts at trying to change his or her circumstances for the better. Make the therapeutic environment as positive as possible so that your patient will find it comfortable to discuss change. The patient should see the clinician as a guide who offers information about paths the patient may choose, not someone who decides the destination.⁵ While as physicians we must continue to educate our patients about the harms of behaviors such as excessive drinking or substance use, we recognize that ultimately the decision is the patient’s. Make every effort to draw from the patients’ goals and values, so that the patient, and not the clinician, can argue for why change is needed. This Acceptance helps foster an attitude that we are on the patient’s side and that his past choices in life do not negatively affect our perception of him. The patient should be accepted for who he is, and not met with disapproval over any personal decisions that he made.⁵ Exercise Compassion towards the patient’s struggles and experiences,⁵ and never be punitive. Make every attempt to have discussions that can be Evocative for the patient. Strong feelings and memories can be particularly salient to discuss, especially if they could help change the patient’s attitude towards maladaptive behaviors.

OARS

OARS can be used to help remember core skills of MI.⁵ These include asking Open-ended questions to get the patient to think before responding, providing frequent Affirmations of the patient’s positive traits, using Reflective listening techniques while your patient talks about his disorder, and providing succinct Summaries of the experiences expressed by your patient throughout the encounter to invite continued exploration of his behaviors.

Getting patients to talk about change

Use RULE, PACE, and OARS to elicit “change talk,”⁴ so that your patient makes his own arguments for change. Here ambivalence is good, in that an ambivalent patient may be open to discuss reasons for making changes. It is important to remember not to use the righting reflex to give suggestions to change.

Continue to: CASE...

You use the last 15 minutes of Mr. C’s visit to conduct MI and acknowledge his ambivalence to change. Mr. C reveals that his motivation for change centers on how he perceives himself as a disappointment to his daughter because of his continuous drug use. At the end of the encounter, Mr. C is in tears but has a renewed motivation to stop using heroin. He agrees to enter substance abuse treatment.

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

CASE Altered mental status after stroke workup

Ms. L, age 91, is admitted to the hospital for a neurologic evaluation of a recent episode of left-sided weakness that occurred 1 week ago. This left-sided weakness resolved without intervention within 2 hours while at home. This presentation is typical of a transient ischemic attack (TIA). She has a history of hypertension, bradycardia, and pacemaker implantation. On initial evaluation, her memory is intact, and she is able to walk normally. Her score on the St. Louis University Mental Status (SLUMS) exam is 25, which suggests normal cognitive functioning for her academic background. A CT scan of the head reveals a subacute stroke of the right posterior limb of the internal capsule consistent with recent TIA.

Ms. L is admitted for a routine stroke workup and prepares to undergo a CT angiogram (CTA) with the use of the iodinated agent iopamidol (100 mL, 76%) to evaluate patency of cerebral vessels. Her baseline blood urea nitrogen (BUN) and creatinine levels are within normal limits.

A day after undergoing CTA, Ms. L starts mumbling to herself, has unpredictable mood outbursts, and is not oriented to time, place, or person.

[polldaddy:10199351]

The authors’ observations

Due to her acute altered mental status (AMS), Ms. L underwent an emergent CT scan of the head to rule out any acute intracranial hemorrhages or thromboembolic events. The results of this test were negative. Urinalysis, BUN, creatinine, basic chemistry, and complete blood count panels were unrevealing. On a repeat SLUMS exam, Ms. L scored 9, indicating cognitive impairment.

Ms. L also underwent a comprehensive metabolic profile, which excluded any electrolyte abnormalities, or any hepatic or renal causes of AMS. There was no sign of dehydration, acidosis, hypoglycemia, hypoxemia, hypotension, or bradycardia/tachycardia. A urinalysis, chest X-ray, complete blood count, and 2 blood cultures conducted 24 hours apart did not reveal any signs of infection. There were no recent changes in her medications and she was not taking any sleep medications or other psychiatric medications that might precipitate a withdrawal syndrome.

There have been multiple reports of contrast-induced nephropathy (CIN), which may be evidenced by high BUN-to-creatinine ratios and could cause AMS in geriatric patients. However, CIN was ruled out as a potential cause in our patient because her BUN-to-creatinine was unremarkable.

Continue to: Routine EEG was clinically...

Routine EEG was clinically inconclusive. Diffusion-weighted MRI may have been helpful to identify ischemic strokes that a CT scan of the head might miss,¹ but we were unable to conduct this test because Ms. L had a pacemaker. Barber et al² suggested that in the setting of acute stroke, the use of MRI may not have an added advantage over the CT scan of the head.

[polldaddy:10199352]

TREATMENT Rapid improvement with supportive therapy

Intravenous fluids are administered as supportive therapy to Ms. L for suspected contrast-induced encephalopathy (CIE). The next day, Ms. L experiences a notable improvement in cognition, beyond that attributed to IV hydration. By 3 days post-contrast injection, her SLUMS score increases to 15. By 72 hours after contrast administration, Ms. L’s cognition returns to baseline. She is monitored for 24 hours after returning to baseline cognitive functioning. After observing her to be in no physical or medical distress and at baseline functioning, she is discharged home under the care of her son with outpatient follow-up and rehab services.

The authors’ observations

For Ms. L, the differential diagnosis included post-ictal phenomenon, new-onset ischemic or hemorrhagic changes, hyperperfusion syndrome, and CIE.

Seizures were ruled out because EEG was inconclusive, and Ms. L did not have the clinical features one would expect in an ictal episode. Transient ischemic attack is, by definition, an ischemic event with clinical return to baseline within 24 hours. Although a CT scan of the head may not be the most sensitive way to detect early ischemic changes and small ischemic zones, the self-limiting course and complete resolution of Ms. L’s symptoms with return to baseline is indicative of a more benign pathology, such as CIE. New hemorrhagic conversions have a dramatic presentation on radiologic studies. Historically, CIE presentations on imaging have been closely associated with the hyperattentuation seen in subarachnoid hemorrhage (SAH). The absence of typical radiologic and clinical findings in our case ruled out SAH.

Continue to: Typical CT scan findings in CIE include...

Typical CT scan findings in CIE include abnormal cortical contrast enhancement and edema, subarachnoid contrast enhancement, and striatal contrast enhancement (Figure 1, Figure 2, and Figure 3). Since the first clinical description, reports of 39 CT-/MRI-confirmed cases of CIE have been published in English language medical literature, with documented clinical follow-up³ and a median recovery time of 2.5 days. In a case report by Ito et al,⁴ there were no supportive radiographic findings. Ours is the second documented case that showed no radiologic signs of CIE. With a paucity of other etiologic evidence, negative lab tests for other causes of delirium, and the rapid resolution of Ms. L’s AMS after providing IV fluids as supportive treatment, a temporal correlation can be deduced, which implicates iodine-based contrast as the inciting factor.

