Pediatrics

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

Care providers encountered significant challenges when addressing the mental health needs of unaccompanied immigrant children in federal custody, including overwhelming caseloads and the deteriorating mental health of some patients, according to a new report by the Office of Inspector General (OIG).

In the report, released Sept. 3, the OIG outlined findings from its analysis of 45 Office of Refugee Resettlement (ORR) facilities between August and September 2018. The U.S. Department of Health & Human Services ORR is the legal custodian of unaccompanied immigrant children in its care who have no parent or legal guardian available. This includes children who arrive in the United States unaccompanied and children who are separated from their parents or guardians by immigration authorities after arriving in the country.

For the analysis, OIG investigators collected data from interviews with mental health clinicians, medical coordinators, facility leadership, and ORR federal field specialists at the 45 selected facilities.

Investigators recorded numerous serious challenges experienced by providers when attempting to provide mental health care to the children. Namely, they cited overwhelming patient caseloads, and difficulty accessing external mental health clinicians and referring children to providers within ORR’s network, according to the OIG’s report.

Mental health clinicians reported that the high caseloads hurt their ability to build rapport with young patients – and allowed less time for counseling and less frequent sessions for children with greater needs. The heavy caseloads were generated by heightened immigration enforcement beginning in 2017, and the separation of many more families at the border and more children being placed in federal custody, according to the report.

In addition, providers reported challenges when addressing the mental health needs of children who had experienced significant trauma before coming into federal custody. Intense trauma was common among children who entered care provider facilities, the report found. This included trauma that occurred while the children lived in the countries of origin, trauma during their journey to the United States, and trauma upon their arrival in the United States.

Separation from parents and a chaotic reunification process added to the trauma that children had already experienced, providers reported, and put extreme pressure on facility staff. Separated children exhibited “more fear, feelings of abandonment, and posttraumatic stress than did children who were not separated,” according to the findings. Separated children also experienced elevated feelings of anxiety and loss as a consequence of unexpected separation from loved ones.

Also, facilities reported that longer lengths of stay resulted in deteriorating mental health for some children and increased demands on staff. Facilities reported that children who stayed in federal custody for longer periods experienced more stress, anxiety, and behavioral issues. According to the facilities, the longer stays resulted in higher levels of defiance, hopelessness, and frustration among children – in addition to more instances of self-harm and suicidal ideation.

As long as the United States continues to detain children, the psychological harm created by such detainments is likely to continue, said Kim A. Baranowski, PhD, a psychologist and lecturer at Columbia University in New York. At a minimum, unaccompanied minors should have access to highly trained licensed clinicians who can respond to their immediate mental health needs within the initial hours and days following their arrival in the United States, and such children should be released rapidly from government custody and reunited with their families, said Dr. Baranowski, a coauthor of the Social Science & Medicine study.

“We need to effectively support their integration into the community, and connect children and their families with linguistically, culturally, and developmentally appropriate trauma-informed pro bono treatment services that respond to their experiences” of premigration, migration, and postmigration stressors, “as well as potential exposure to trauma,” she said in an interview.

The OIG issued several recommendations for practical steps that ORR can take to assist facilities and better provide mental health care to immigrant children in federal custody. The agency advised that the ORR should provide facilities with evidence-based guidance on addressing trauma in short-term therapy and that the ORR also should develop strategies for overcoming challenges to hiring and retaining qualified mental health clinicians.

The Office of Inspector General also suggested that facilities consider maximum caseloads for individual clinicians. Finally, the OIG recommends that ORR address gaps in options for children who require more specialized treatment and that the office take reasonable steps to minimize the length of time that children remain in custody.

[email protected]

*This article was updated 9/5/2019.

Care providers encountered significant challenges when addressing the mental health needs of unaccompanied immigrant children in federal custody, including overwhelming caseloads and the deteriorating mental health of some patients, according to a new report by the Office of Inspector General (OIG).

In the report, released Sept. 3, the OIG outlined findings from its analysis of 45 Office of Refugee Resettlement (ORR) facilities between August and September 2018. The U.S. Department of Health & Human Services ORR is the legal custodian of unaccompanied immigrant children in its care who have no parent or legal guardian available. This includes children who arrive in the United States unaccompanied and children who are separated from their parents or guardians by immigration authorities after arriving in the country.

