In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Cigarette smoking has been linked to the diagnosis of bacterial vaginosis (BV) and other genital infections including herpes simplex virus type 2, Chlamydia trachomatis, and oral and genital human papillomavirus (HPV).  Nicotine’s major metabolite, cotinine, has been found to concentrate in cervical mucus.

In 2014, researchers from Montana State University confirmed that the composition of the vaginal microbiota is “strongly associated with smoking.” They reported that women whose vaginal microbiota lacked significant numbers of Lactobacillus spp were 25-fold more likely to report current smoking than those with microbiota dominated by Lactobacillus crispatus (L crispatus). The researchers note that most Lactobacillus spp are thought to provide broad-spectrum protection to pathogenic infections by reducing vaginal pH.

But what is the mechanistic link between smoking and its effects on the vaginal microenvironment? The researchers conducted further study to assess the metabolome, a set of small molecule chemicals that includes host and microbial-produced and modified biomolecules as well as exogenous chemicals. The metabolome is an important characteristic of the vaginal microenvironment; the researchers say; differences in some metabolites are associated with functional variations of the vaginal microbiota. 

The analysis revealed samples clustered into 3 community state types (CSTs): CST-I (L crispatus dominated), CST-III (L iners dominated) and CST-IV (low Lactobacillus). Overall, smoking did not affect the vaginal metabolome after controlling for CSTs, but the researchers identified “an extensive and diverse range” of vaginal metabolites for which profiles were affected by both the microbiology and smoking status. They found 607 compounds in 36 women, including 12 metabolites that differed significantly between smokers and nonsmokers. Bacterial composition was the most pronounced driver of the vaginal metabolome, they say, associated with changes in 57% of all metabolites. As expected, nicotine, cotinine, and hydroxycotinine were markedly elevated in smokers’ vaginas.

Another “key finding,” the researchers say, was a significant increase in the abundance of various biogenic amines among smokers, far more pronounced in women with a low level of Lactobacillus. Biogenic amines are essential, they note, to mammalian and bacterial physiology. (Several are implicated in the “fishy” odor of BV.)

Their study serves as a pilot study, the researchers say, for future examinations of the connections between smoking and poor gynecologic and reproductive health outcomes.

Click here to access May 2019 Advances in Hematology and Oncology

Table of Contents

• Cardiovascular Effects of Tyrosine Kinase Inhibitors in Patients With Advanced Renal Cell Carcinoma at the VA San Diego Healthcare System
• Testicular Swelling as an Initial Presentation of a Patient With Metastatic Gastric Cancer
• Sharing Cancer Care Information Across VA Health Care Systems
• Liver Imaging Reporting and Data System in Patients at High Risk for Hepatocellular Carcinoma in the Memphis Veterans Affairs Population
• Roundtable: The Diagnosis and Management of Cutaneous T-Cell Lymphomas

Click here to access May 2019 Advances in Hematology and Oncology

Table of Contents

• Cardiovascular Effects of Tyrosine Kinase Inhibitors in Patients With Advanced Renal Cell Carcinoma at the VA San Diego Healthcare System
• Testicular Swelling as an Initial Presentation of a Patient With Metastatic Gastric Cancer
• Sharing Cancer Care Information Across VA Health Care Systems
• Liver Imaging Reporting and Data System in Patients at High Risk for Hepatocellular Carcinoma in the Memphis Veterans Affairs Population
• Roundtable: The Diagnosis and Management of Cutaneous T-Cell Lymphomas

Click here to access May 2019 Advances in Hematology and Oncology

Table of Contents

• Cardiovascular Effects of Tyrosine Kinase Inhibitors in Patients With Advanced Renal Cell Carcinoma at the VA San Diego Healthcare System
• Testicular Swelling as an Initial Presentation of a Patient With Metastatic Gastric Cancer
• Sharing Cancer Care Information Across VA Health Care Systems
• Liver Imaging Reporting and Data System in Patients at High Risk for Hepatocellular Carcinoma in the Memphis Veterans Affairs Population
• Roundtable: The Diagnosis and Management of Cutaneous T-Cell Lymphomas

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

Here are 5 articles from the May issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Subclinical hypothyroidism boosts immediate risk of heart failure