Iodine-based contrast agents have been used since the 1920s. Today, >75 million procedures requiring iodine dyes are performed annually worldwide.⁵ This level of routine iodine contrast usage compels a mention of risk factors and complications from using such dyes. As a general rule, contrast agent reactions can be categorized as immediate (<1 day) or delayed (1 to 7 days after contrast administration). Immediate reactions are immunoglobulin E (IgE)-mediated anaphylactic reactions. Delayed reactions involve a T-cell mediated response that ranges from pruritus and urticaria (approximately 70%) to cardiac complications such as cardiovascular shock, arrhythmia, arrest, and Kounis syndrome. Other less prevalent complications include hypotension, bronchospasm, and CIN. Patients with the following factors may be at higher risk for contrast-induced reactions:

• asthma
• cardiac arrhythmias
• central myasthenia gravis
• >70 years of age
• pheochromocytoma
• sickle cell anemia
• hyperthyroidism
• dehydration
• hypotension.

Although some older literature reported correlations between seafood and shellfish allergies and iodine contrast reactions, more recent reports suggest there may not be a direct correlation, or any correlation at all.^5,6

Iodinated CIE is a rare complication of contrast angiography. It was first reported in 1970 as transient cortical blindness after coronary angiography.⁷ Clinical manifestations include encephalopathy evidenced by AMS, affected orientation, and acute psychotic changes, including paranoia and hallucinations, seizures, cortical blindness, and focal neurologic deficits. Neuroimaging has been pivotal in confirming the diagnosis and in excluding thromboembolic and hemorrhagic complications of angiography.⁸

Encephalopathy has been documented after administration of iopromide,^9,10iohexol,¹¹ioxilan,⁴ and metrizamide. The mechanism of neurotoxicity is unclear, but several theories have been formulated. The contrast agent may disturb the blood-brain barrier and enter the brain. This may be a primary mechanism leading to encephalopathy when the hypertonic contrast agent draws water out of the endothelial cells of brain capillaries, arterioles, and venules. This may cause the endothelial cells to shrink and to separate at tight junctions directly affecting the blood-brain barrier. Alternatively, the increase in intraluminal pressure caused by injection of the contrast agent, in concert with contrast agent-induced cerebral vasodilatation, might contribute to increasing vascular wall tension, further separating tight junctions. A third theory suggests that vesicular transport may be a mechanism of osmotic barrier opening. Further studies would be required to investigate these mechanisms.

Continue to: Regardless of the mechanism...

Regardless of the mechanism, all the above-mentioned studies note a reversal of radiologic and neurologic findings without any deficits within 48 to 72 hours (median recovery time of 2.5 days).³ All reported cases of CIE, including ours, were found to be completely reversible without any neurologic or radiologic deficits after resolution (48 to 72 hours post-contrast administration).

Clinicians should have a high index of suspicion for CIE in patients with recent iodine-based contrast exposure. From a practical standpoint, such a mechanism could be easily missed because while use of a single-administration contrast agent may appear in procedure notes or medication administration records, it might not necessarily appear in documentation of currently administered medications. Also, such cases might not always present with unique radiologic findings, as illustrated by Ms. L’s case.

Bottom Line

Have a high index of suspicion for contrast-induced encephalopathy, especially in geriatric patients, even in the absence of radiologic findings. A full delirium/dementia workup is warranted to rule out other life-threatening causes of altered mental status. Timely recognition could enable implementation of medicationsparing approaches to the disorder, such as IV fluids and frequent reorientation.

Related Resources

• Donepudi B, Trottier S. A seizure and hemiplegia following contrast exposure: Understanding contrast-induced encephalopathy. Case Rep Med. 2018;2018:9278526. doi:10.1155/2018/9278526.
• Hamra M, Bakhit Y, Khan M, et al. Case report and literature review on contrast-induced encephalopathy. Future Cardiol. 2017;13(4):331-335.

Drug Brand Names

Iohexol • Omnipaque
Iopamidol • Isovue-370
Iopromide • Ultravist
Ioxilan • Oxilan

Death by drug overdose is the number one cause of death in Americans 50 years of age and younger.¹ In 2016, there were 63,632 drug overdose deaths in the United States² Opioids were involved in 42,249 of these deaths, which represents 66.4% of all drug overdose deaths.² From 2015 to 2016, the age-adjusted rate of overdose deaths increased significantly by 21.5% from 16.3 per 100,000 to 19.8 per 100,000.² This means that every day, more than 115 people in the United States die after overdosing on opioids. The misuse of and addiction to opioids—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects public health as well as social and economic welfare.

The gold standard treatment is medication-assisted treatment (MAT)—the use of FDA-approved medications, in combination with counseling and behavioral therapies, to provide a “whole-patient” approach.³ When it comes to MAT options for opioid use disorder (OUD), there are 3 medications, each with its own caveats.

Methadone is an opioid mu-receptor full agonist that prevents withdrawal but does not block other narcotics. It requires daily dosing as a liquid formulation that is dispensed only in regulated clinics.

Buprenorphine is a mu-receptor high affinity partial agonist/antagonist that blocks the majority of other narcotics while reducing withdrawal risk. It requires daily dosing as either a dissolving tablet or cheek film. Recently it has also become available as a 6-month implant as well as a 1-month subcutaneous injection. Buprenorphine is also available as a combined medication with naloxone; naloxone is an opioid antagonist.

Naltrexone is a mu-receptor antagonist that blocks the effects of most narcotics. It does not lead to dependence, and is administered daily as a pill or monthly as a deep IM injection of its extended-release formulation.

The first 2 medications are tightly regulated options that are not available in many areas of the United States. Naltrexone, when provided as a daily pill, has adherence issues. As with any illness, lack of adherence to treatment is problematic; in the case of patients with OUD, this includes a high risk of overdose and death.

The use of injectable extended-release naltrexone (XR-NTX) may be a way to address nonadherence and thus prevent relapse. One of the challenges limiting naltrexone’s applicability has been the length of time required for an “opioid washout” of the mu receptors prior to administering naltrexone, which is a mu blocker. The washout can take as long as 7 to 10 days. This interval is not feasible for patients receiving inpatient treatment, and patients receiving treatment as outpatients are vulnerable to relapse during this time. Recently, there have been several attempts to shorten this gap through various experimental protocols based on incremental doses of NTX to facilitate withdrawal while managing symptoms.

Continue to: When selecting appropriate candidates for NTX treatment...

When selecting appropriate candidates for NTX treatment, clinicians should consider individuals who are:

• not interested in or able to receive agonist maintenance treatment (ie, patients who do not have access to an appropriate clinic in their area, or who are restricted to agonist treatment by probation/parole)
• highly abstinence-oriented (eg, active in a 12-step program)
• in professions where agonists are controversial (eg, healthcare and airlines)
• detoxified and abstinent but at risk for relapse.

Individuals who have failed agonist treatment (eg, who experience cravings for opioids and use opioids while receiving it, or are nonadherent or diverting/misusing the medication), who have a less severe form of OUD (short history and low level of use), or who use sporadically are also optimal candidates for NTX. Aside from the relapse-vulnerable washout gap prior to induction, one of the concerns with antagonist treatments is treatment retention; anecdotal clinical reports suggest that individuals often discontinue antagonists in favor of agonists.

Several studies have investigated this by comparing XR-NTX with buprenorphine-naloxone (BUP-NX). Here we summarize 3 studies^4-6 to describe which patients might be optimal candidates for XR-NTX, its success in comparison with BUP-NX, and challenges in induction of NTX, with a focus on emerging protocols (Table).

