The ‘worried well’ and the ‘walking wounded’: How will we know them?
One of Dr. Henry A. Nasrallah’s resolutions (16 New Year’s resolutions for psychiatrists in 2016, From the Editor, January 2016, p. 23,24) stated that a significant percentage of one’s practice should be dedicated to the sickest patients, followed by the statement, “There are enough non-physician mental health professionals to handle the walking wounded and worried well.”

Who are the “walking wounded” and the “worried well”? These are commonly used terms, but who falls into these categories? I think it is important to get a sense of who is in these groups, because my takeaway from this editorial is that it is acceptable to let the walking wounded and worried well be treated by lesser-trained clinicians. Do these terms refer to a diagnostic group? Level of functioning? Severity of symptoms? Or severity plus chronicity? Level of suffering? Ability to “fake” looking less severe? 

I wonder, am I a walking wounded or worried well? Are some of my friends, or my family members? When I see a patient, I ask myself if he (she) might be in that category.

Susan Fredriksen, MD
Private Practice
Hayesville, North Carolina

Dr. Nasrallah responds
I use those terms to refer to persons who have psychiatric symptoms but are not disabled socially or vocationally. They deserve a full psychiatric evaluation when they initially seek help, but generally do well with various types of psychotherapy, including cognitive-behavioral therapy, interpersonal therapy, psychodynamic therapy, or dialectic behavior therapy. There are many well-trained psychologists and licensed therapists who can administer those therapies as well as, or better than, some psychiatrists. 

I recommended that psychiatrists dedicate a significant percentage (more than 50%) of their practice to more severely ill patients (those with psychosis, bipolar disorder, major depressive disorder, panic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, etc.) because we are the only mental health professionals who can competently integrate biopsychosocial treatments for these patients and administer pharmacotherapeutic agents in addition to non-drug approaches. The supply of psychiatrists is short, and the number of seriously ill patients who need the medical expertise we can provide is large.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry
Saint Louis University School of Medicine
St. Louis, Missouri

‘Struggling with inner demons’
I would hope that Dr. Nasrallah would understand that the use of the metaphor, “struggling with inner demons,” does not suggest “stupid” (Stop blaming ‘demons’ for bizarre delusions or behavior!, From the Editor, February 2016, p. 19,20,22). A celebrity, or any other person, might be struggling with intense, conflicting emotions that create chaos and distress. I would shudder if I read in The New York Times, “Well known actor’s divorce and drug use clearly leading to hypertrophied amygdala.” The term inner demons does not necessarily imply medieval superstition, but rather a well-established use of creative language.

Ron Samarian, MD
Chief, Department of Psychiatry
William Beaumont Hospital
Royal Oak, Michigan
Chair, Oakland University
William Beaumont Medical School
Rochester, Michigan

Dr. Nasrallah responds
Dr. Samarian missed the reason for my umbrage with the “inner demons” metaphor. As a psychiatrist, educator, and researcher, I am exquisitely sensitive to the poor understanding of mental illness and the rampant stigma associated with psychiatric disorders despite the incredible neurobiologic advances. Thus, I regard the metaphor that employs words like “demons” when describing intense struggles with emotional upheavals and stress as having an unfortunate connotation to the obsolete beliefs that abnormal behavior, thoughts, or mood are due to the devil and his nefarious demons.

I would welcome a metaphor that describes a depressed person as having a shrunken hippocampus, which would regrow with antidepressant or electroconvulsive therapy, because that’s the biologic truth and has no misleading connotations; the same with Dr. Samarian’s example of a hypertrophied amygdala in a person with chronic stress.

The ‘worried well’ and the ‘walking wounded’: How will we know them?
One of Dr. Henry A. Nasrallah’s resolutions (16 New Year’s resolutions for psychiatrists in 2016, From the Editor, January 2016, p. 23,24) stated that a significant percentage of one’s practice should be dedicated to the sickest patients, followed by the statement, “There are enough non-physician mental health professionals to handle the walking wounded and worried well.”

Who are the “walking wounded” and the “worried well”? These are commonly used terms, but who falls into these categories? I think it is important to get a sense of who is in these groups, because my takeaway from this editorial is that it is acceptable to let the walking wounded and worried well be treated by lesser-trained clinicians. Do these terms refer to a diagnostic group? Level of functioning? Severity of symptoms? Or severity plus chronicity? Level of suffering? Ability to “fake” looking less severe? 

I wonder, am I a walking wounded or worried well? Are some of my friends, or my family members? When I see a patient, I ask myself if he (she) might be in that category.

Susan Fredriksen, MD
Private Practice
Hayesville, North Carolina

Dr. Nasrallah responds
I use those terms to refer to persons who have psychiatric symptoms but are not disabled socially or vocationally. They deserve a full psychiatric evaluation when they initially seek help, but generally do well with various types of psychotherapy, including cognitive-behavioral therapy, interpersonal therapy, psychodynamic therapy, or dialectic behavior therapy. There are many well-trained psychologists and licensed therapists who can administer those therapies as well as, or better than, some psychiatrists. 

I recommended that psychiatrists dedicate a significant percentage (more than 50%) of their practice to more severely ill patients (those with psychosis, bipolar disorder, major depressive disorder, panic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, etc.) because we are the only mental health professionals who can competently integrate biopsychosocial treatments for these patients and administer pharmacotherapeutic agents in addition to non-drug approaches. The supply of psychiatrists is short, and the number of seriously ill patients who need the medical expertise we can provide is large.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry
Saint Louis University School of Medicine
St. Louis, Missouri

‘Struggling with inner demons’
I would hope that Dr. Nasrallah would understand that the use of the metaphor, “struggling with inner demons,” does not suggest “stupid” (Stop blaming ‘demons’ for bizarre delusions or behavior!, From the Editor, February 2016, p. 19,20,22). A celebrity, or any other person, might be struggling with intense, conflicting emotions that create chaos and distress. I would shudder if I read in The New York Times, “Well known actor’s divorce and drug use clearly leading to hypertrophied amygdala.” The term inner demons does not necessarily imply medieval superstition, but rather a well-established use of creative language.

Ron Samarian, MD
Chief, Department of Psychiatry
William Beaumont Hospital
Royal Oak, Michigan
Chair, Oakland University
William Beaumont Medical School
Rochester, Michigan

Dr. Nasrallah responds
Dr. Samarian missed the reason for my umbrage with the “inner demons” metaphor. As a psychiatrist, educator, and researcher, I am exquisitely sensitive to the poor understanding of mental illness and the rampant stigma associated with psychiatric disorders despite the incredible neurobiologic advances. Thus, I regard the metaphor that employs words like “demons” when describing intense struggles with emotional upheavals and stress as having an unfortunate connotation to the obsolete beliefs that abnormal behavior, thoughts, or mood are due to the devil and his nefarious demons.

I would welcome a metaphor that describes a depressed person as having a shrunken hippocampus, which would regrow with antidepressant or electroconvulsive therapy, because that’s the biologic truth and has no misleading connotations; the same with Dr. Samarian’s example of a hypertrophied amygdala in a person with chronic stress.

The ‘worried well’ and the ‘walking wounded’: How will we know them?
One of Dr. Henry A. Nasrallah’s resolutions (16 New Year’s resolutions for psychiatrists in 2016, From the Editor, January 2016, p. 23,24) stated that a significant percentage of one’s practice should be dedicated to the sickest patients, followed by the statement, “There are enough non-physician mental health professionals to handle the walking wounded and worried well.”

Who are the “walking wounded” and the “worried well”? These are commonly used terms, but who falls into these categories? I think it is important to get a sense of who is in these groups, because my takeaway from this editorial is that it is acceptable to let the walking wounded and worried well be treated by lesser-trained clinicians. Do these terms refer to a diagnostic group? Level of functioning? Severity of symptoms? Or severity plus chronicity? Level of suffering? Ability to “fake” looking less severe? 

I wonder, am I a walking wounded or worried well? Are some of my friends, or my family members? When I see a patient, I ask myself if he (she) might be in that category.

Susan Fredriksen, MD
Private Practice
Hayesville, North Carolina

Dr. Nasrallah responds
I use those terms to refer to persons who have psychiatric symptoms but are not disabled socially or vocationally. They deserve a full psychiatric evaluation when they initially seek help, but generally do well with various types of psychotherapy, including cognitive-behavioral therapy, interpersonal therapy, psychodynamic therapy, or dialectic behavior therapy. There are many well-trained psychologists and licensed therapists who can administer those therapies as well as, or better than, some psychiatrists. 