To take the posttest, go to: https://bit.ly/2IK0YiL
Expires January 24, 2020

2. Meta-analysis supports aspirin to reduce cardiovascular events

To take the posttest, go to: https://bit.ly/2GJLgSB
Expires January 24, 2020

3. Age of migraine onset may affect stroke risk

To take the posttest, go to: https://bit.ly/2ZAJ5YR
Expires January 24, 2020

4. Women with RA have reduced chance of live birth after assisted reproduction treatment

To take the posttest, go to: https://bit.ly/2VvKRLF
Expires January 27, 2020

5. New SLE disease activity measure beats SLEDAI-2K

To take the posttest, go to: https://bit.ly/2W8SVPA
Expires January 31, 2020

Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech¹—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.

Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.

Major depressive disorder

Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.² Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.¹ Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.³ These patients might benefit from augmentation with a mood stabilizer such as lithium⁴ or a second-generation antipsychotic.⁵

Other potential causes

Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table¹).

In summary, when caring for a patient who reports having racing thoughts, consider:

• whether that patient actually does have racing thoughts
• the potential causes, severity, duration, and treatment of the racing thoughts
• the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.

Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech¹—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.

Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.

Major depressive disorder

Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.² Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.¹ Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.³ These patients might benefit from augmentation with a mood stabilizer such as lithium⁴ or a second-generation antipsychotic.⁵

Other potential causes

Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table¹).

In summary, when caring for a patient who reports having racing thoughts, consider:

• whether that patient actually does have racing thoughts
• the potential causes, severity, duration, and treatment of the racing thoughts
• the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.

Have you ever had times in your life when you had a tremendous amount of energy, like too much energy, with racing thoughts? I initially ask patients this question when evaluating for bipolar disorder. Some patients insist that they have racing thoughts—thoughts occurring at a rate faster than they can be expressed through speech¹—but not episodes of hyperactivity. This response suggests that some patients can have racing thoughts without a diagnosis of bipolar disorder.

Among the patients I treat, racing thoughts vary in severity, duration, and treatment. When untreated, a patient’s racing thoughts may range from a mild disturbance lasting a few days to a more severe disturbance occurring daily. In this article, I suggest treatments that may help ameliorate racing thoughts, and describe possible causes that include, but are not limited to, mood disorders.

Major depressive disorder

Many patients with major depressive disorder (MDD) have racing thoughts that often go unrecognized, and this symptom is associated with more severe depression.² Those with a DSM-5 diagnosis of MDD with mixed features could experience prolonged racing thoughts during a major depressive episode.¹ Untreated racing thoughts may explain why many patients with MDD do not improve with an antidepressant alone.³ These patients might benefit from augmentation with a mood stabilizer such as lithium⁴ or a second-generation antipsychotic.⁵

Other potential causes

Racing thoughts are a symptom, not a diagnosis. Apprehension and anxiety could cause racing thoughts that do not require treatment with a mood stabilizer or antipsychotic. Patients who often worry about having panic attacks or experience severe chronic stress may have racing thoughts. Also, some patients may be taking medications or illicit drugs or have a medical disorder that could cause symptoms of mania or hypomania that include racing thoughts (Table¹).

In summary, when caring for a patient who reports having racing thoughts, consider:

• whether that patient actually does have racing thoughts
• the potential causes, severity, duration, and treatment of the racing thoughts
• the possibility that for a patient with MDD, augmenting an antidepressant with a mood stabilizer or antipsychotic could decrease racing thoughts, thereby helping to alleviate many cases of MDD.

Childbirth is a trigger for first-onset or recurrence of various psychiatric disorders; however, research and clinical efforts have focused mainly on postpartum mood disorders. Unfortunately, there is little research on identifying and managing obsessive-compulsive disorder (OCD) in the postpartum period.

In one prospective study of 461 women who recently gave birth, researchers found the prevalence of OCD symptoms was 11% at 2 weeks postpartum.¹ Mothers with OCD may have time-consuming or functionally impairing obsessions and/or compulsions that can include:

• anticipatory anxiety of contamination (eg, germs, illness)
• thoughts of accidental or intentional harm to their infant
• compulsions comprised of cleaning and checking behaviors
• avoidance of situations
• thought suppression.