1. Tanum l, Solli KK, Latif ZH, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74(12):1197-1205.

This study aimed to determine whether XR-NTX was not inferior to BUP-NX in the treatment of OUD.

Study design

• N = 159, multicenter, randomized, 12-week outpatient study in Norway
• After detoxification, participants were randomized to receive BUP-NX, 4 to 24 mg/d, or XR-NTX, 380 mg/month.

Continue to: Outcomes

Outcomes

• Comparable treatment retention between groups
• Comparable opioid-negative urine drug screens (UDS)
• Significantly lower opioid use in the XR-NTX group.

Conclusion

• XR-NTX was as effective as BUP-NX in maintaining short-term abstinence from heroin and other illicit opioids, and thus should be considered as a treatment option for opioid-dependent individuals.

While this study showed similar efficacy for XR-NTX and BUP-NX, it is important to note that the randomization occurred after patients were detoxified. As a full opioid antagonist, XR-NTX can precipitate severe withdrawal, so patients need to be completely detoxified before starting XR-NTX, in contrast to BUP-NX, which patients can start even while still in mild withdrawal. Additional studies are needed in which individuals are randomized before detoxification, which would make it possible to measure the success of induction.

2. Lee JD, Nunes, EV, Novo P, et al. Compar­ative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318.

This study evaluated XR-NTX vs BUP-NX among adults with OUD who were actively using heroin at baseline and were admitted to community detoxification and treatment programs. Although the study began on inpatient units, it aimed to replicate usual community outpatient conditions across a 24-week outpatient treatment phase of this open-label, comparative effectiveness trial. Researchers assessed the effects on relapse-free survival, opioid use rates, and overdose events.

Study design

• N = 570, multicenter, randomized, 24-week study in the United States
• Detoxification methods: no opioids (clonidine or adjunctive medications), 3- to 5-day methadone taper, and 3- to 14-day BUP taper
• Protocol requirement: opioid-negative UDS before XR-NTX induction
• XR-NTX induction success ranged from 50% at a short-methadone-taper unit to 95% at an extended-opioid-free inpatient program. Nearly all induction failures quickly relapsed
• More participants inducted on BUP-NX group than XR-NTX group (94% vs 72%, respectively).

Continue to: Outcomes

Outcomes (once successfully inducted to treatment [n = 474])

• Comparable relapse events
• Comparable opioid-negative urine drug screens and opioid-abstinent days
• Opioid craving initially less with XR-NTX.

Conclusion

• It was more difficult to initiate patients on XR-NTX than BUP-NX, which negatively affected overall relapse rates. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.

Regarding induction on NTX, patients must be detoxified and opioid-free for at least 7 days. If this medication is given to patients who are physically dependent and/or have opioids in their system, NTX will displace opioids off the receptor and precipitate a severe withdrawal (rather than a slow and gradual spontaneous withdrawal).

Several studies have examined the severity of opioid withdrawal (using Self Opioid Withdrawal Scale scoring) of patients undergoing detoxification with symptomatic management (eg, clonidine, loperamide, etc.), agonist-managed (eg, with a BUP taper), and without any assistance. As expected, the latter yielded the highest scoring and most uncomfortable experiences. Using scores from the first 2 groups, a threshold of symptom tolerability was established where patients remained somewhat comfortable during the process. During detoxification from heroin, administering any dose of NTX during the first 48 to 72 hours after the last use placed patients in a withdrawal of a magnitude above the limit of tolerability. At 48 to 72 hours, however, a very low NTX dose (3 to 6 mg) was found to be well tolerated, and withdrawal symptoms were easily managed supportively to accelerate the detoxification process. Several studies have attempted to devise protocols based on these findings in order to facilitate rapid induction onto NTX. The following study offers encouragement:

Continue to: 3. Sullivan M, Bisaga A, Pavlicova M...

3. Sullivan M, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry. 2017;174:459-467.

Study design

• N = 150 adults with OUD, randomized to outpatient opioid detoxification
• Patients were randomized to BUP- or NTX-facilitated detoxification, followed by XR-NTX
• BUP detoxification group underwent a 7-day BUP taper followed by a opioid-free week
• NTX group received a 1-day BUP dose followed by 6 days of ascending doses of oral NTX, along with clonidine and other adjunctive medications.

Outcomes

• NTX-assisted detoxification was significantly more successful for XR-NTX induction (56.1% vs 32.7%).

Conclusion

• Compared with the BUP-assisted detoxification group, NTX-assisted detoxification appears to make it significantly more likely for patients to be successfully inducted to XR-NTX.

The evidence discussed here holds promise in addressing some of the major issues surrounding MAT. For suitable candidates, XR-NTX seems to be as efficacious an option as agonist (BUP) MAT, and its induction limitations could be overcome by using NTX-facilitated detoxification protocols.

Death by drug overdose is the number one cause of death in Americans 50 years of age and younger.¹ In 2016, there were 63,632 drug overdose deaths in the United States² Opioids were involved in 42,249 of these deaths, which represents 66.4% of all drug overdose deaths.² From 2015 to 2016, the age-adjusted rate of overdose deaths increased significantly by 21.5% from 16.3 per 100,000 to 19.8 per 100,000.² This means that every day, more than 115 people in the United States die after overdosing on opioids. The misuse of and addiction to opioids—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects public health as well as social and economic welfare.

The gold standard treatment is medication-assisted treatment (MAT)—the use of FDA-approved medications, in combination with counseling and behavioral therapies, to provide a “whole-patient” approach.³ When it comes to MAT options for opioid use disorder (OUD), there are 3 medications, each with its own caveats.

Methadone is an opioid mu-receptor full agonist that prevents withdrawal but does not block other narcotics. It requires daily dosing as a liquid formulation that is dispensed only in regulated clinics.

Buprenorphine is a mu-receptor high affinity partial agonist/antagonist that blocks the majority of other narcotics while reducing withdrawal risk. It requires daily dosing as either a dissolving tablet or cheek film. Recently it has also become available as a 6-month implant as well as a 1-month subcutaneous injection. Buprenorphine is also available as a combined medication with naloxone; naloxone is an opioid antagonist.

Naltrexone is a mu-receptor antagonist that blocks the effects of most narcotics. It does not lead to dependence, and is administered daily as a pill or monthly as a deep IM injection of its extended-release formulation.

The first 2 medications are tightly regulated options that are not available in many areas of the United States. Naltrexone, when provided as a daily pill, has adherence issues. As with any illness, lack of adherence to treatment is problematic; in the case of patients with OUD, this includes a high risk of overdose and death.

The use of injectable extended-release naltrexone (XR-NTX) may be a way to address nonadherence and thus prevent relapse. One of the challenges limiting naltrexone’s applicability has been the length of time required for an “opioid washout” of the mu receptors prior to administering naltrexone, which is a mu blocker. The washout can take as long as 7 to 10 days. This interval is not feasible for patients receiving inpatient treatment, and patients receiving treatment as outpatients are vulnerable to relapse during this time. Recently, there have been several attempts to shorten this gap through various experimental protocols based on incremental doses of NTX to facilitate withdrawal while managing symptoms.