I recommended that psychiatrists dedicate a significant percentage (more than 50%) of their practice to more severely ill patients (those with psychosis, bipolar disorder, major depressive disorder, panic disorders, obsessive-compulsive disorder, posttraumatic stress disorder, etc.) because we are the only mental health professionals who can competently integrate biopsychosocial treatments for these patients and administer pharmacotherapeutic agents in addition to non-drug approaches. The supply of psychiatrists is short, and the number of seriously ill patients who need the medical expertise we can provide is large.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry
Saint Louis University School of Medicine
St. Louis, Missouri

‘Struggling with inner demons’
I would hope that Dr. Nasrallah would understand that the use of the metaphor, “struggling with inner demons,” does not suggest “stupid” (Stop blaming ‘demons’ for bizarre delusions or behavior!, From the Editor, February 2016, p. 19,20,22). A celebrity, or any other person, might be struggling with intense, conflicting emotions that create chaos and distress. I would shudder if I read in The New York Times, “Well known actor’s divorce and drug use clearly leading to hypertrophied amygdala.” The term inner demons does not necessarily imply medieval superstition, but rather a well-established use of creative language.

Ron Samarian, MD
Chief, Department of Psychiatry
William Beaumont Hospital
Royal Oak, Michigan
Chair, Oakland University
William Beaumont Medical School
Rochester, Michigan

Dr. Nasrallah responds
Dr. Samarian missed the reason for my umbrage with the “inner demons” metaphor. As a psychiatrist, educator, and researcher, I am exquisitely sensitive to the poor understanding of mental illness and the rampant stigma associated with psychiatric disorders despite the incredible neurobiologic advances. Thus, I regard the metaphor that employs words like “demons” when describing intense struggles with emotional upheavals and stress as having an unfortunate connotation to the obsolete beliefs that abnormal behavior, thoughts, or mood are due to the devil and his nefarious demons.

I would welcome a metaphor that describes a depressed person as having a shrunken hippocampus, which would regrow with antidepressant or electroconvulsive therapy, because that’s the biologic truth and has no misleading connotations; the same with Dr. Samarian’s example of a hypertrophied amygdala in a person with chronic stress.

The 2015-2016 U.S. flu season may have reached its peak. The proportion of outpatient visits for influenza-like illness (ILI) dropped to 3.2% for the week ending March 19, according to the Centers for Disease Control and Prevention.

The drop came after 9 consecutive weeks without a decrease, as the proportion of outpatient visits for ILI topped out at 3.7%, the CDC reported. The national baseline is 2.1%.

For the week ending March 19, three states – Kentucky, New Jersey, and New Mexico – were at level 10 on the CDC’s 1-10 scale of ILI activity, compared with seven the week before. Other states in the “high” range for the week were North Carolina at level 9 and Alabama, New York, and Virginia at level 8, according to data from the CDC’s Influenza-like Illness Surveillance Network (ILINet).

The CDC also reported a cumulative rate of 18.2 laboratory-confirmed influenza-associated hospitalizations per 100,000 population for the 2015-2016 flu season.

Two flu-related pediatric deaths were reported during the most recent week, one of which occurred during the week ending March 5. That brings the total to 30 reported for the 2015-2016 season. For the three previous flu seasons, the pediatric death totals were 148 (2014-2015), 111 (2013-2014), and 171 (2012-2013), according to the CDC report.

[email protected]

The 2015-2016 U.S. flu season may have reached its peak. The proportion of outpatient visits for influenza-like illness (ILI) dropped to 3.2% for the week ending March 19, according to the Centers for Disease Control and Prevention.

The drop came after 9 consecutive weeks without a decrease, as the proportion of outpatient visits for ILI topped out at 3.7%, the CDC reported. The national baseline is 2.1%.

For the week ending March 19, three states – Kentucky, New Jersey, and New Mexico – were at level 10 on the CDC’s 1-10 scale of ILI activity, compared with seven the week before. Other states in the “high” range for the week were North Carolina at level 9 and Alabama, New York, and Virginia at level 8, according to data from the CDC’s Influenza-like Illness Surveillance Network (ILINet).

The CDC also reported a cumulative rate of 18.2 laboratory-confirmed influenza-associated hospitalizations per 100,000 population for the 2015-2016 flu season.

Two flu-related pediatric deaths were reported during the most recent week, one of which occurred during the week ending March 5. That brings the total to 30 reported for the 2015-2016 season. For the three previous flu seasons, the pediatric death totals were 148 (2014-2015), 111 (2013-2014), and 171 (2012-2013), according to the CDC report.

[email protected]

The 2015-2016 U.S. flu season may have reached its peak. The proportion of outpatient visits for influenza-like illness (ILI) dropped to 3.2% for the week ending March 19, according to the Centers for Disease Control and Prevention.

The drop came after 9 consecutive weeks without a decrease, as the proportion of outpatient visits for ILI topped out at 3.7%, the CDC reported. The national baseline is 2.1%.

For the week ending March 19, three states – Kentucky, New Jersey, and New Mexico – were at level 10 on the CDC’s 1-10 scale of ILI activity, compared with seven the week before. Other states in the “high” range for the week were North Carolina at level 9 and Alabama, New York, and Virginia at level 8, according to data from the CDC’s Influenza-like Illness Surveillance Network (ILINet).

The CDC also reported a cumulative rate of 18.2 laboratory-confirmed influenza-associated hospitalizations per 100,000 population for the 2015-2016 flu season.

Two flu-related pediatric deaths were reported during the most recent week, one of which occurred during the week ending March 5. That brings the total to 30 reported for the 2015-2016 season. For the three previous flu seasons, the pediatric death totals were 148 (2014-2015), 111 (2013-2014), and 171 (2012-2013), according to the CDC report.

[email protected]

I completely agree with Dr. Selinger in his letter, “I will click those boxes, but first, I will care for my patient” (J Fam Pract. 2015;64:762). I graduated from medical school in 1969 and enjoyed the actual “laying on of hands” that characterized medicine at that time. Now that electronic health records (EHRs) are mandated, much of our time is spent as data entry personnel, rather than as physicians. Personally, I couldn’t stand it; I went into medicine to care for patients, not computers. I left medicine, as I am sure many of my fellow physicians have.

How did we allow EHRs to enter our field?

I am sure that there are many people who believe that EHRs allow us to be more efficient and to meet “the rules.” But to that I say, “Baloney!” Let us return to the true practice of medicine.

Deborah R. Ishida, MD
Beverly Hills, Calif

I completely agree with Dr. Selinger in his letter, “I will click those boxes, but first, I will care for my patient” (J Fam Pract. 2015;64:762). I graduated from medical school in 1969 and enjoyed the actual “laying on of hands” that characterized medicine at that time. Now that electronic health records (EHRs) are mandated, much of our time is spent as data entry personnel, rather than as physicians. Personally, I couldn’t stand it; I went into medicine to care for patients, not computers. I left medicine, as I am sure many of my fellow physicians have.

How did we allow EHRs to enter our field?

I am sure that there are many people who believe that EHRs allow us to be more efficient and to meet “the rules.” But to that I say, “Baloney!” Let us return to the true practice of medicine.

Deborah R. Ishida, MD
Beverly Hills, Calif

I completely agree with Dr. Selinger in his letter, “I will click those boxes, but first, I will care for my patient” (J Fam Pract. 2015;64:762). I graduated from medical school in 1969 and enjoyed the actual “laying on of hands” that characterized medicine at that time. Now that electronic health records (EHRs) are mandated, much of our time is spent as data entry personnel, rather than as physicians. Personally, I couldn’t stand it; I went into medicine to care for patients, not computers. I left medicine, as I am sure many of my fellow physicians have.

How did we allow EHRs to enter our field?

I am sure that there are many people who believe that EHRs allow us to be more efficient and to meet “the rules.” But to that I say, “Baloney!” Let us return to the true practice of medicine.

Deborah R. Ishida, MD
Beverly Hills, Calif

Soin, et al, reported an interesting case of strongyloidiasis in a refugee in their Photo Rounds article, “Rash, diarrhea, and eosinophilia” (J Fam Pract. 2015;64:655-658). They mentioned the importance of having a high degree of suspicion for parasitic infections among refugees. Indeed, health screenings for refugees are necessary and should include testing for parasitoses. However, there are several other issues to consider.