Because both clinicians and patients may not be aware of the effects of childbirth on women with OCD, postpartum OCD may go underdiagnosed or be misdiagnosed as major depressive disorder (MDD) or an anxiety disorder. Additionally, women with OCD who lack insight or have delusional beliefs might be misdiagnosed with postpartum psychosis.

Here I offer methods to help effectively identify OCD in postpartum women, and suggest how to implement an individualized treatment approach.

Keys to identification and diagnosis

Mothers who present with postpartum anxiety or depression may have obsessions and compulsions. It is important to specifically screen for these symptoms because some mothers may be reluctant to discuss the content of their thoughts or behaviors.

Screen women who present with postpartum anxiety or depression for obsessions and compulsions by using questions based on DSM-5 criteria,² such as:

• Do you have unpleasant thoughts, urges, or images that repeatedly enter your mind?
• Do you feel driven to perform certain behaviors or mental acts over and over again?

A validated scale, such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),³ can also be used to screen for obsessive/compulsive symptoms in these patients.

Continue to: Evaluate women who endorse...

Evaluate women who endorse obsessions or compulsions for OCD. Women who meet diagnostic criteria for OCD should also be assessed for common psychiatric comorbidities, including MDD, anxiety disorders, or bipolar disorder. Obsessive-compulsive disorder with absent insight and delusional beliefs should be differentiated from postpartum psychosis, which is often a manifestation of bipolar disorder.

Treatment: What to consider

When selecting a treatment, consider factors such as symptom severity, psychiatric comorbidities, the patient’s insight into her OCD symptoms, patient preference, and breastfeeding status. Cognitive-behavioral therapy with exposure response prevention is indicated for patients with mild to moderate OCD. Pharmacotherapy should be reserved for individuals with severe OCD. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay pharmacologic treatment of postpartum OCD; however, there are currently no randomized controlled trials of SSRIs for women with postpartum OCD. Augmentation with quetiapine should be considered for women who have an inadequate response to SSRIs.

Acknowledgment

The author thanks Christine Baczynski for her help with the preparation of this article.

Childbirth is a trigger for first-onset or recurrence of various psychiatric disorders; however, research and clinical efforts have focused mainly on postpartum mood disorders. Unfortunately, there is little research on identifying and managing obsessive-compulsive disorder (OCD) in the postpartum period.

In one prospective study of 461 women who recently gave birth, researchers found the prevalence of OCD symptoms was 11% at 2 weeks postpartum.¹ Mothers with OCD may have time-consuming or functionally impairing obsessions and/or compulsions that can include:

• anticipatory anxiety of contamination (eg, germs, illness)
• thoughts of accidental or intentional harm to their infant
• compulsions comprised of cleaning and checking behaviors
• avoidance of situations
• thought suppression.

Because both clinicians and patients may not be aware of the effects of childbirth on women with OCD, postpartum OCD may go underdiagnosed or be misdiagnosed as major depressive disorder (MDD) or an anxiety disorder. Additionally, women with OCD who lack insight or have delusional beliefs might be misdiagnosed with postpartum psychosis.

Here I offer methods to help effectively identify OCD in postpartum women, and suggest how to implement an individualized treatment approach.

Keys to identification and diagnosis

Mothers who present with postpartum anxiety or depression may have obsessions and compulsions. It is important to specifically screen for these symptoms because some mothers may be reluctant to discuss the content of their thoughts or behaviors.

Screen women who present with postpartum anxiety or depression for obsessions and compulsions by using questions based on DSM-5 criteria,² such as:

• Do you have unpleasant thoughts, urges, or images that repeatedly enter your mind?
• Do you feel driven to perform certain behaviors or mental acts over and over again?

A validated scale, such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),³ can also be used to screen for obsessive/compulsive symptoms in these patients.

Continue to: Evaluate women who endorse...

Evaluate women who endorse obsessions or compulsions for OCD. Women who meet diagnostic criteria for OCD should also be assessed for common psychiatric comorbidities, including MDD, anxiety disorders, or bipolar disorder. Obsessive-compulsive disorder with absent insight and delusional beliefs should be differentiated from postpartum psychosis, which is often a manifestation of bipolar disorder.