Continue to: When selecting appropriate candidates for NTX treatment...

When selecting appropriate candidates for NTX treatment, clinicians should consider individuals who are:

• not interested in or able to receive agonist maintenance treatment (ie, patients who do not have access to an appropriate clinic in their area, or who are restricted to agonist treatment by probation/parole)
• highly abstinence-oriented (eg, active in a 12-step program)
• in professions where agonists are controversial (eg, healthcare and airlines)
• detoxified and abstinent but at risk for relapse.

Individuals who have failed agonist treatment (eg, who experience cravings for opioids and use opioids while receiving it, or are nonadherent or diverting/misusing the medication), who have a less severe form of OUD (short history and low level of use), or who use sporadically are also optimal candidates for NTX. Aside from the relapse-vulnerable washout gap prior to induction, one of the concerns with antagonist treatments is treatment retention; anecdotal clinical reports suggest that individuals often discontinue antagonists in favor of agonists.

Several studies have investigated this by comparing XR-NTX with buprenorphine-naloxone (BUP-NX). Here we summarize 3 studies^4-6 to describe which patients might be optimal candidates for XR-NTX, its success in comparison with BUP-NX, and challenges in induction of NTX, with a focus on emerging protocols (Table).

1. Tanum l, Solli KK, Latif ZH, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74(12):1197-1205.

This study aimed to determine whether XR-NTX was not inferior to BUP-NX in the treatment of OUD.

Study design

• N = 159, multicenter, randomized, 12-week outpatient study in Norway
• After detoxification, participants were randomized to receive BUP-NX, 4 to 24 mg/d, or XR-NTX, 380 mg/month.

Continue to: Outcomes

Outcomes

• Comparable treatment retention between groups
• Comparable opioid-negative urine drug screens (UDS)
• Significantly lower opioid use in the XR-NTX group.

Conclusion

• XR-NTX was as effective as BUP-NX in maintaining short-term abstinence from heroin and other illicit opioids, and thus should be considered as a treatment option for opioid-dependent individuals.

While this study showed similar efficacy for XR-NTX and BUP-NX, it is important to note that the randomization occurred after patients were detoxified. As a full opioid antagonist, XR-NTX can precipitate severe withdrawal, so patients need to be completely detoxified before starting XR-NTX, in contrast to BUP-NX, which patients can start even while still in mild withdrawal. Additional studies are needed in which individuals are randomized before detoxification, which would make it possible to measure the success of induction.

2. Lee JD, Nunes, EV, Novo P, et al. Compar­ative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318.

This study evaluated XR-NTX vs BUP-NX among adults with OUD who were actively using heroin at baseline and were admitted to community detoxification and treatment programs. Although the study began on inpatient units, it aimed to replicate usual community outpatient conditions across a 24-week outpatient treatment phase of this open-label, comparative effectiveness trial. Researchers assessed the effects on relapse-free survival, opioid use rates, and overdose events.

Study design

• N = 570, multicenter, randomized, 24-week study in the United States
• Detoxification methods: no opioids (clonidine or adjunctive medications), 3- to 5-day methadone taper, and 3- to 14-day BUP taper
• Protocol requirement: opioid-negative UDS before XR-NTX induction
• XR-NTX induction success ranged from 50% at a short-methadone-taper unit to 95% at an extended-opioid-free inpatient program. Nearly all induction failures quickly relapsed
• More participants inducted on BUP-NX group than XR-NTX group (94% vs 72%, respectively).

Continue to: Outcomes

Outcomes (once successfully inducted to treatment [n = 474])

• Comparable relapse events
• Comparable opioid-negative urine drug screens and opioid-abstinent days
• Opioid craving initially less with XR-NTX.

Conclusion

• It was more difficult to initiate patients on XR-NTX than BUP-NX, which negatively affected overall relapse rates. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.

Regarding induction on NTX, patients must be detoxified and opioid-free for at least 7 days. If this medication is given to patients who are physically dependent and/or have opioids in their system, NTX will displace opioids off the receptor and precipitate a severe withdrawal (rather than a slow and gradual spontaneous withdrawal).

Several studies have examined the severity of opioid withdrawal (using Self Opioid Withdrawal Scale scoring) of patients undergoing detoxification with symptomatic management (eg, clonidine, loperamide, etc.), agonist-managed (eg, with a BUP taper), and without any assistance. As expected, the latter yielded the highest scoring and most uncomfortable experiences. Using scores from the first 2 groups, a threshold of symptom tolerability was established where patients remained somewhat comfortable during the process. During detoxification from heroin, administering any dose of NTX during the first 48 to 72 hours after the last use placed patients in a withdrawal of a magnitude above the limit of tolerability. At 48 to 72 hours, however, a very low NTX dose (3 to 6 mg) was found to be well tolerated, and withdrawal symptoms were easily managed supportively to accelerate the detoxification process. Several studies have attempted to devise protocols based on these findings in order to facilitate rapid induction onto NTX. The following study offers encouragement:

Continue to: 3. Sullivan M, Bisaga A, Pavlicova M...

3. Sullivan M, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry. 2017;174:459-467.

Study design

• N = 150 adults with OUD, randomized to outpatient opioid detoxification
• Patients were randomized to BUP- or NTX-facilitated detoxification, followed by XR-NTX
• BUP detoxification group underwent a 7-day BUP taper followed by a opioid-free week
• NTX group received a 1-day BUP dose followed by 6 days of ascending doses of oral NTX, along with clonidine and other adjunctive medications.

Outcomes

• NTX-assisted detoxification was significantly more successful for XR-NTX induction (56.1% vs 32.7%).

Conclusion

• Compared with the BUP-assisted detoxification group, NTX-assisted detoxification appears to make it significantly more likely for patients to be successfully inducted to XR-NTX.

The evidence discussed here holds promise in addressing some of the major issues surrounding MAT. For suitable candidates, XR-NTX seems to be as efficacious an option as agonist (BUP) MAT, and its induction limitations could be overcome by using NTX-facilitated detoxification protocols.

Death by drug overdose is the number one cause of death in Americans 50 years of age and younger.¹ In 2016, there were 63,632 drug overdose deaths in the United States² Opioids were involved in 42,249 of these deaths, which represents 66.4% of all drug overdose deaths.² From 2015 to 2016, the age-adjusted rate of overdose deaths increased significantly by 21.5% from 16.3 per 100,000 to 19.8 per 100,000.² This means that every day, more than 115 people in the United States die after overdosing on opioids. The misuse of and addiction to opioids—including prescription pain relievers, heroin, and synthetic opioids such as fentanyl—is a serious national crisis that affects public health as well as social and economic welfare.

The gold standard treatment is medication-assisted treatment (MAT)—the use of FDA-approved medications, in combination with counseling and behavioral therapies, to provide a “whole-patient” approach.³ When it comes to MAT options for opioid use disorder (OUD), there are 3 medications, each with its own caveats.

Methadone is an opioid mu-receptor full agonist that prevents withdrawal but does not block other narcotics. It requires daily dosing as a liquid formulation that is dispensed only in regulated clinics.