First, a single screening may not be effective. Thus, results should be verified with repeat screening tests. In my experience in Thailand, a single screening of migrants from nearby Indochinese countries failed to detect several infectious cases, including tuberculosis, malaria, and intestinal parasite infections. To optimize early detection and infection control, a repeated check-up system is needed. It should be noted, however, that a false-negative result for strongyloidiasis is not common from a stool examination or immunological test.¹

Second, the mentioned symptoms of “rash, diarrhea, and eosinophilia” can be due to several etiologies and may have been caused by a completely separate illness. Or the findings might have been due to a forgotten condition, such as post-dengue infection illness.²

Finally, the existence of strongyloidiasis in the case presented by Soin, et al, could have been an incidental finding without a relationship to the exact pathology.

Viroj Wiwanitkit, MD
Bangkok, Thailand

Soin, et al, reported an interesting case of strongyloidiasis in a refugee in their Photo Rounds article, “Rash, diarrhea, and eosinophilia” (J Fam Pract. 2015;64:655-658). They mentioned the importance of having a high degree of suspicion for parasitic infections among refugees. Indeed, health screenings for refugees are necessary and should include testing for parasitoses. However, there are several other issues to consider.

First, a single screening may not be effective. Thus, results should be verified with repeat screening tests. In my experience in Thailand, a single screening of migrants from nearby Indochinese countries failed to detect several infectious cases, including tuberculosis, malaria, and intestinal parasite infections. To optimize early detection and infection control, a repeated check-up system is needed. It should be noted, however, that a false-negative result for strongyloidiasis is not common from a stool examination or immunological test.¹

Second, the mentioned symptoms of “rash, diarrhea, and eosinophilia” can be due to several etiologies and may have been caused by a completely separate illness. Or the findings might have been due to a forgotten condition, such as post-dengue infection illness.²

Finally, the existence of strongyloidiasis in the case presented by Soin, et al, could have been an incidental finding without a relationship to the exact pathology.

Viroj Wiwanitkit, MD
Bangkok, Thailand

Soin, et al, reported an interesting case of strongyloidiasis in a refugee in their Photo Rounds article, “Rash, diarrhea, and eosinophilia” (J Fam Pract. 2015;64:655-658). They mentioned the importance of having a high degree of suspicion for parasitic infections among refugees. Indeed, health screenings for refugees are necessary and should include testing for parasitoses. However, there are several other issues to consider.

First, a single screening may not be effective. Thus, results should be verified with repeat screening tests. In my experience in Thailand, a single screening of migrants from nearby Indochinese countries failed to detect several infectious cases, including tuberculosis, malaria, and intestinal parasite infections. To optimize early detection and infection control, a repeated check-up system is needed. It should be noted, however, that a false-negative result for strongyloidiasis is not common from a stool examination or immunological test.¹

Second, the mentioned symptoms of “rash, diarrhea, and eosinophilia” can be due to several etiologies and may have been caused by a completely separate illness. Or the findings might have been due to a forgotten condition, such as post-dengue infection illness.²

Finally, the existence of strongyloidiasis in the case presented by Soin, et al, could have been an incidental finding without a relationship to the exact pathology.

Viroj Wiwanitkit, MD
Bangkok, Thailand

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

Like many physicians, I struggle with looking at my patients while they are talking and getting the stories that they tell me transcribed as accurately and completely as possible. After I read the article, “EHR use and patient satisfaction: What we learned” by Farber, et al, (J Fam Pract. 2015;64:687-696), I was struck by something.

Of the 126 patients chosen for the research, the educational level breakdown included 75% with at least some college education and 28% with postgraduate education. A study performed by the National Center for Veterans Analysis and Statistics published in 2015 has different statistics.¹ Although a similar percentage had at least some college education, only 10.5% of the men and 12.4% of the women had postgraduate education.

In my practice, most of my patients who have worked with computers empathize with the amount of time that I spend looking at the screen. Those with less education are less agreeable. Since the patients were picked by their physicians to take part in the study, I wonder if there was an unconscious bias present.

Holly Leeds, MD
Auburn, Calif

1. National Center for Veterans Analysis and Statistics. Profile of Veterans: 2013. US Department of Veterans Affairs Web site. Available at: http://www.va.gov/vetdata/docs/SpecialReports/Profile_of_Veterans_2013.pdf. Accessed March 21, 2016.

Author's response:
Dr. Leeds brings up an interesting issue. It is possible that there is an unconscious bias on the part of physicians who participated in this study. Although the demographics are fairly similar to those that she cites, the veterans in our study were somewhat more educated.

If less well-educated subjects participated, this would make the data more impressive, in terms of less satisfaction with physicians who more readily focus their eyes on computer screens rather than on their patients. The fact that we did find this association is important for physicians who use EHR systems.

Neil J. Farber, MD, FACP
San Diego, Calif

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; [email protected].

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; [email protected].

CASE › A 39-year-old Hispanic man with a body mass index (BMI) of 35 kg/m², type 2 diabetes mellitus (T2DM), and hypertension is referred for evaluation of abnormal liver function tests (LFTs) and fatty liver on ultrasound. He is taking metformin and lisinopril, and a patient alcohol screening survey is negative. LFT results reveal the following: alanine aminotransferase (ALT) 27 IU/dL; aspartate aminotransferase (AST) 43 IU/dL; albumin 4.2 g/dL; gamma glutamyl transferase 22 u/L; alkaline phosphatase 51 IU/L; and total bilirubin 0.3 mg/dL. Lactate dehydrogenase and prothrombin time are normal.

Results of his liver screen are as follows: hepatitis B surface antigen, hepatitis C antibody, antimitochondrial antibody, and anti-smooth muscle antibody are negative, and iron, transferrin saturation, and ceruloplasmin are in normal range. Antinuclear antibody (1:20 dilution) is weakly positive, and alpha-1 antitrypsin (264 mg/dL) and serum ferritin (300 ng/mL) are mildly increased.

The patient undergoes a liver biopsy that shows grade 2 steatosis, grade 1 lobular inflammation, few ballooned hepatocytes, and stage 1 fibrosis. Based on these clinical findings, he is given a diagnosis of non-alcoholic fatty liver disease (NAFLD).

NAFLD is the most frequent cause of chronic liver disease both in the United States and globally.¹ In fact, a number of long-term epidemiologic studies report that nearly one-third of the US population has the disease.² The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) to cirrhosis. Of patients with NAFLD, 10% to 30% have the more severe form—NASH—and about 10% of those with NASH progress to cirrhosis and other liver-related complications.³

People with NAFLD consume no alcohol, or only a modest amount (ie, weekly intake <140 g in women and <210 g in men). Typically, they are asymptomatic with normal or mildly abnormal LFTs discovered as part of a preventive health screening. In patients with simple hepatic steatosis alone, serum ALT levels are higher than serum AST levels. (In contrast, patients with alcoholic liver injury and NASH with progressive fibrosis have higher serum AST than ALT levels.) A serum hepatitis panel and liver screen are negative for other explanations of chronic liver disease.

NAFLD is strongly associated with obesity, insulin resistance/T2DM, and hyperlipidemia, all of which are components of metabolic syndrome. Obesity, particularly central obesity, is highly predictive of hepatic steatosis and disease progression.⁴ T2DM occurs 5 to 9 times more frequently in people with NAFLD than in the general population,⁵ and, conversely, nearly 66% of patients with T2DM have NAFLD.^6,7 Furthermore, nearly 70% of patients with T2DM develop fatty liver and its consequences, including NASH, fibrosis, cirrhosis, and hepatocellular carcinoma.^5,7

4 therapeutic strategies. Based on our current understanding of the pathogenesis of NAFLD, there are 4 main therapeutic avenues: lifestyle modification, liver-directed pharmacotherapy, management of metabolic syndrome, and surveillance of the complications of cirrhosis. The review that follows explores the evidence to date for each.

Take steps to reduce weight and increase physical activity

The primary objective with NAFLD is to right the imbalance between calorie intake and utilization so as to reverse the obesity and insulin resistance underlying the disease.