Treatment: What to consider

When selecting a treatment, consider factors such as symptom severity, psychiatric comorbidities, the patient’s insight into her OCD symptoms, patient preference, and breastfeeding status. Cognitive-behavioral therapy with exposure response prevention is indicated for patients with mild to moderate OCD. Pharmacotherapy should be reserved for individuals with severe OCD. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay pharmacologic treatment of postpartum OCD; however, there are currently no randomized controlled trials of SSRIs for women with postpartum OCD. Augmentation with quetiapine should be considered for women who have an inadequate response to SSRIs.

Acknowledgment

The author thanks Christine Baczynski for her help with the preparation of this article.

Childbirth is a trigger for first-onset or recurrence of various psychiatric disorders; however, research and clinical efforts have focused mainly on postpartum mood disorders. Unfortunately, there is little research on identifying and managing obsessive-compulsive disorder (OCD) in the postpartum period.

In one prospective study of 461 women who recently gave birth, researchers found the prevalence of OCD symptoms was 11% at 2 weeks postpartum.¹ Mothers with OCD may have time-consuming or functionally impairing obsessions and/or compulsions that can include:

• anticipatory anxiety of contamination (eg, germs, illness)
• thoughts of accidental or intentional harm to their infant
• compulsions comprised of cleaning and checking behaviors
• avoidance of situations
• thought suppression.

Because both clinicians and patients may not be aware of the effects of childbirth on women with OCD, postpartum OCD may go underdiagnosed or be misdiagnosed as major depressive disorder (MDD) or an anxiety disorder. Additionally, women with OCD who lack insight or have delusional beliefs might be misdiagnosed with postpartum psychosis.

Here I offer methods to help effectively identify OCD in postpartum women, and suggest how to implement an individualized treatment approach.

Keys to identification and diagnosis

Mothers who present with postpartum anxiety or depression may have obsessions and compulsions. It is important to specifically screen for these symptoms because some mothers may be reluctant to discuss the content of their thoughts or behaviors.

Screen women who present with postpartum anxiety or depression for obsessions and compulsions by using questions based on DSM-5 criteria,² such as:

• Do you have unpleasant thoughts, urges, or images that repeatedly enter your mind?
• Do you feel driven to perform certain behaviors or mental acts over and over again?

A validated scale, such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),³ can also be used to screen for obsessive/compulsive symptoms in these patients.

Continue to: Evaluate women who endorse...

Evaluate women who endorse obsessions or compulsions for OCD. Women who meet diagnostic criteria for OCD should also be assessed for common psychiatric comorbidities, including MDD, anxiety disorders, or bipolar disorder. Obsessive-compulsive disorder with absent insight and delusional beliefs should be differentiated from postpartum psychosis, which is often a manifestation of bipolar disorder.

Treatment: What to consider

When selecting a treatment, consider factors such as symptom severity, psychiatric comorbidities, the patient’s insight into her OCD symptoms, patient preference, and breastfeeding status. Cognitive-behavioral therapy with exposure response prevention is indicated for patients with mild to moderate OCD. Pharmacotherapy should be reserved for individuals with severe OCD. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay pharmacologic treatment of postpartum OCD; however, there are currently no randomized controlled trials of SSRIs for women with postpartum OCD. Augmentation with quetiapine should be considered for women who have an inadequate response to SSRIs.

Acknowledgment

The author thanks Christine Baczynski for her help with the preparation of this article.

CASE Rash, fever, extreme lethargy; multiple hospital visits

Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.

One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.

After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.

During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.

When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.

On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.

[polldaddy:10307646]

The authors’ observations

The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.

Continue to: A review of the records...

A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.

Liver damage from valproic acid

Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches¹ (Table 2¹). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.² Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 3¹). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.³

There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid²:

• hyperammonemia
• acute liver failure and jaundice
• Myriad ProReye-like syndrome, which is generally seen in children.

In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.^4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.³ Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.^2-4

At Visit 2, Ms. L’s presentation was not initially consistent with hepatic enceph­­alopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).

Continue to: At Visit 2 in the ED...

At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.

In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.² In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.² This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.⁶ Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.^2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.^2,6,7

Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.

EVALUATION Consent for transplantation

As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.

During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.

Continue to: Ms. L becomes agitated...

Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.

When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.

On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.