Buprenorphine is a mu-receptor high affinity partial agonist/antagonist that blocks the majority of other narcotics while reducing withdrawal risk. It requires daily dosing as either a dissolving tablet or cheek film. Recently it has also become available as a 6-month implant as well as a 1-month subcutaneous injection. Buprenorphine is also available as a combined medication with naloxone; naloxone is an opioid antagonist.

Naltrexone is a mu-receptor antagonist that blocks the effects of most narcotics. It does not lead to dependence, and is administered daily as a pill or monthly as a deep IM injection of its extended-release formulation.

The first 2 medications are tightly regulated options that are not available in many areas of the United States. Naltrexone, when provided as a daily pill, has adherence issues. As with any illness, lack of adherence to treatment is problematic; in the case of patients with OUD, this includes a high risk of overdose and death.

The use of injectable extended-release naltrexone (XR-NTX) may be a way to address nonadherence and thus prevent relapse. One of the challenges limiting naltrexone’s applicability has been the length of time required for an “opioid washout” of the mu receptors prior to administering naltrexone, which is a mu blocker. The washout can take as long as 7 to 10 days. This interval is not feasible for patients receiving inpatient treatment, and patients receiving treatment as outpatients are vulnerable to relapse during this time. Recently, there have been several attempts to shorten this gap through various experimental protocols based on incremental doses of NTX to facilitate withdrawal while managing symptoms.

Continue to: When selecting appropriate candidates for NTX treatment...

When selecting appropriate candidates for NTX treatment, clinicians should consider individuals who are:

• not interested in or able to receive agonist maintenance treatment (ie, patients who do not have access to an appropriate clinic in their area, or who are restricted to agonist treatment by probation/parole)
• highly abstinence-oriented (eg, active in a 12-step program)
• in professions where agonists are controversial (eg, healthcare and airlines)
• detoxified and abstinent but at risk for relapse.

Individuals who have failed agonist treatment (eg, who experience cravings for opioids and use opioids while receiving it, or are nonadherent or diverting/misusing the medication), who have a less severe form of OUD (short history and low level of use), or who use sporadically are also optimal candidates for NTX. Aside from the relapse-vulnerable washout gap prior to induction, one of the concerns with antagonist treatments is treatment retention; anecdotal clinical reports suggest that individuals often discontinue antagonists in favor of agonists.

Several studies have investigated this by comparing XR-NTX with buprenorphine-naloxone (BUP-NX). Here we summarize 3 studies^4-6 to describe which patients might be optimal candidates for XR-NTX, its success in comparison with BUP-NX, and challenges in induction of NTX, with a focus on emerging protocols (Table).

1. Tanum l, Solli KK, Latif ZH, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical noninferiority trial. JAMA Psychiatry. 2017;74(12):1197-1205.

This study aimed to determine whether XR-NTX was not inferior to BUP-NX in the treatment of OUD.

Study design

• N = 159, multicenter, randomized, 12-week outpatient study in Norway
• After detoxification, participants were randomized to receive BUP-NX, 4 to 24 mg/d, or XR-NTX, 380 mg/month.

Continue to: Outcomes

Outcomes

• Comparable treatment retention between groups
• Comparable opioid-negative urine drug screens (UDS)
• Significantly lower opioid use in the XR-NTX group.

Conclusion

• XR-NTX was as effective as BUP-NX in maintaining short-term abstinence from heroin and other illicit opioids, and thus should be considered as a treatment option for opioid-dependent individuals.

While this study showed similar efficacy for XR-NTX and BUP-NX, it is important to note that the randomization occurred after patients were detoxified. As a full opioid antagonist, XR-NTX can precipitate severe withdrawal, so patients need to be completely detoxified before starting XR-NTX, in contrast to BUP-NX, which patients can start even while still in mild withdrawal. Additional studies are needed in which individuals are randomized before detoxification, which would make it possible to measure the success of induction.

2. Lee JD, Nunes, EV, Novo P, et al. Compar­ative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318.

This study evaluated XR-NTX vs BUP-NX among adults with OUD who were actively using heroin at baseline and were admitted to community detoxification and treatment programs. Although the study began on inpatient units, it aimed to replicate usual community outpatient conditions across a 24-week outpatient treatment phase of this open-label, comparative effectiveness trial. Researchers assessed the effects on relapse-free survival, opioid use rates, and overdose events.

Study design

• N = 570, multicenter, randomized, 24-week study in the United States
• Detoxification methods: no opioids (clonidine or adjunctive medications), 3- to 5-day methadone taper, and 3- to 14-day BUP taper
• Protocol requirement: opioid-negative UDS before XR-NTX induction
• XR-NTX induction success ranged from 50% at a short-methadone-taper unit to 95% at an extended-opioid-free inpatient program. Nearly all induction failures quickly relapsed
• More participants inducted on BUP-NX group than XR-NTX group (94% vs 72%, respectively).

Continue to: Outcomes

Outcomes (once successfully inducted to treatment [n = 474])

• Comparable relapse events
• Comparable opioid-negative urine drug screens and opioid-abstinent days
• Opioid craving initially less with XR-NTX.

Conclusion

• It was more difficult to initiate patients on XR-NTX than BUP-NX, which negatively affected overall relapse rates. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.

Regarding induction on NTX, patients must be detoxified and opioid-free for at least 7 days. If this medication is given to patients who are physically dependent and/or have opioids in their system, NTX will displace opioids off the receptor and precipitate a severe withdrawal (rather than a slow and gradual spontaneous withdrawal).

Several studies have examined the severity of opioid withdrawal (using Self Opioid Withdrawal Scale scoring) of patients undergoing detoxification with symptomatic management (eg, clonidine, loperamide, etc.), agonist-managed (eg, with a BUP taper), and without any assistance. As expected, the latter yielded the highest scoring and most uncomfortable experiences. Using scores from the first 2 groups, a threshold of symptom tolerability was established where patients remained somewhat comfortable during the process. During detoxification from heroin, administering any dose of NTX during the first 48 to 72 hours after the last use placed patients in a withdrawal of a magnitude above the limit of tolerability. At 48 to 72 hours, however, a very low NTX dose (3 to 6 mg) was found to be well tolerated, and withdrawal symptoms were easily managed supportively to accelerate the detoxification process. Several studies have attempted to devise protocols based on these findings in order to facilitate rapid induction onto NTX. The following study offers encouragement:

Continue to: 3. Sullivan M, Bisaga A, Pavlicova M...

3. Sullivan M, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry. 2017;174:459-467.

Study design

• N = 150 adults with OUD, randomized to outpatient opioid detoxification
• Patients were randomized to BUP- or NTX-facilitated detoxification, followed by XR-NTX
• BUP detoxification group underwent a 7-day BUP taper followed by a opioid-free week
• NTX group received a 1-day BUP dose followed by 6 days of ascending doses of oral NTX, along with clonidine and other adjunctive medications.

Outcomes

• NTX-assisted detoxification was significantly more successful for XR-NTX induction (56.1% vs 32.7%).

Conclusion

• Compared with the BUP-assisted detoxification group, NTX-assisted detoxification appears to make it significantly more likely for patients to be successfully inducted to XR-NTX.