Target carbohydrates. Current data clearly suggest that energy intake is significantly higher in patients with NAFLD than in those without the disease.⁸ Thus, reducing dietary carbohydrate and overall energy intake is beneficial to preventing and halting the progression of liver damage. Increased intake of high fructose corn syrup may be at least partially to blame; research has linked the substance to the occurrence of obesity, metabolic syndrome, and NAFLD.⁹

The optimal diet to treat NAFLD is not known because of the difficulties inherent to performing well-designed dietary intervention trials and ensuring long-term compliance. At least one study reported that a Mediterranean diet helped reduce hepatic steatosis and improve insulin sensitivity in nondiabetic individuals.¹⁰ Generally, patients should avoid saturated fats, simple carbohydrates, and sweetened drinks, and they should be instructed to restrict calories to cause weight loss of about .5 kg to 1 kg per week until the target weight is achieved.¹¹

Current observational studies indicate that prudent calorie restriction combined with increased physical activity is the best strategy for achieving and sustaining optimum body weight; severe calorie restriction is likely to cause skeletal muscle loss that can aggravate NAFLD.

Encourage exercise. Aerobic exercise improves skeletal muscle insulin sensitivity—the primary underlying mechanism that causes NAFLD.¹² Although the optimum duration and intensity of exercise is not known, several randomized controlled trials (RCTs) found that moderately intense training, high-intensity training, and/or resistance training improved hepatic steatosis and insulin resistance, but an effect on ALT was inconsistent.¹³ (None of these studies included histology as an outcome measure.)

Given the multitude of benefits of aerobic exercise, there is no question that patients with NAFLD should try to increase their physical activity and incorporate exercise into their daily routine.

Hold off on pharmacologic weight loss. Orlistat, an enteric lipase inhibitor, causes malabsorption of dietary fat, which leads to weight loss. Although one study demonstrated that orlistat improves ALT and steatosis in patients with NAFLD, a subsequent RCT concluded that orlistat with caloric restriction and vitamin E (800 IU/d) did not enhance weight loss over caloric restriction and vitamin E alone.¹⁴ Additionally, in patients with weight loss >9% of body weight, histologic improvement occurred independent of orlistat.¹⁴ Therefore, orlistat is not currently recommended for weight loss in patients with NAFLD.

Keep bariatric surgery on your radar. Bariatric-metabolic surgery provides the most reliable method for achieving sustained weight loss in morbidly obese individuals with NAFLD. Commonly used surgical procedures are associated with reduced steatosis and lobular inflammatory changes, but reports are conflicting regarding fibrosis.¹⁵

The majority of published data indicate that bariatric surgery improves the histologic and metabolic changes associated with NAFLD and has potential as a treatment option for patients with morbid obesity and NAFLD. However, the timing and type of surgery that is most effective, and whether bariatric surgery can cure the disease, remain unanswered questions. Long-term follow-up and RCTs are needed to address these issues. As a result, no definitive recommendations regarding bariatric surgery as a treatment for NAFLD can be made at this time.¹⁵

Liver-directed pharmacotherapy: Evidence is lacking for many agents

Lifestyle modification remains the mainstay of therapy for NAFLD because of its efficacy and lack of adverse effects. But low compliance rates often make pharmacotherapy necessary to reduce the health burden related to NAFLD. Despite the success rate of pharmacologic agents that focus on insulin resistance and lipid metabolism and that have antioxidant properties, the long-term safety and efficacy of many of these agents is largely unknown. Furthermore, the FDA has not approved any pharmacologic agents specifically for the treatment of NAFLD. Here’s what we know:

Vitamin E. Five RCTs have evaluated the antioxidant vitamin E in patients with NASH. The best study published to date found that 96 weeks of therapy with 800 IU/d vitamin E was associated with a 42% improvement in hepatic histology, compared with 19% improvement in the placebo group.¹⁶ Vitamin E was also associated with improved serum ALT.

Although vitamin E seems to be a promising agent for the treatment of NASH, concerns exist about its long-term safety because of an increased risk of all-cause mortality and hemorrhagic stroke.¹⁷ In addition, because the optimal dose and duration of treatment is unknown and because studies have not evaluated the supplement in patients who have diabetes and NASH, vitamin E is not currently considered to be a standard therapy for NASH.

Insulin sensitizers. Because insulin resistance is believed to be the underlying mechanism for the development and progression of NAFLD, a compelling rationale exists for the use of insulin sensitizers in the management of the disease. Metformin, an activator of adenosine monophosphate-activated protein kinase, and the thiazolidinediones (pioglitazone and rosiglitazone) are the most extensively studied agents in clinical trials. A number of studies looking at the effects of metformin on NAFLD found that liver function, steatosis, and insulin sensitivity improved;¹⁸ however, a recent meta-analysis found that metformin failed to improve liver histology.¹⁹

Similarly, although clinical trials have shown that thiazolidinediones improve liver enzymes, inflammatory markers, and hepatic steatosis, questions surround their long-term safety.²⁰ The largest placebo-controlled trial on this issue to date—PIVENS (pioglitazone vs vitamin E vs placebo)—found that pioglitazone was beneficial in improving hepatic histology.¹⁶ However, the well-recognized adverse effects of pioglitazone (eg, upper respiratory tract infection, edema, and hypoglycemia) may temper its utility.

Clinical trials involving newer antidiabetic agents, such as dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues, indicate that such agents improve insulin resistance, steatosis, and inflammation.²¹ However, these drugs are not considered to be routine therapy because of limited data and the lack of long-term benefits.

Bile acid regulatory agents. Ursodeoxycholic acid (UDCA), a bile acid with antiapoptotic and cytoprotective properties, is used as a hepatoprotectant in NAFLD. Although early studies showed no significant differences in LFT results between UDCA-treated and untreated groups, recent RCTs indicate that UDCA improves ALT and serum fibrosis.^22,23 The FLINT trial, a recent multicenter RCT involving obeticholic acid, found that UDCA was associated with improvement in histologic outcomes, although long-term benefits and safety—especially with regard to worsening hyperlipidemia—are questionable.²⁴

Pentoxifylline. Researchers have evaluated pentoxifylline, a hepatoprotectant with anti-tumor necrosis factor effect, in the treatment of NAFLD.²⁵ In fact, pooled results from 5 well-designed studies indicate that pentoxifylline significantly reduces ALT and AST and improves steatosis, lobular inflammation, and fibrosis.²⁶ Although these data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large multicenter studies and FDA approval temper its utility in the management of NASH at this time.

Cholesterol-lowering agents. Statins inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase in the liver and have anti-inflammatory and anti-fibrogenic properties. They have been used in patients with NAFLD, primarily because of their cardiovascular benefit. Two RCTs with high risk of bias and a small number of participants found statin therapy to be associated with improved serum transaminases and ultrasound findings; however, liver biopsies were not performed in either of these studies.²⁷

While the data suggest that pentoxifylline holds promise as a therapeutic option, the lack of large studies and FDA approval temper its utility in the management of non-alcoholic steatohepatitis.

Lowering cholesterol using an absorption inhibitor, such as ezetimibe, was associated with improvement in liver histology in a single RCT.²⁸ Even though statins are not considered to be a treatment for NAFLD, they can be used to safely lower plasma cholesterol in patients with the disease.

Renin-angiotensin system (RAS) inhibitors. Research in animals indicates that activation of the renin-angiotensin system contributes to the pathogenesis of NAFLD, but data on the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with NAFLD are limited, conflicting, and derived largely from retrospective²⁹ and pilot prospective studies.

Based on currently published literature, RAS inhibitors are not considered an NAFLD treatment. However, because cardiovascular disease is a major cause of death in patients with NAFLD, the renal and cardiovascular protection offered by these agents likely lowers mortality in patients with the disease.

Probiotics. The use of probiotics in the treatment of NAFLD is based on the premise that alterations in intestinal microbes and the inflammatory response may improve the disease. Three RCTs involving different formulations of probiotics, synbiotics, or placebo, showed improvement in serum liver markers and insulin resistance, but did not include histologic outcome measures.³⁰ Furthermore, the long-term consequences of altered gut flora are presently unknown. As such, the available evidence does not support the use of probiotics for the treatment of NAFLD.