For the analysis, OIG investigators collected data from interviews with mental health clinicians, medical coordinators, facility leadership, and ORR federal field specialists at the 45 selected facilities.

Investigators recorded numerous serious challenges experienced by providers when attempting to provide mental health care to the children. Namely, they cited overwhelming patient caseloads, and difficulty accessing external mental health clinicians and referring children to providers within ORR’s network, according to the OIG’s report.

Mental health clinicians reported that the high caseloads hurt their ability to build rapport with young patients – and allowed less time for counseling and less frequent sessions for children with greater needs. The heavy caseloads were generated by heightened immigration enforcement beginning in 2017, and the separation of many more families at the border and more children being placed in federal custody, according to the report.

In addition, providers reported challenges when addressing the mental health needs of children who had experienced significant trauma before coming into federal custody. Intense trauma was common among children who entered care provider facilities, the report found. This included trauma that occurred while the children lived in the countries of origin, trauma during their journey to the United States, and trauma upon their arrival in the United States.

Separation from parents and a chaotic reunification process added to the trauma that children had already experienced, providers reported, and put extreme pressure on facility staff. Separated children exhibited “more fear, feelings of abandonment, and posttraumatic stress than did children who were not separated,” according to the findings. Separated children also experienced elevated feelings of anxiety and loss as a consequence of unexpected separation from loved ones.

Also, facilities reported that longer lengths of stay resulted in deteriorating mental health for some children and increased demands on staff. Facilities reported that children who stayed in federal custody for longer periods experienced more stress, anxiety, and behavioral issues. According to the facilities, the longer stays resulted in higher levels of defiance, hopelessness, and frustration among children – in addition to more instances of self-harm and suicidal ideation.

As long as the United States continues to detain children, the psychological harm created by such detainments is likely to continue, said Kim A. Baranowski, PhD, a psychologist and lecturer at Columbia University in New York. At a minimum, unaccompanied minors should have access to highly trained licensed clinicians who can respond to their immediate mental health needs within the initial hours and days following their arrival in the United States, and such children should be released rapidly from government custody and reunited with their families, said Dr. Baranowski, a coauthor of the Social Science & Medicine study.

“We need to effectively support their integration into the community, and connect children and their families with linguistically, culturally, and developmentally appropriate trauma-informed pro bono treatment services that respond to their experiences” of premigration, migration, and postmigration stressors, “as well as potential exposure to trauma,” she said in an interview.

The OIG issued several recommendations for practical steps that ORR can take to assist facilities and better provide mental health care to immigrant children in federal custody. The agency advised that the ORR should provide facilities with evidence-based guidance on addressing trauma in short-term therapy and that the ORR also should develop strategies for overcoming challenges to hiring and retaining qualified mental health clinicians.

The Office of Inspector General also suggested that facilities consider maximum caseloads for individual clinicians. Finally, the OIG recommends that ORR address gaps in options for children who require more specialized treatment and that the office take reasonable steps to minimize the length of time that children remain in custody.

[email protected]

*This article was updated 9/5/2019.

Care providers encountered significant challenges when addressing the mental health needs of unaccompanied immigrant children in federal custody, including overwhelming caseloads and the deteriorating mental health of some patients, according to a new report by the Office of Inspector General (OIG).

In the report, released Sept. 3, the OIG outlined findings from its analysis of 45 Office of Refugee Resettlement (ORR) facilities between August and September 2018. The U.S. Department of Health & Human Services ORR is the legal custodian of unaccompanied immigrant children in its care who have no parent or legal guardian available. This includes children who arrive in the United States unaccompanied and children who are separated from their parents or guardians by immigration authorities after arriving in the country.

For the analysis, OIG investigators collected data from interviews with mental health clinicians, medical coordinators, facility leadership, and ORR federal field specialists at the 45 selected facilities.

Investigators recorded numerous serious challenges experienced by providers when attempting to provide mental health care to the children. Namely, they cited overwhelming patient caseloads, and difficulty accessing external mental health clinicians and referring children to providers within ORR’s network, according to the OIG’s report.