[polldaddy:10307651]

The authors’ observations

L-carnitine supplementation

Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.^8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.⁸ Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.⁸ L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,¹⁰ and it is currently recommended in cases of valproic acid toxicity, especially in children.⁸ Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.¹¹ It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,⁸ but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.¹²

TREATMENT Decompensation and transplantation

Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.

Continue to: On hospital Day 6...

On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.

On hospital Day 9, she undergoes a liver transplantation.

[polldaddy:10307652]

The authors’ observations

Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.

This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.

Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 4¹). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 5^13,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution. 

Continue to: Consider patient-specific factors

Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.

OUTCOME Discharged after 20 days

Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.

Bottom Line

Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.

Related Resource

• Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.

Drug Brand Names

Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene

CASE Rash, fever, extreme lethargy; multiple hospital visits

Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.

One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.

After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.

During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.

When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.

On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.

[polldaddy:10307646]

The authors’ observations

The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.

Continue to: A review of the records...

A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.

Liver damage from valproic acid

Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches¹ (Table 2¹). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.² Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 3¹). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.³

There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid²:

• hyperammonemia
• acute liver failure and jaundice
• Myriad ProReye-like syndrome, which is generally seen in children.

In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.^4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.³ Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.^2-4

At Visit 2, Ms. L’s presentation was not initially consistent with hepatic enceph­­alopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).

Continue to: At Visit 2 in the ED...

At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.

In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.² In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.² This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.⁶ Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.^2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.^2,6,7

Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.

EVALUATION Consent for transplantation

As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.

During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.

Continue to: Ms. L becomes agitated...

Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.

When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.

On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.

[polldaddy:10307651]

The authors’ observations

L-carnitine supplementation

Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.^8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.⁸ Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.⁸ L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,¹⁰ and it is currently recommended in cases of valproic acid toxicity, especially in children.⁸ Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.¹¹ It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,⁸ but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.¹²

TREATMENT Decompensation and transplantation

Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.

Continue to: On hospital Day 6...

On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.

On hospital Day 9, she undergoes a liver transplantation.

[polldaddy:10307652]

The authors’ observations

Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.

This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.

Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 4¹). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 5^13,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution. 

Continue to: Consider patient-specific factors

Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.

OUTCOME Discharged after 20 days

Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.

Bottom Line

Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.

Related Resource

• Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.

Drug Brand Names

Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene

CASE Rash, fever, extreme lethargy; multiple hospital visits

Ms. L, age 21, a single woman with a history of major depressive disorder (MDD), is directly admitted from an outside community hospital to our tertiary care academic hospital with acute liver failure.

One month earlier, Ms. L had an argument with her family and punched a wall, fracturing her hand. Following the episode, Ms. L’s primary care physician (PCP) prescribed valproic acid, 500 mg/d, to address “mood swings,” which included angry outbursts and irritability. According to her PCP, no baseline laboratory tests were ordered for Ms. L when she started valproic acid because she was young and otherwise healthy.

After Ms. L had been taking valproic acid for approximately 2 weeks, her mother noticed she became extremely lethargic and took her to the emergency department (ED) of a community hospital (Visit 1) (Table 1). At this time, her laboratory results were notable for an aspartate aminotransferase (AST) level of 303 IU/L (reference range: 8 to 40 IU/L) and an alanine aminotransferase (ALT) level of 241 IU/L (reference range: 20 to 60 IU/L). She also underwent a liver ultrasound, urine toxicology screen, blood alcohol level, and acetaminophen level; the results of all of these tests were unremarkable. Her valproic acid level was within therapeutic limits, consistent with patient adherence; her ammonia level was within normal limits. At Visit 1, Ms. L’s transaminitis was presumed to be secondary to valproic acid. The ED clinicians told her to stop taking valproic acid and discharged her. Her PCP did not give her any follow-up instructions for further laboratory tests or any other recommendations.

During the next week, even though she stopped taking the valproic acid as instructed, Ms. L developed a rash and fever, and continued to have lethargy and general malaise. When she returned to the ED (Visit 2) (Table 1), she was febrile, tachycardic, and hypotensive, with an elevated white blood cell count, eosinophilia, low platelets, and elevated liver function tests. At Visit 2, she was alert and oriented to person, place, time, and situation. Ms. L insisted that she had not overdosed on any medications, or used illicit drugs or alcohol. A test for hepatitis C was negative. Her ammonia level was 58 µmol/L (reference range: 11 to 32 µmol/L). Ms. L received N-acetylcysteine (NAC), prednisone, diphenhydramine, famotidine, and ibuprofen before she was transferred to our tertiary care hospital.