Polyunsaturated fatty acids (PUFA). Clearly, omega-3 fatty acids have beneficial effects on cardiometabolic risk factors and positively impact lipid metabolism and insulin sensitivity. In addition, a few studies have reported improvement in non-histologic outcome measures of NAFLD, but 2 high-quality RCTs found no benefit of fish oil-based PUFA on histology.^31,32 Thus, current evidence does not support recommending PUFA supplementation for the treatment of NAFLD.

Chinese herbal medicines. At least 56 trials have looked at 75 different Chinese herbal medicines in varying formulations, dosages, routes of administration, and durations of treatment, using various controlled interventions.³³ No trial reported primary outcomes, such as hepatic-related mortality, morbidity, or health care quality of life. Although a large number of the trials reported some positive effects on various biochemical or radiologic measures, the high risk of bias and the limited number of trials testing individual herbal medicines leave efficacy and safety open to question. As such, no Chinese herbal medicines are regarded as treatment for NAFLD at this time.

Target components of metabolic syndrome

Management of the components of metabolic syndrome remains one of the safest and most effective ways to manage NAFLD. Therefore, screening for and treating T2DM, hypertension, and dyslipidemia are priorities. Although obstructive sleep apnea (OSA) is not part of metabolic syndrome, the condition frequently coexists with metabolic syndrome because both entities have obesity as a risk factor.

T2DM. Screen all patients with NAFLD for T2DM and vice-versa because, as noted earlier, patients with diabetes have more severe and progressive NAFLD, and a high proportion of patients with NAFLD have T2DM.^5,6 Although research has not shown metformin to improve histology in NASH, metformin is recommended as a first-line agent for the treatment of T2DM because it aids in weight loss and lowers diabetes-related mortality.³⁴

Pioglitazone is considered a second-line agent. Despite its beneficial effects on insulin sensitivity and hepatic histology, there are concerns about the adverse effects of thiazolidinediones. GLP1 analogues, which improve liver enzymes and reduce hepatic steatosis, are considered third-line agents.

Hypertension. Because approximately 70% of patients with NAFLD have hypertension,³⁵ it is imperative to screen patients for the condition. If blood pressure is >140/90 mm Hg, patients should be managed according to hypertension guidelines. ACE inhibitors or ARBs are recommended as first-line therapy, since blocking the renin-angiotensin system potentially reduces hepatic fibrosis,³⁶ and ARBs may lower transaminases and improve insulin sensitivity in NAFLD.

Dyslipidemia. Treatment of dyslipidemia is essential to lowering cardiovascular mortality in patients with NAFLD. Even though elevated transaminases occur with NAFLD, this should not preclude starting therapy to lower triglycerides to <150 mg/dL and total cholesterol to <200 mg/dL.

OSA. Because of the high prevalence of OSA in patients with NAFLD, physicians should have a high index of suspicion and screen this population for sleep disorders. OSA is associated with an increased risk of NAFLD and advanced fibrosis in NASH.³⁷ Treatment of OSA improves quality of life and controls blood pressure in patients with NAFLD, but it’s currently unclear whether targeting sleep disorders can slow the progression of fibrosis in NAFLD.

Concentrate on the complications of cirrhosis

Patients with NASH cirrhosis, like those with cirrhosis of other etiologies, are at risk for complications, including hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal variceal hemorrhage. Surveillance to detect these include an annual liver ultrasound, an alpha-fetoprotein test every 6 months, esophagogastroduodenoscopy for varices, and an assessment for liver transplantation. For more on these complications, see, “Cirrhosis complications: Keeping them under control,” J Fam Pract. 2015;64:338-342. NAFLD-associated cirrhosis is the third most frequent indication for liver transplantation in the United States and may become the most frequent indication in the next decade.³⁸

CASE ›  Because the patient’s liver biopsy showed early NASH, we recommended that he aggressively pursue lifestyle modification, including regular physical activity and dietary changes. Additionally, we discussed optimization of glycemic control and continued use of lisinopril for control of hypertension. On follow-up 6 months later, he had lost weight and his BMI was 32 kg/m². In addition, his transaminase levels had improved, but they had not normalized.

We recommended that he continue the same measures, with follow-up every 6 months to ensure compliance with lifestyle modifications and with diabetes and hypertension control.

CORRESPONDENCE
Jaividhya Dasarathy, MD, Metro Health Medical Center, 2500 Metro Health Drive, Cleveland, OH 44109; [email protected].

Hormonal contraceptives don’t appear to increase the risk of recurrence of venous thromboembolism among women taking anticoagulants, according to a report published in Blood.

Clinicians are often reluctant to prescribe hormonal contraceptives for women who develop venous thromboembolism (VTE) because the drugs are known to raise the risk of VTE and are considered to be contraindicated in either active or previous VTE. But effective contraception is necessary for women of childbearing age who are taking anticoagulants, because these drugs cross the placenta and could cause fetal bleeding and other adverse events, wrote Dr. Ida Martinelli of the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, and her associates (Blood 2016;127[11]:1417-25).

©ThinkStockPhotos.com

Adding further to the confusion, World Health Organization guidelines state that estrogen-containing contraceptives confer “an unacceptable health risk” during anticoagulant therapy for VTE, but the International Society on Thrombosis and Haemostasis recommends that women diagnosed with VTE continue oral contraceptive and estrogen-replacement hormonal therapy until they discontinue anticoagulant therapy “because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation,” the investigators noted.

In the current study, the investigators performed a secondary analysis of data accrued in two large trials evaluating rivaroxaban versus enoxaparin plus vitamin K antagonists, which involved 1,888 women younger than age 60 (mean age, 41 years) who were being treated for acute deep vein thrombosis or acute pulmonary embolism. A total of 402 of these women used hormonal therapy during the 4-year studies.

There were 7 VTE recurrences during hormonal contraceptive use and 38 without hormonal contraceptive use. The incidence densities were 3.7% per year with hormonal therapy and 4.7% per year without it, for a hazard ratio of 0.56.

This indicates that hormonal contraceptive use did not make a clinically important difference in the rate of VTE recurrence. Moreover, these findings were consistent regardless of whether the contraceptives contained estrogen (incidence density, 3.7% per year) or progestin only (incidence density, 3.8% per year), and remained consistent in sensitivity analyses.

“These results challenge the WHO guidelines and instead support the International Society on Thrombosis and Haemostasis recommendations,” the investigators wrote.

“Our finding of similar risks of recurrent VTE for women who did or did not receive hormonal therapy, whether progestin-only or estrogen-containing therapy, supports a treatment selection that incorporates patient preference, including the choice of estrogen-containing contraception,” they added.

The study was funded in part by Bayer Healthcare Pharmaceuticals, which also provided editorial assistance. Dr. Martinelli reported having no relevant financial disclosures; her associates reported ties to numerous industry sources.

Hormonal contraceptives don’t appear to increase the risk of recurrence of venous thromboembolism among women taking anticoagulants, according to a report published in Blood.

Clinicians are often reluctant to prescribe hormonal contraceptives for women who develop venous thromboembolism (VTE) because the drugs are known to raise the risk of VTE and are considered to be contraindicated in either active or previous VTE. But effective contraception is necessary for women of childbearing age who are taking anticoagulants, because these drugs cross the placenta and could cause fetal bleeding and other adverse events, wrote Dr. Ida Martinelli of the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, and her associates (Blood 2016;127[11]:1417-25).

©ThinkStockPhotos.com

Adding further to the confusion, World Health Organization guidelines state that estrogen-containing contraceptives confer “an unacceptable health risk” during anticoagulant therapy for VTE, but the International Society on Thrombosis and Haemostasis recommends that women diagnosed with VTE continue oral contraceptive and estrogen-replacement hormonal therapy until they discontinue anticoagulant therapy “because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation,” the investigators noted.

In the current study, the investigators performed a secondary analysis of data accrued in two large trials evaluating rivaroxaban versus enoxaparin plus vitamin K antagonists, which involved 1,888 women younger than age 60 (mean age, 41 years) who were being treated for acute deep vein thrombosis or acute pulmonary embolism. A total of 402 of these women used hormonal therapy during the 4-year studies.

There were 7 VTE recurrences during hormonal contraceptive use and 38 without hormonal contraceptive use. The incidence densities were 3.7% per year with hormonal therapy and 4.7% per year without it, for a hazard ratio of 0.56.