The evidence discussed here holds promise in addressing some of the major issues surrounding MAT. For suitable candidates, XR-NTX seems to be as efficacious an option as agonist (BUP) MAT, and its induction limitations could be overcome by using NTX-facilitated detoxification protocols.

“To every thing there is a season, and a time to every purpose under the heaven.”

— Ecclesiastes

The month of birth is not just relevant to one’s astrological sign. It may have medical consequences. An impressive number of published studies have found that the month and season of birth may be related to a higher risk of various medical and psychiatric disorders.

For decades, it has been reported in more than 250 studies¹ that a disproportionate number of individuals with schizophrenia are born during the winter months (January/February/March in the Northern Hemisphere and July/August/September in the Southern Hemisphere). This seasonal pattern was eventually linked to the lack of sunlight during winter months and a deficiency of vitamin D, a hormone that is critical for normal brain development. Recent studies have reported that very low serum levels of vitamin D during pregnancy significantly increase the risk of schizophrenia in offspring.²

But the plot thickens. Numerous studies over the past 20 to 30 years have reported an association between month or season of birth with sundry general medical and psychiatric conditions. Even longevity has been reported to vary with season of birth, with a longer life span for people born in autumn (October to December), compared with those born in spring (April to June).³ Of note, a longer life span for an individual born in autumn has been attributed to a higher birth weight during that season compared with those born in other seasons. In addition, the shorter life span of those with spring births has been attributed to factors during fetal life that increase the susceptibility to disease later in life (after age 50).

The following studies have reported an association between month/season of birth and general medical disorders:

• Higher rate of myopia for summer births⁴
• Tenfold higher risk of respiratory syntactical virus in babies born in January compared with October, and a 2 to 3 times higher risk of hospitalization⁵
• Higher rates of asthma during childhood for March and April births⁶
• Lower rate of lung cancer for winter births compared with all other seasons⁷
• An excess of colon and rectal cancer for people born in September, and the lowest rate for spring births⁸
• Lowest diabetes risk for summer births⁹
• For males: Cardiac mortality is 11% less likely for 4th-quarter births compared with 1st-quarter births. For females: Cancer mortality is lowest in 3rd-quarter vs 1st-quarter births¹⁰
• The peak risk for both Hodgkin and non-Hodgkin lymphoma is for April births compared with other months¹¹
• A strong trend for malignant neoplasm in males was reported for births during the 1st trimester of the year (January through April) compared with the rest of the year¹²
• Higher rate of spring births among patients who have insulin-dependent diabetes¹³
• Breast cancer is 5% higher for June births compared with December births¹⁴
• Higher risk of developing an allergy later in life for those born approximately 3 months before the main allergy season.¹⁵

The above studies may imply that birth seasonality is medical destiny. However, most such reports need further replication, or may be due to chance findings in various databases. However, they are worth considering as hypothesis-generating signals.

Continue to: And now for the risk of psychiatric disorders...

And now for the risk of psychi­atric disorders and month or season of birth. Here, too, there are multiple published reports:

• Higher social anhedonia and schizoid features among persons born in June and July¹⁶
• Higher autism rates for children conceived in December to March compared with those conceived during summer months¹⁷
• In contrast to the above report, the risk of autism spectrum disorders in the United Kingdom was higher for those born in summer¹⁸
• Another study labeled seasonality of birth in autism as “fiction”!¹⁹
• Significant spring births for persons with anxiety²⁰
• Highest occurrence of postpartum depression in December²¹
• High prepartum depression in winter and postpartum depression in fall²²
• Lower performance IQ among spring births²³
• Disproportionate excess of births in April, May, and June for those who die by suicide²⁴
• Suicide by burning oneself is higher among individuals born in January compared with any other month²⁵
• Relative increase in March and August births among patients with anorexia²⁶
• Season of birth is a predictor of emotional and behavioral regulation²⁷
• Serotonin metabolites show a peak in spring and a trough in fall²⁸
• Increase of spring births in individuals with Down syndrome²⁹
• Excess of spring births among patients with Alzheimer’s disease.³⁰

As with the seasonality of medical illness risk, the association of the month or season of birth with psychiatric disorders may be based on skewed samples or simply a chance finding. However, there may be some seasonal environmental factors that could increase the risk for disorders of the body or the brain/mind. The most plausible factors may be season-related fetal developmental disruptions caused by maternal infection, diet, lack of sunlight, temperature, substance use, or immune dysregulation from comorbid medical conditions during pregnancy. Some researchers have speculated that fluctuations in the availability of various fresh fruits and vegetables during certain seasons of the year may influence fetal development or increase the susceptibility to some medical disorders. This may be at the time of conception or during the 2nd trimester of pregnancy, when the brain develops.

On the other hand, those studies, published in peer-reviewed journals, may constitute a sophisticated form of “psychiatric astrology” whose credibility could be as suspect as the imaginative predictions of one’s horoscope in the daily newspaper…

To comment on this editorial or other topics of interest: [email protected].

“To every thing there is a season, and a time to every purpose under the heaven.”

— Ecclesiastes

The month of birth is not just relevant to one’s astrological sign. It may have medical consequences. An impressive number of published studies have found that the month and season of birth may be related to a higher risk of various medical and psychiatric disorders.

For decades, it has been reported in more than 250 studies¹ that a disproportionate number of individuals with schizophrenia are born during the winter months (January/February/March in the Northern Hemisphere and July/August/September in the Southern Hemisphere). This seasonal pattern was eventually linked to the lack of sunlight during winter months and a deficiency of vitamin D, a hormone that is critical for normal brain development. Recent studies have reported that very low serum levels of vitamin D during pregnancy significantly increase the risk of schizophrenia in offspring.²

But the plot thickens. Numerous studies over the past 20 to 30 years have reported an association between month or season of birth with sundry general medical and psychiatric conditions. Even longevity has been reported to vary with season of birth, with a longer life span for people born in autumn (October to December), compared with those born in spring (April to June).³ Of note, a longer life span for an individual born in autumn has been attributed to a higher birth weight during that season compared with those born in other seasons. In addition, the shorter life span of those with spring births has been attributed to factors during fetal life that increase the susceptibility to disease later in life (after age 50).

The following studies have reported an association between month/season of birth and general medical disorders:

• Higher rate of myopia for summer births⁴
• Tenfold higher risk of respiratory syntactical virus in babies born in January compared with October, and a 2 to 3 times higher risk of hospitalization⁵
• Higher rates of asthma during childhood for March and April births⁶
• Lower rate of lung cancer for winter births compared with all other seasons⁷
• An excess of colon and rectal cancer for people born in September, and the lowest rate for spring births⁸
• Lowest diabetes risk for summer births⁹
• For males: Cardiac mortality is 11% less likely for 4th-quarter births compared with 1st-quarter births. For females: Cancer mortality is lowest in 3rd-quarter vs 1st-quarter births¹⁰
• The peak risk for both Hodgkin and non-Hodgkin lymphoma is for April births compared with other months¹¹
• A strong trend for malignant neoplasm in males was reported for births during the 1st trimester of the year (January through April) compared with the rest of the year¹²
• Higher rate of spring births among patients who have insulin-dependent diabetes¹³
• Breast cancer is 5% higher for June births compared with December births¹⁴
• Higher risk of developing an allergy later in life for those born approximately 3 months before the main allergy season.¹⁵

The above studies may imply that birth seasonality is medical destiny. However, most such reports need further replication, or may be due to chance findings in various databases. However, they are worth considering as hypothesis-generating signals.