When she arrives at our facility (Visit 3) (Table 1), Ms. L is admitted with acute liver failure. She has an ALT level of 4,091 IU/L, and an AST level of 2,049 IU/L. Ms. L’s mother says that her daughter had been taking sertraline for depression for “some time” with no adverse effects, although she is not clear on the dose or frequency. Her mother says that Ms. L generally likes to spend most of her time at home, and does not believe her daughter is a danger to herself or others. Ms. L’s mother could not describe any episodes of mania or recurrent, dangerous anger episodes. Ms. L has no other medical history and has otherwise been healthy.

On hospital Day 2, Ms. L’s ammonia level is 72 µmol/L, which is slightly elevated. The hepatology team confirms that Ms. L may require a liver transplantation. The primary team consults the inpatient psychiatry consultation-liaison (C-L) team for a pre-transplant psychiatric evaluation.

[polldaddy:10307646]

The authors’ observations

The differential diagnosis for Ms. L was broad and included both accidental and intentional medication overdose. The primary team consulted the inpatient psychiatry C-L team not only for a pre-transplant evaluation, but also to assess for possible overdose.

Continue to: A review of the records...

A review of the records from Visit 1 and Visit 2 at the outside hospital found no acetaminophen in Ms. L’s system and verified that there was no evidence of a current valproic acid overdose. Ms. L had stated that she had not overdosed on any other medications or used any illicit drugs or alcohol. Ms. L’s complex symptoms—namely fever, acute liver failure, and rash—were more consistent with an adverse effect of valproic acid or possibly an inherent autoimmune process.

Liver damage from valproic acid

Valproic acid is FDA-approved for treating bipolar disorder, epilepsy, and migraine headaches¹ (Table 2¹). Common adverse effects include nausea, vomiting, sleepiness, and dry mouth. Rarely, valproic acid can impair liver function. While receiving valproic acid, 5% to 10% of patients develop elevated ALT levels, but most are asymptomatic and resolve with time, even if the patient continues taking valproic acid.² Valproic acid hepatotoxicity resulting in liver transplantation for a healthy patient is extremely rare (Table 3¹). Liver failure, both fatal and non-fatal, is more prevalent in patients concurrently taking other medications, such as antiepileptics, benzodiazepines, and antipsychotics, as compared with patients receiving only valproic acid.³

There are 3 clinically distinguishable forms of hepatotoxicity due to valproic acid²:

• hyperammonemia
• acute liver failure and jaundice
• Myriad ProReye-like syndrome, which is generally seen in children.

In case reports of hyperammonemia due to valproic acid, previously healthy patients experience confusion, lethargy, and eventual coma in the context of elevated serum ammonia levels; these symptoms resolved upon discontinuing valproic acid.^4,5 Liver function remained normal, with normal to near-normal liver enzymes and bilirubin.³ Hyperammonemia and resulting encephalopathy generally occurred within 1 to 3 weeks after initiation of valproate therapy, with resolution of hyperammonemia and resulting symptoms within a few days after stopping valproic acid.^2-4

At Visit 2, Ms. L’s presentation was not initially consistent with hepatic enceph­­alopathy. She was alert and oriented to person, place, time, and situation. Additionally, Ms. L’s presenting problem was elevated liver function tests, not elevated ammonia levels. At Visit 2, her ammonia level was 58 µmol/L; on Day 2 (Visit 3) of her hospital stay, her ammonia level was 72 µmol/L (slightly elevated).

Continue to: At Visit 2 in the ED...

At Visit 2 in the ED, Ms. L was started on NAC because the team suspected she was experiencing drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by extensive rash, fever, and involvement of at least 1 internal organ. It is a variation of a drug-induced hypersensitivity syndrome. Ms. L’s unremarkable valproic acid levels combined with the psychiatry assessment ruled out valproic hepatotoxicity due to overdose, either intentional or accidental.