This indicates that hormonal contraceptive use did not make a clinically important difference in the rate of VTE recurrence. Moreover, these findings were consistent regardless of whether the contraceptives contained estrogen (incidence density, 3.7% per year) or progestin only (incidence density, 3.8% per year), and remained consistent in sensitivity analyses.

“These results challenge the WHO guidelines and instead support the International Society on Thrombosis and Haemostasis recommendations,” the investigators wrote.

“Our finding of similar risks of recurrent VTE for women who did or did not receive hormonal therapy, whether progestin-only or estrogen-containing therapy, supports a treatment selection that incorporates patient preference, including the choice of estrogen-containing contraception,” they added.

The study was funded in part by Bayer Healthcare Pharmaceuticals, which also provided editorial assistance. Dr. Martinelli reported having no relevant financial disclosures; her associates reported ties to numerous industry sources.

Hormonal contraceptives don’t appear to increase the risk of recurrence of venous thromboembolism among women taking anticoagulants, according to a report published in Blood.

Clinicians are often reluctant to prescribe hormonal contraceptives for women who develop venous thromboembolism (VTE) because the drugs are known to raise the risk of VTE and are considered to be contraindicated in either active or previous VTE. But effective contraception is necessary for women of childbearing age who are taking anticoagulants, because these drugs cross the placenta and could cause fetal bleeding and other adverse events, wrote Dr. Ida Martinelli of the A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Milan, and her associates (Blood 2016;127[11]:1417-25).

©ThinkStockPhotos.com

Adding further to the confusion, World Health Organization guidelines state that estrogen-containing contraceptives confer “an unacceptable health risk” during anticoagulant therapy for VTE, but the International Society on Thrombosis and Haemostasis recommends that women diagnosed with VTE continue oral contraceptive and estrogen-replacement hormonal therapy until they discontinue anticoagulant therapy “because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation,” the investigators noted.

In the current study, the investigators performed a secondary analysis of data accrued in two large trials evaluating rivaroxaban versus enoxaparin plus vitamin K antagonists, which involved 1,888 women younger than age 60 (mean age, 41 years) who were being treated for acute deep vein thrombosis or acute pulmonary embolism. A total of 402 of these women used hormonal therapy during the 4-year studies.

There were 7 VTE recurrences during hormonal contraceptive use and 38 without hormonal contraceptive use. The incidence densities were 3.7% per year with hormonal therapy and 4.7% per year without it, for a hazard ratio of 0.56.

This indicates that hormonal contraceptive use did not make a clinically important difference in the rate of VTE recurrence. Moreover, these findings were consistent regardless of whether the contraceptives contained estrogen (incidence density, 3.7% per year) or progestin only (incidence density, 3.8% per year), and remained consistent in sensitivity analyses.

“These results challenge the WHO guidelines and instead support the International Society on Thrombosis and Haemostasis recommendations,” the investigators wrote.

“Our finding of similar risks of recurrent VTE for women who did or did not receive hormonal therapy, whether progestin-only or estrogen-containing therapy, supports a treatment selection that incorporates patient preference, including the choice of estrogen-containing contraception,” they added.

The study was funded in part by Bayer Healthcare Pharmaceuticals, which also provided editorial assistance. Dr. Martinelli reported having no relevant financial disclosures; her associates reported ties to numerous industry sources.

CASE From soft-spoken to manic
Mr. K, age 36, an Asian male with no psychiatric history, arrives at the outpatient psychiatry clinic accompanied by his wife, after being referred from the emergency room the night before. He reports racing thoughts, euphoric mood, increased speech, hypergraphia, elevated self-esteem, decreased need for sleep, distractibility, and increased goal-directed activity. Notably, Mr. K states that he likes how he is feeling.

Mr. K’s wife says that his condition is a clear change from his baseline demeanor: soft-spoken and mild-mannered.

Mr. K reports that his symptoms started approximately 10 days earlier, after he returned from a cruise with his wife. During the cruise, he used a scopolamine patch to prevent motion sickness. Mr. K and his wife say that they believe that the scopolamine patch caused his symptoms.

Can scopolamine cause mania?
   a) No
   b) Yes; this is well-documented in the literature
   c) It is theoretically possible because of scopolamine’s antidepressant and central anticholinergic effects

TREATMENT Lithium, close follow up
Mr. K has no history of psychiatric illness or substance use and no recent use of psycho­active substances—other than scopolamine—that could trigger a manic episode. His family history is significant for a younger brother who had a single manic episode at age 12 and a suicide attempt as a young adult.

Mr. K works full-time on rotating shifts—including some overnight shifts—as a manufacturing supervisor at a biotechnology company. He has been unable to work since returning from the cruise because of his psychiatric symptoms.

Mr. K is started on sustained-release (SR) lithium, 900 mg/d. In addition, the psychiatrist advises Mr. K to continue taking clonazepam, 0.5 to 1 mg as needed, which the emergency medicine physician prescribed, for insomnia. Mr. K is referred to a psychiatric intensive outpatient program (IOP), 3 days a week for 2 weeks, and is advised to stay home from work until symptoms stabilize.

Mr. K follows up closely with the psychiatrist in the clinic, every 1 to 2 weeks for the first month, as well as by several telephone and e-mail contacts. Lithium SR is titrated to 1,200 mg/d, to a therapeutic serum level of 1.1 mEq/L. Clonazepam is switched to quetiapine, 25 to 50 mg as needed, to address ongoing insomnia and to reduce the risk of dependency on clonazepam.

Mr. K’s mania gradually abates. He finishes the IOP and returns to work 3 weeks after his initial presentation. At an office visit, Mr. K’s wife gives the psychiatrist 2 scientific articles documenting the antidepressant effect of scopolamine.^1,2 Mr. K and his wife both continue to believe that Mr. K’s manic episode was triggered by the scopolamine patch he used while on the cruise. They think this is important because Mr. K believes he would not have developed mania otherwise, and he does not want to take a mood stabilizer for the rest of his life.

The author’s observations
There are several proposed mechanisms for scopolamine’s antidepressant effect (Table 1).^3-9 Scopolamine blocks central muscarinic cholinergic receptors, which reduces production of glutamate receptors and leads to reduced glutamate transmission and neurotoxicity.^3,4 Scopolamine—similar to ketamine—could enhance synaptogenesis and synaptic signaling.^5,6 Also, by blocking muscarinic autoreceptors, scopolamine results in an acute upregulation of acetylcholine release, which, in turn, influences the nicotinic, dopamine, serotonin, and neuropeptide Y systems. This action could contribute to anti-inflammatory effects, all of which can benefit mood.^7-9 These antidepressant mechanisms also could explain why, theoretically, scopolamine could precipitate mania in a person predisposed to mental illness.

Proposed by Janowsky et al¹⁰ in 1972, the cholinergic−adrenergic balance hypothesis of affective disorders suggests that depression represents an excess of central cholinergic tone over adrenergic tone, and that mania represents the opposite imbalance. Several lines of evidence in the literature support this theory. For example, depressed patients have been found to have hypersensitive central cholinergic receptors.^11,12 Also, central cholinesterase inhibition has been shown to affect pituitary hormone and epinephrine levels via central muscarinic receptors.¹³ In addition, scopolamine has been shown to attenuate these effects via the central anti-muscarinic mechanism.¹⁴

Rapid antidepressant therapy. Scopolamine is being studied as a rapid antidepressant treatment, although it usually is administered via IV infusion, rather than patch form, in trials.^15-17 IV ketamine is another therapy being investigated for rapid treatment of depression, which might have downstream mechanisms of action related to scopolamine.^5,18 Electroconvulsive therapy is a well-known for its quick antidepressant effect, which could involve synaptogenesis or effects on the neuroendocrine system.¹⁹ Sleep deprivation also can produce a rapid antidepressant effect²⁰ (Table 2^{1,2,5,6,15,16,18-20}).

Mr. K is prone to motion sickness, and asks if he can take over-the-counter dimenhydrinate tablets for long car rides. He reports that dimenhydrinate has worked well for him in the past without triggering manic episodes, and he did not anticipate needing to take it very often.