Continue to: And now for the risk of psychiatric disorders...

And now for the risk of psychi­atric disorders and month or season of birth. Here, too, there are multiple published reports:

• Higher social anhedonia and schizoid features among persons born in June and July¹⁶
• Higher autism rates for children conceived in December to March compared with those conceived during summer months¹⁷
• In contrast to the above report, the risk of autism spectrum disorders in the United Kingdom was higher for those born in summer¹⁸
• Another study labeled seasonality of birth in autism as “fiction”!¹⁹
• Significant spring births for persons with anxiety²⁰
• Highest occurrence of postpartum depression in December²¹
• High prepartum depression in winter and postpartum depression in fall²²
• Lower performance IQ among spring births²³
• Disproportionate excess of births in April, May, and June for those who die by suicide²⁴
• Suicide by burning oneself is higher among individuals born in January compared with any other month²⁵
• Relative increase in March and August births among patients with anorexia²⁶
• Season of birth is a predictor of emotional and behavioral regulation²⁷
• Serotonin metabolites show a peak in spring and a trough in fall²⁸
• Increase of spring births in individuals with Down syndrome²⁹
• Excess of spring births among patients with Alzheimer’s disease.³⁰

As with the seasonality of medical illness risk, the association of the month or season of birth with psychiatric disorders may be based on skewed samples or simply a chance finding. However, there may be some seasonal environmental factors that could increase the risk for disorders of the body or the brain/mind. The most plausible factors may be season-related fetal developmental disruptions caused by maternal infection, diet, lack of sunlight, temperature, substance use, or immune dysregulation from comorbid medical conditions during pregnancy. Some researchers have speculated that fluctuations in the availability of various fresh fruits and vegetables during certain seasons of the year may influence fetal development or increase the susceptibility to some medical disorders. This may be at the time of conception or during the 2nd trimester of pregnancy, when the brain develops.

On the other hand, those studies, published in peer-reviewed journals, may constitute a sophisticated form of “psychiatric astrology” whose credibility could be as suspect as the imaginative predictions of one’s horoscope in the daily newspaper…

To comment on this editorial or other topics of interest: [email protected].

“To every thing there is a season, and a time to every purpose under the heaven.”

— Ecclesiastes

The month of birth is not just relevant to one’s astrological sign. It may have medical consequences. An impressive number of published studies have found that the month and season of birth may be related to a higher risk of various medical and psychiatric disorders.

For decades, it has been reported in more than 250 studies¹ that a disproportionate number of individuals with schizophrenia are born during the winter months (January/February/March in the Northern Hemisphere and July/August/September in the Southern Hemisphere). This seasonal pattern was eventually linked to the lack of sunlight during winter months and a deficiency of vitamin D, a hormone that is critical for normal brain development. Recent studies have reported that very low serum levels of vitamin D during pregnancy significantly increase the risk of schizophrenia in offspring.²

But the plot thickens. Numerous studies over the past 20 to 30 years have reported an association between month or season of birth with sundry general medical and psychiatric conditions. Even longevity has been reported to vary with season of birth, with a longer life span for people born in autumn (October to December), compared with those born in spring (April to June).³ Of note, a longer life span for an individual born in autumn has been attributed to a higher birth weight during that season compared with those born in other seasons. In addition, the shorter life span of those with spring births has been attributed to factors during fetal life that increase the susceptibility to disease later in life (after age 50).

The following studies have reported an association between month/season of birth and general medical disorders:

• Higher rate of myopia for summer births⁴
• Tenfold higher risk of respiratory syntactical virus in babies born in January compared with October, and a 2 to 3 times higher risk of hospitalization⁵
• Higher rates of asthma during childhood for March and April births⁶
• Lower rate of lung cancer for winter births compared with all other seasons⁷
• An excess of colon and rectal cancer for people born in September, and the lowest rate for spring births⁸
• Lowest diabetes risk for summer births⁹
• For males: Cardiac mortality is 11% less likely for 4th-quarter births compared with 1st-quarter births. For females: Cancer mortality is lowest in 3rd-quarter vs 1st-quarter births¹⁰
• The peak risk for both Hodgkin and non-Hodgkin lymphoma is for April births compared with other months¹¹
• A strong trend for malignant neoplasm in males was reported for births during the 1st trimester of the year (January through April) compared with the rest of the year¹²
• Higher rate of spring births among patients who have insulin-dependent diabetes¹³
• Breast cancer is 5% higher for June births compared with December births¹⁴
• Higher risk of developing an allergy later in life for those born approximately 3 months before the main allergy season.¹⁵

The above studies may imply that birth seasonality is medical destiny. However, most such reports need further replication, or may be due to chance findings in various databases. However, they are worth considering as hypothesis-generating signals.

Continue to: And now for the risk of psychiatric disorders...

And now for the risk of psychi­atric disorders and month or season of birth. Here, too, there are multiple published reports:

• Higher social anhedonia and schizoid features among persons born in June and July¹⁶
• Higher autism rates for children conceived in December to March compared with those conceived during summer months¹⁷
• In contrast to the above report, the risk of autism spectrum disorders in the United Kingdom was higher for those born in summer¹⁸
• Another study labeled seasonality of birth in autism as “fiction”!¹⁹
• Significant spring births for persons with anxiety²⁰
• Highest occurrence of postpartum depression in December²¹
• High prepartum depression in winter and postpartum depression in fall²²
• Lower performance IQ among spring births²³
• Disproportionate excess of births in April, May, and June for those who die by suicide²⁴
• Suicide by burning oneself is higher among individuals born in January compared with any other month²⁵
• Relative increase in March and August births among patients with anorexia²⁶
• Season of birth is a predictor of emotional and behavioral regulation²⁷
• Serotonin metabolites show a peak in spring and a trough in fall²⁸
• Increase of spring births in individuals with Down syndrome²⁹
• Excess of spring births among patients with Alzheimer’s disease.³⁰

As with the seasonality of medical illness risk, the association of the month or season of birth with psychiatric disorders may be based on skewed samples or simply a chance finding. However, there may be some seasonal environmental factors that could increase the risk for disorders of the body or the brain/mind. The most plausible factors may be season-related fetal developmental disruptions caused by maternal infection, diet, lack of sunlight, temperature, substance use, or immune dysregulation from comorbid medical conditions during pregnancy. Some researchers have speculated that fluctuations in the availability of various fresh fruits and vegetables during certain seasons of the year may influence fetal development or increase the susceptibility to some medical disorders. This may be at the time of conception or during the 2nd trimester of pregnancy, when the brain develops.

On the other hand, those studies, published in peer-reviewed journals, may constitute a sophisticated form of “psychiatric astrology” whose credibility could be as suspect as the imaginative predictions of one’s horoscope in the daily newspaper…

To comment on this editorial or other topics of interest: [email protected].