In case reports, patients who developed acute liver failure due to valproic acid typically had a hepatitis-like syndrome consisting of moderate elevation in liver enzymes, jaundice, and liver failure necessitating transplantation after at least 1 month of treatment with valproic acid.² In addition to the typical hepatitis-like syndrome resulting from valproic acid, case reports have also linked treatment with valproic acid to DRESS syndrome.² This syndrome is known to occur with anticonvulsants such as phenobarbital, lamotrigine, and phenytoin, but there are only a few reported cases of DRESS syndrome due to valproic acid therapy alone.⁶ Drug rash with eosinophilia and systemic symptoms syndrome differs from other acute liver failure cases in that patients also develop lymphadenopathy, fever, and rash.^2,6,7 Patients with DRESS syndrome typically respond to corticosteroid therapy and discontinuation of valproic acid, and the liver damage resolves after several weeks, without a need for transplantation.^2,6,7

Ms. L seemed to have similarities to DRESS syndrome. However, the severity of her liver damage, which might require transplantation even after only 2 weeks of valproic acid therapy, initially led the hepatology and C-L teams to consider her presentation similar to severe hepatitis-like cases.

EVALUATION Consent for transplantation

As an inpatient, Ms. L undergoes further laboratory testing. Her hepatic function panel demonstrates a total protein level of 4.8 g/dL, an albumin level of 2.0 g/dL, total bilirubin level of 12.2 mg/dL, and alkaline phosphatase of 166 IU/L. Her laboratory results indicate a prothrombin time (PT) of 77.4 seconds, partial thromboplastin time of 61.5 seconds, and PT international normalized ratio (INR) of 9.6. Ms. L’s basic metabolic panel is within normal limits except for a blood urea nitrogen level of 6 mg/dL, glucose level of 136 mg/dL, and calcium level of 7.0 mg/dL. Her complete blood count indicates a white blood cell count of 12.1, hemoglobin of 10.3 g/dL, hematocrit of 30.4%, mean corpuscular volume of 85.9 fL, and platelet count of 84. Her lipase level is normal at 49 U/L. Her serum acetaminophen concentration is <3.0 mcg/mL, valproic acid level was <2 µg/mL, and she is negative for hepatitis A, B, and C. A urine toxicology screen and testing for herpes simplex, rapid plasma reagin, and human immunodeficiency virus are all negative. Results from several auto-antibodies tests are negative and within normal limits, except filamentous actin (F-actin) antibody, which is slightly higher than normal at 21.4 ELISA units. Based on these results, Ms. L’s liver failure seemed most likely secondary to a reaction to valproic acid.

During her pre-transplant psychiatric evaluation, Ms. L is found to be a poor historian with minimal speech production, flat affect, and clouded sensorium. She denies overdosing on her prescribed valproic acid or sertraline, reports no current suicidal ideation, and does not want to die. She accurately recalls her correct daily dosing of each medication, and verifies that she stopped taking valproic acid 2 weeks ago after being advised to do so by the ED clinicians at Visit 2. She continued to take sertraline until Visit 2. She denied any past or present episodes consistent with mania, which was consistent with her mother’s report.

Continue to: Ms. L becomes agitated...

Ms. L becomes agitated upon further questioning, and requests immediate discharge so that she can return to her family. The evaluation is postponed briefly.

When they reconvene, the C-L team performs a decision-making capacity evaluation, which reveals that Ms. L’s mood and affect are consistent with fear of her impending liver transplant and being alone and approximately 2 hours from her family. This is likely complicated by delirium due to hepatotoxicity. Further discussion between Ms. L and the multidisciplinary team focuses on the risks, benefits, adverse effects of, and alternatives to her current treatment; the possibility of needing a liver transplantation; and how to help her family with transportation to the hospital. Following the discussion, Ms. L is fully cooperative with further treatment, and the pre-transplant psychiatric evaluation is completed.

On physical examination, Ms. L is noted to have a widespread morbilliform rash covering 50% to 60% of her body.