What would you tell Mr. K about dimenhydrinate for motion sickness during car rides?
   a) Mr. K should not take dimenhydrinate to prevent motion sickness because he experienced a manic episode triggered by a scopolamine patch
   b) Mr. K can use dimenhydrinate as much as he wants to prevent motion sickness because it poses no risk of mania
   c) Mr. K can use dimenhydrinate with caution and sparingly on a trial basis, as long as he is taking his mood stabilizer

FOLLOW UP Cautious use
The psychiatrist advised Mr. K to take dimenhydrinate cautiously when needed for long car rides. The psychiatrist feels this is safe because Mr. K is taking a mood stabilizer (lithium). Also, although dimenhydrinate has anticholinergic properties, occasional use is thought to pose less risk of triggering mania than the constant anticholinergic exposure over several days with a scopolamine patch. (The scopolamine patch contains 1.5 mg of the drug delivered over 3 days [ie, 0.5 mg/d]. In trials of IV scopolamine for depression, the dosage was 0.4 mcg/kg/d administered over 3 consecutive days.^15-17 For an adult weighing 70 kg, this would be equivalent to 0.24 mg/d. Therefore, using a scopolamine patch over 3 days would appear to deliver a robust antidepressant-level dosage, even taking into account possible lower bioavailability with transdermal administration compared with IV infusion.)

The psychiatrist concludes that sporadic use of dimenhydrinate tablets for motion sickness during occasional long car rides poses less of a risk for Mr. K of triggering mania than repeat use of a scopolamine patch.

The author’s observations
Mr. K’s case is notable for several reasons:

• Novelty. This might be the first report of scopolamine-induced mania in the literature. In clinical trials by Furey and Drevets,¹⁵ Drevets and Furey,¹⁶ and Ellis et al,¹⁷ no study participants who received scopolamine infusion developed mania or hypomania. Although it is possible that Mr. K’s manic episode could have occurred spontaneously and was coincidental to his scopolamine use, there are valid reasons why scopolamine could trigger mania in a vulnerable person.
• Biochemical insight. The case underscores the role of the muscarinic cholinergic system in regulating mood.¹⁰
• Rational medical care. Sensible clinical decision-making was needed when Mr. K asked about using dimenhydrinate for motion sickness during car rides. Although there might not be definitively correct answers for questions that arose during Mr. K’s care (in the absence of research literature), theoretical understanding of the antidepressant effects of anticholinergic medications helped inform the psychiatrist’s responses to Mr. K and his wife.

CASE From soft-spoken to manic
Mr. K, age 36, an Asian male with no psychiatric history, arrives at the outpatient psychiatry clinic accompanied by his wife, after being referred from the emergency room the night before. He reports racing thoughts, euphoric mood, increased speech, hypergraphia, elevated self-esteem, decreased need for sleep, distractibility, and increased goal-directed activity. Notably, Mr. K states that he likes how he is feeling.

Mr. K’s wife says that his condition is a clear change from his baseline demeanor: soft-spoken and mild-mannered.

Mr. K reports that his symptoms started approximately 10 days earlier, after he returned from a cruise with his wife. During the cruise, he used a scopolamine patch to prevent motion sickness. Mr. K and his wife say that they believe that the scopolamine patch caused his symptoms.

Can scopolamine cause mania?
   a) No
   b) Yes; this is well-documented in the literature
   c) It is theoretically possible because of scopolamine’s antidepressant and central anticholinergic effects

TREATMENT Lithium, close follow up
Mr. K has no history of psychiatric illness or substance use and no recent use of psycho­active substances—other than scopolamine—that could trigger a manic episode. His family history is significant for a younger brother who had a single manic episode at age 12 and a suicide attempt as a young adult.

Mr. K works full-time on rotating shifts—including some overnight shifts—as a manufacturing supervisor at a biotechnology company. He has been unable to work since returning from the cruise because of his psychiatric symptoms.

Mr. K is started on sustained-release (SR) lithium, 900 mg/d. In addition, the psychiatrist advises Mr. K to continue taking clonazepam, 0.5 to 1 mg as needed, which the emergency medicine physician prescribed, for insomnia. Mr. K is referred to a psychiatric intensive outpatient program (IOP), 3 days a week for 2 weeks, and is advised to stay home from work until symptoms stabilize.

Mr. K follows up closely with the psychiatrist in the clinic, every 1 to 2 weeks for the first month, as well as by several telephone and e-mail contacts. Lithium SR is titrated to 1,200 mg/d, to a therapeutic serum level of 1.1 mEq/L. Clonazepam is switched to quetiapine, 25 to 50 mg as needed, to address ongoing insomnia and to reduce the risk of dependency on clonazepam.

Mr. K’s mania gradually abates. He finishes the IOP and returns to work 3 weeks after his initial presentation. At an office visit, Mr. K’s wife gives the psychiatrist 2 scientific articles documenting the antidepressant effect of scopolamine.^1,2 Mr. K and his wife both continue to believe that Mr. K’s manic episode was triggered by the scopolamine patch he used while on the cruise. They think this is important because Mr. K believes he would not have developed mania otherwise, and he does not want to take a mood stabilizer for the rest of his life.

The author’s observations
There are several proposed mechanisms for scopolamine’s antidepressant effect (Table 1).^3-9 Scopolamine blocks central muscarinic cholinergic receptors, which reduces production of glutamate receptors and leads to reduced glutamate transmission and neurotoxicity.^3,4 Scopolamine—similar to ketamine—could enhance synaptogenesis and synaptic signaling.^5,6 Also, by blocking muscarinic autoreceptors, scopolamine results in an acute upregulation of acetylcholine release, which, in turn, influences the nicotinic, dopamine, serotonin, and neuropeptide Y systems. This action could contribute to anti-inflammatory effects, all of which can benefit mood.^7-9 These antidepressant mechanisms also could explain why, theoretically, scopolamine could precipitate mania in a person predisposed to mental illness.

Proposed by Janowsky et al¹⁰ in 1972, the cholinergic−adrenergic balance hypothesis of affective disorders suggests that depression represents an excess of central cholinergic tone over adrenergic tone, and that mania represents the opposite imbalance. Several lines of evidence in the literature support this theory. For example, depressed patients have been found to have hypersensitive central cholinergic receptors.^11,12 Also, central cholinesterase inhibition has been shown to affect pituitary hormone and epinephrine levels via central muscarinic receptors.¹³ In addition, scopolamine has been shown to attenuate these effects via the central anti-muscarinic mechanism.¹⁴

Rapid antidepressant therapy. Scopolamine is being studied as a rapid antidepressant treatment, although it usually is administered via IV infusion, rather than patch form, in trials.^15-17 IV ketamine is another therapy being investigated for rapid treatment of depression, which might have downstream mechanisms of action related to scopolamine.^5,18 Electroconvulsive therapy is a well-known for its quick antidepressant effect, which could involve synaptogenesis or effects on the neuroendocrine system.¹⁹ Sleep deprivation also can produce a rapid antidepressant effect²⁰ (Table 2^{1,2,5,6,15,16,18-20}).

Mr. K is prone to motion sickness, and asks if he can take over-the-counter dimenhydrinate tablets for long car rides. He reports that dimenhydrinate has worked well for him in the past without triggering manic episodes, and he did not anticipate needing to take it very often.

What would you tell Mr. K about dimenhydrinate for motion sickness during car rides?
   a) Mr. K should not take dimenhydrinate to prevent motion sickness because he experienced a manic episode triggered by a scopolamine patch
   b) Mr. K can use dimenhydrinate as much as he wants to prevent motion sickness because it poses no risk of mania
   c) Mr. K can use dimenhydrinate with caution and sparingly on a trial basis, as long as he is taking his mood stabilizer

FOLLOW UP Cautious use
The psychiatrist advised Mr. K to take dimenhydrinate cautiously when needed for long car rides. The psychiatrist feels this is safe because Mr. K is taking a mood stabilizer (lithium). Also, although dimenhydrinate has anticholinergic properties, occasional use is thought to pose less risk of triggering mania than the constant anticholinergic exposure over several days with a scopolamine patch. (The scopolamine patch contains 1.5 mg of the drug delivered over 3 days [ie, 0.5 mg/d]. In trials of IV scopolamine for depression, the dosage was 0.4 mcg/kg/d administered over 3 consecutive days.^15-17 For an adult weighing 70 kg, this would be equivalent to 0.24 mg/d. Therefore, using a scopolamine patch over 3 days would appear to deliver a robust antidepressant-level dosage, even taking into account possible lower bioavailability with transdermal administration compared with IV infusion.)

The psychiatrist concludes that sporadic use of dimenhydrinate tablets for motion sickness during occasional long car rides poses less of a risk for Mr. K of triggering mania than repeat use of a scopolamine patch.