They say success without fulfillment is of little value in life. Whether this concept is actually driving the spate of depression and substance abuse currently experienced by youth and middle-aged adults in developed countries is rarely discussed and needs to be explored.

We have all reflected on the tragic ends of Anthony Bourdain, Kate Spade, and Robin Williams. Much has been said about the accolades they achieved and the heights they scaled, and just as much about their struggles with substance abuse over the years. Sensational portrayals by the media also encouraged youth to spend time dissecting the details of these high-profile deaths, lending popularity to the notion of suicide contagion. But somewhere in the myriad theories and conclusions, we still seem baffled by the questions of why these suicides occurred, and why no one had seen them coming.

As humans, we are designed to build. For many people, including physicians, the final product is a rewarding career built on years of hard work, or a flourishing family to look back on be proud of. Sometimes, however, these larger ideas barely intersect with our pictures of success.

As physicians and high achievers, we dream of goals and ambitions and set stringent deadlines for achieving them. Falling short sometimes finds us grappling with self-punishment and doubt. When one goal is achieved, another one is automatically created, or the goal post is pushed further. And the cycle continues.

Having said this, I will ask: What are you looking for? What is it that will give you a sense of purpose?

This is not a redundant question, nor is it an easy one. So are you really taking the time to think about it? Does any of this border on self-reflection and self-awareness for you? If it does, then developing that insight into yourself is perhaps a better way of serving your patients.

Peace and gratification often lie in the little things; not everything you do has to be acknowledged with an award. There is a sense of fulfillment that comes from developing others. The key is to realize that there is never a moment to start doing that—it is an ongoing journey. Therefore, give generously, of your time, of your skills, of your knowledge, but above all, of your kindness. Do it because in the end, you will have something to look back on and be proud of. Do it because maybe somewhere you will find meaning in it. And your success may not be bereft of fulfillment.

They say success without fulfillment is of little value in life. Whether this concept is actually driving the spate of depression and substance abuse currently experienced by youth and middle-aged adults in developed countries is rarely discussed and needs to be explored.

We have all reflected on the tragic ends of Anthony Bourdain, Kate Spade, and Robin Williams. Much has been said about the accolades they achieved and the heights they scaled, and just as much about their struggles with substance abuse over the years. Sensational portrayals by the media also encouraged youth to spend time dissecting the details of these high-profile deaths, lending popularity to the notion of suicide contagion. But somewhere in the myriad theories and conclusions, we still seem baffled by the questions of why these suicides occurred, and why no one had seen them coming.

As humans, we are designed to build. For many people, including physicians, the final product is a rewarding career built on years of hard work, or a flourishing family to look back on be proud of. Sometimes, however, these larger ideas barely intersect with our pictures of success.

As physicians and high achievers, we dream of goals and ambitions and set stringent deadlines for achieving them. Falling short sometimes finds us grappling with self-punishment and doubt. When one goal is achieved, another one is automatically created, or the goal post is pushed further. And the cycle continues.

Having said this, I will ask: What are you looking for? What is it that will give you a sense of purpose?

This is not a redundant question, nor is it an easy one. So are you really taking the time to think about it? Does any of this border on self-reflection and self-awareness for you? If it does, then developing that insight into yourself is perhaps a better way of serving your patients.

Peace and gratification often lie in the little things; not everything you do has to be acknowledged with an award. There is a sense of fulfillment that comes from developing others. The key is to realize that there is never a moment to start doing that—it is an ongoing journey. Therefore, give generously, of your time, of your skills, of your knowledge, but above all, of your kindness. Do it because in the end, you will have something to look back on and be proud of. Do it because maybe somewhere you will find meaning in it. And your success may not be bereft of fulfillment.

They say success without fulfillment is of little value in life. Whether this concept is actually driving the spate of depression and substance abuse currently experienced by youth and middle-aged adults in developed countries is rarely discussed and needs to be explored.

We have all reflected on the tragic ends of Anthony Bourdain, Kate Spade, and Robin Williams. Much has been said about the accolades they achieved and the heights they scaled, and just as much about their struggles with substance abuse over the years. Sensational portrayals by the media also encouraged youth to spend time dissecting the details of these high-profile deaths, lending popularity to the notion of suicide contagion. But somewhere in the myriad theories and conclusions, we still seem baffled by the questions of why these suicides occurred, and why no one had seen them coming.

As humans, we are designed to build. For many people, including physicians, the final product is a rewarding career built on years of hard work, or a flourishing family to look back on be proud of. Sometimes, however, these larger ideas barely intersect with our pictures of success.

As physicians and high achievers, we dream of goals and ambitions and set stringent deadlines for achieving them. Falling short sometimes finds us grappling with self-punishment and doubt. When one goal is achieved, another one is automatically created, or the goal post is pushed further. And the cycle continues.

Having said this, I will ask: What are you looking for? What is it that will give you a sense of purpose?

This is not a redundant question, nor is it an easy one. So are you really taking the time to think about it? Does any of this border on self-reflection and self-awareness for you? If it does, then developing that insight into yourself is perhaps a better way of serving your patients.

Peace and gratification often lie in the little things; not everything you do has to be acknowledged with an award. There is a sense of fulfillment that comes from developing others. The key is to realize that there is never a moment to start doing that—it is an ongoing journey. Therefore, give generously, of your time, of your skills, of your knowledge, but above all, of your kindness. Do it because in the end, you will have something to look back on and be proud of. Do it because maybe somewhere you will find meaning in it. And your success may not be bereft of fulfillment.

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

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

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

Physical exercise

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

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

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

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

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

Continue to: From a pathophysiological standpoint...

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

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

Mental activity

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

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

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

Continue to: Physicians should encourage their patients...

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

Social activity

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

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

Meditation/spiritual activity

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

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

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

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

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

Diet

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

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

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

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

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

Alcohol

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

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

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

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

Continue to: Coffee/tea

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

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

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

Which lifestyle change is the most important?

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

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

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

Continue to: This multi-domain approach...

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Name

Curcumin • Theracurmin

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

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

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

Physical exercise

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

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

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

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

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

Continue to: From a pathophysiological standpoint...

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

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

Mental activity

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

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

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

Continue to: Physicians should encourage their patients...

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

Social activity

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

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

Meditation/spiritual activity

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

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

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

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

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

Diet

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

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

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

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

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

Alcohol

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

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

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

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

Continue to: Coffee/tea

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

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

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

Which lifestyle change is the most important?

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

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

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

Continue to: This multi-domain approach...

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Name

Curcumin • Theracurmin

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

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

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

Physical exercise

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

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

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

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

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

Continue to: From a pathophysiological standpoint...

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

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

Mental activity

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

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

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

Continue to: Physicians should encourage their patients...

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

Social activity

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

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

Meditation/spiritual activity

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

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

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

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

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

Diet

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

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

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

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

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

Alcohol

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

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

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

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

Continue to: Coffee/tea

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

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

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

Which lifestyle change is the most important?

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

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

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

Continue to: This multi-domain approach...

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

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

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

Bottom Line

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

Related Resources

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

Drug Brand Name

Curcumin • Theracurmin

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

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

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

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