[polldaddy:10307651]

The authors’ observations

L-carnitine supplementation

Multiple studies have shown that supplementation with L-carnitine may increase survival from severe hepatotoxicity due to valproic acid.^8,9 Valproic acid may contribute to carnitine deficiency due to its inhibition of carnitine biosynthesis via a decrease in alpha-ketoglutarate concentration.⁸ Hepatotoxicity or hyperammonemia due to valproic acid may be potentiated by a carnitine deficiency, either pre-existing or resulting from valproic acid.⁸ L-carnitine supplementation has hastened the decrease of valproic acid–induced ammonemia in a dose-dependent manner,¹⁰ and it is currently recommended in cases of valproic acid toxicity, especially in children.⁸ Children at high risk for developing carnitine deficiency who need to receive valproic acid can be given carnitine supplementation.¹¹ It is not known whether L-carnitine is clinically effective in protecting the liver or hastening liver recovery,⁸ but it is believed that it might prevent adverse effects of hepatotoxicity and hyperammonemia, especially in patients who receive long-term valproic acid therapy.¹²

TREATMENT Decompensation and transplantation

Ms. L’s treatment regimen includes NAC, lactulose, and L-carnitine supplementation. During the course of Ms. L’s hospital stay, her liver enzymes begin to trend downward, but her INR and PT remain elevated.

Continue to: On hospital Day 6...

On hospital Day 6, she develops more severe symptoms of hepatic encephalopathy, with significant altered mental status and inattention. Ms. L is transferred to the ICU, intubated, and placed on the liver transplant list.

On hospital Day 9, she undergoes a liver transplantation.

[polldaddy:10307652]

The authors’ observations

Baseline laboratory testing should have been conducted prior to initiating valproic acid. As Ms. L’s symptoms worsened, better communication with her PCP and closer monitoring after starting valproic acid might have resulted in more immediate care. Early recognition of her symptoms and decompensation may have triggered earlier inpatient admission and/or transfer to a tertiary care facility for observation and treatment. Additionally, repeat laboratory testing and instructions on when to return to the ED should have been provided at Visit 1.

This case demonstrates the need for all clinicians who prescribe valproic acid to remain diligent about the accurate diagnosis of mood and behavioral symptoms, knowing when psychotropic medications are indicated, and carefully considering and discussing even rare, potentially life-threatening adverse effects of all medications with patients.

Although rare, after starting valproic acid, a patient may experience a rapid decompensation and life-threatening illness. Ideally, clinicians should closely monitor patients after initiating valproic acid (Table 4¹). Clinicians must have a clear knowledge of the recommended monitoring and indications for hospitalization and treatment when they note adverse effects such as elevated liver enzymes or transaminitis (Table 5^13,14). Even after stopping valproic acid, patients who have experienced adverse events should be closely monitored to ensure complete resolution. 

Continue to: Consider patient-specific factors

Consider the mental state, intellectual capacity, and social support of each patient before initiating valproic acid. Its use as a mood stabilizer for “mood swings” outside of the context of bipolar disorder is questionable. Valproic acid is FDA-approved for treating bipolar disorder and seizures, but not for anger outbursts/irritability. Prior to starting valproic acid, Ms. L may have benefited from alternative nonpharmacologic treatments, such as psychotherapy, for her anger outbursts and poor coping skills. Therapeutic techniques that focused on helping her acquire better coping mechanisms may have been useful, especially because her mood symptoms did not meet criteria for bipolar disorder, and her depression had long been controlled with sertraline monotherapy.

OUTCOME Discharged after 20 days

Ms. L stays in the hospital for 10 days after receiving her liver transplant. She has low appetite and some difficulty with sleep after the transplant; therefore, the C-L team recommends mirtazapine, 15 mg/d. She has no behavioral problems during her stay, and is set up with home health, case management, and psychiatry follow-up. On hospital Day 20, she is discharged.

Bottom Line

Use caution when prescribing valproic acid, even in young, otherwise healthy patients. Although rare, some patients may experience a rapid decompensation and life-threatening illness after starting valproic acid. When prescribing valproic acid, ensure close follow-up after initiation, including mental status examinations, physical examinations, and laboratory testing.

Related Resource

• Doroudgar S, Chou TI. How to modify psychotropic therapy for patients who have liver dysfunction. Current Psychiatry. 2014;13(12):46-49.

Drug Brand Names

Diphenhydramine • Benadryl
Famotidine • Fluxid, Pepcid
Lamotrigine • Lamictal
Mirtazapine • Remeron
N-acetylcysteine • Mucomyst
Phenobarbital • Luminal
Phenytoin • Dilantin
Prednisone • Cortan, Deltasone
Sertraline • Zoloft
Valproic acid • Depakene

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.