The author’s observations
Mr. K’s case is notable for several reasons:

• Novelty. This might be the first report of scopolamine-induced mania in the literature. In clinical trials by Furey and Drevets,¹⁵ Drevets and Furey,¹⁶ and Ellis et al,¹⁷ no study participants who received scopolamine infusion developed mania or hypomania. Although it is possible that Mr. K’s manic episode could have occurred spontaneously and was coincidental to his scopolamine use, there are valid reasons why scopolamine could trigger mania in a vulnerable person.
• Biochemical insight. The case underscores the role of the muscarinic cholinergic system in regulating mood.¹⁰
• Rational medical care. Sensible clinical decision-making was needed when Mr. K asked about using dimenhydrinate for motion sickness during car rides. Although there might not be definitively correct answers for questions that arose during Mr. K’s care (in the absence of research literature), theoretical understanding of the antidepressant effects of anticholinergic medications helped inform the psychiatrist’s responses to Mr. K and his wife.

CASE From soft-spoken to manic
Mr. K, age 36, an Asian male with no psychiatric history, arrives at the outpatient psychiatry clinic accompanied by his wife, after being referred from the emergency room the night before. He reports racing thoughts, euphoric mood, increased speech, hypergraphia, elevated self-esteem, decreased need for sleep, distractibility, and increased goal-directed activity. Notably, Mr. K states that he likes how he is feeling.

Mr. K’s wife says that his condition is a clear change from his baseline demeanor: soft-spoken and mild-mannered.

Mr. K reports that his symptoms started approximately 10 days earlier, after he returned from a cruise with his wife. During the cruise, he used a scopolamine patch to prevent motion sickness. Mr. K and his wife say that they believe that the scopolamine patch caused his symptoms.

Can scopolamine cause mania?
   a) No
   b) Yes; this is well-documented in the literature
   c) It is theoretically possible because of scopolamine’s antidepressant and central anticholinergic effects

TREATMENT Lithium, close follow up
Mr. K has no history of psychiatric illness or substance use and no recent use of psycho­active substances—other than scopolamine—that could trigger a manic episode. His family history is significant for a younger brother who had a single manic episode at age 12 and a suicide attempt as a young adult.

Mr. K works full-time on rotating shifts—including some overnight shifts—as a manufacturing supervisor at a biotechnology company. He has been unable to work since returning from the cruise because of his psychiatric symptoms.

Mr. K is started on sustained-release (SR) lithium, 900 mg/d. In addition, the psychiatrist advises Mr. K to continue taking clonazepam, 0.5 to 1 mg as needed, which the emergency medicine physician prescribed, for insomnia. Mr. K is referred to a psychiatric intensive outpatient program (IOP), 3 days a week for 2 weeks, and is advised to stay home from work until symptoms stabilize.

Mr. K follows up closely with the psychiatrist in the clinic, every 1 to 2 weeks for the first month, as well as by several telephone and e-mail contacts. Lithium SR is titrated to 1,200 mg/d, to a therapeutic serum level of 1.1 mEq/L. Clonazepam is switched to quetiapine, 25 to 50 mg as needed, to address ongoing insomnia and to reduce the risk of dependency on clonazepam.

Mr. K’s mania gradually abates. He finishes the IOP and returns to work 3 weeks after his initial presentation. At an office visit, Mr. K’s wife gives the psychiatrist 2 scientific articles documenting the antidepressant effect of scopolamine.^1,2 Mr. K and his wife both continue to believe that Mr. K’s manic episode was triggered by the scopolamine patch he used while on the cruise. They think this is important because Mr. K believes he would not have developed mania otherwise, and he does not want to take a mood stabilizer for the rest of his life.

The author’s observations
There are several proposed mechanisms for scopolamine’s antidepressant effect (Table 1).^3-9 Scopolamine blocks central muscarinic cholinergic receptors, which reduces production of glutamate receptors and leads to reduced glutamate transmission and neurotoxicity.^3,4 Scopolamine—similar to ketamine—could enhance synaptogenesis and synaptic signaling.^5,6 Also, by blocking muscarinic autoreceptors, scopolamine results in an acute upregulation of acetylcholine release, which, in turn, influences the nicotinic, dopamine, serotonin, and neuropeptide Y systems. This action could contribute to anti-inflammatory effects, all of which can benefit mood.^7-9 These antidepressant mechanisms also could explain why, theoretically, scopolamine could precipitate mania in a person predisposed to mental illness.

Proposed by Janowsky et al¹⁰ in 1972, the cholinergic−adrenergic balance hypothesis of affective disorders suggests that depression represents an excess of central cholinergic tone over adrenergic tone, and that mania represents the opposite imbalance. Several lines of evidence in the literature support this theory. For example, depressed patients have been found to have hypersensitive central cholinergic receptors.^11,12 Also, central cholinesterase inhibition has been shown to affect pituitary hormone and epinephrine levels via central muscarinic receptors.¹³ In addition, scopolamine has been shown to attenuate these effects via the central anti-muscarinic mechanism.¹⁴

Rapid antidepressant therapy. Scopolamine is being studied as a rapid antidepressant treatment, although it usually is administered via IV infusion, rather than patch form, in trials.^15-17 IV ketamine is another therapy being investigated for rapid treatment of depression, which might have downstream mechanisms of action related to scopolamine.^5,18 Electroconvulsive therapy is a well-known for its quick antidepressant effect, which could involve synaptogenesis or effects on the neuroendocrine system.¹⁹ Sleep deprivation also can produce a rapid antidepressant effect²⁰ (Table 2^{1,2,5,6,15,16,18-20}).

Mr. K is prone to motion sickness, and asks if he can take over-the-counter dimenhydrinate tablets for long car rides. He reports that dimenhydrinate has worked well for him in the past without triggering manic episodes, and he did not anticipate needing to take it very often.

What would you tell Mr. K about dimenhydrinate for motion sickness during car rides?
   a) Mr. K should not take dimenhydrinate to prevent motion sickness because he experienced a manic episode triggered by a scopolamine patch
   b) Mr. K can use dimenhydrinate as much as he wants to prevent motion sickness because it poses no risk of mania
   c) Mr. K can use dimenhydrinate with caution and sparingly on a trial basis, as long as he is taking his mood stabilizer

FOLLOW UP Cautious use
The psychiatrist advised Mr. K to take dimenhydrinate cautiously when needed for long car rides. The psychiatrist feels this is safe because Mr. K is taking a mood stabilizer (lithium). Also, although dimenhydrinate has anticholinergic properties, occasional use is thought to pose less risk of triggering mania than the constant anticholinergic exposure over several days with a scopolamine patch. (The scopolamine patch contains 1.5 mg of the drug delivered over 3 days [ie, 0.5 mg/d]. In trials of IV scopolamine for depression, the dosage was 0.4 mcg/kg/d administered over 3 consecutive days.^15-17 For an adult weighing 70 kg, this would be equivalent to 0.24 mg/d. Therefore, using a scopolamine patch over 3 days would appear to deliver a robust antidepressant-level dosage, even taking into account possible lower bioavailability with transdermal administration compared with IV infusion.)

The psychiatrist concludes that sporadic use of dimenhydrinate tablets for motion sickness during occasional long car rides poses less of a risk for Mr. K of triggering mania than repeat use of a scopolamine patch.

The author’s observations
Mr. K’s case is notable for several reasons:

• Novelty. This might be the first report of scopolamine-induced mania in the literature. In clinical trials by Furey and Drevets,¹⁵ Drevets and Furey,¹⁶ and Ellis et al,¹⁷ no study participants who received scopolamine infusion developed mania or hypomania. Although it is possible that Mr. K’s manic episode could have occurred spontaneously and was coincidental to his scopolamine use, there are valid reasons why scopolamine could trigger mania in a vulnerable person.
• Biochemical insight. The case underscores the role of the muscarinic cholinergic system in regulating mood.¹⁰
• Rational medical care. Sensible clinical decision-making was needed when Mr. K asked about using dimenhydrinate for motion sickness during car rides. Although there might not be definitively correct answers for questions that arose during Mr. K’s care (in the absence of research literature), theoretical understanding of the antidepressant effects of anticholinergic medications helped inform the psychiatrist’s responses to Mr. K and his wife.