Mental health clinicians reported that the high caseloads hurt their ability to build rapport with young patients – and allowed less time for counseling and less frequent sessions for children with greater needs. The heavy caseloads were generated by heightened immigration enforcement beginning in 2017, and the separation of many more families at the border and more children being placed in federal custody, according to the report.

In addition, providers reported challenges when addressing the mental health needs of children who had experienced significant trauma before coming into federal custody. Intense trauma was common among children who entered care provider facilities, the report found. This included trauma that occurred while the children lived in the countries of origin, trauma during their journey to the United States, and trauma upon their arrival in the United States.

Separation from parents and a chaotic reunification process added to the trauma that children had already experienced, providers reported, and put extreme pressure on facility staff. Separated children exhibited “more fear, feelings of abandonment, and posttraumatic stress than did children who were not separated,” according to the findings. Separated children also experienced elevated feelings of anxiety and loss as a consequence of unexpected separation from loved ones.

Also, facilities reported that longer lengths of stay resulted in deteriorating mental health for some children and increased demands on staff. Facilities reported that children who stayed in federal custody for longer periods experienced more stress, anxiety, and behavioral issues. According to the facilities, the longer stays resulted in higher levels of defiance, hopelessness, and frustration among children – in addition to more instances of self-harm and suicidal ideation.

As long as the United States continues to detain children, the psychological harm created by such detainments is likely to continue, said Kim A. Baranowski, PhD, a psychologist and lecturer at Columbia University in New York. At a minimum, unaccompanied minors should have access to highly trained licensed clinicians who can respond to their immediate mental health needs within the initial hours and days following their arrival in the United States, and such children should be released rapidly from government custody and reunited with their families, said Dr. Baranowski, a coauthor of the Social Science & Medicine study.

“We need to effectively support their integration into the community, and connect children and their families with linguistically, culturally, and developmentally appropriate trauma-informed pro bono treatment services that respond to their experiences” of premigration, migration, and postmigration stressors, “as well as potential exposure to trauma,” she said in an interview.

The OIG issued several recommendations for practical steps that ORR can take to assist facilities and better provide mental health care to immigrant children in federal custody. The agency advised that the ORR should provide facilities with evidence-based guidance on addressing trauma in short-term therapy and that the ORR also should develop strategies for overcoming challenges to hiring and retaining qualified mental health clinicians.

The Office of Inspector General also suggested that facilities consider maximum caseloads for individual clinicians. Finally, the OIG recommends that ORR address gaps in options for children who require more specialized treatment and that the office take reasonable steps to minimize the length of time that children remain in custody.

[email protected]

*This article was updated 9/5/2019.

Michigan Governor Gretchen Whitmer (D) has ordered the state Department of Health and Human Services to issue emergency rules banning the sale of flavored nicotine vaping products in retail stores and online.

VlaDee/Getty Images

The state health agency is expected to issue rules outlining the ban within the next 30 days. The emergency ban will be in effect for 6 months, with the possibility of a 6-month extension while state health regulators craft rules to set in place a permanent ban.

The ban will also prohibit “misleading marketing of vaping products, including the use of terms like ‘clean,’ ‘safe,’ and ‘healthy,’ that perpetuate beliefs that these products are harmless,” according to a statement issued by Gov. Whitmer.

Companies selling vaping products “are using candy flavors to hook children on nicotine and misleading claims to promote the belief that these products are safe,” she said in a statement. “That ends today. Our kids deserve leaders who are going to fight to protect them. These bold steps will finally put an end to these irresponsible and deceptive practices and protect Michiganders’ public health.”

The ban also will cover mint- and menthol-flavors in addition to sweet flavors but will not ban tobacco-flavored e-cigarette products.

The American Academy of Pediatrics, American Heart Association, American Lung Association, American Cancer Society Cancer Action Network and other organizations praised the action taken by the state, calling the steps “necessary and appropriate.”

“The need for action is even more urgent in light of the recent outbreak of severe lung illness associated with e-cigarette use and the failure of the U.S. Food and Drug Administration to take strong regulatory action such as prohibiting the sale of the flavored products nationwide that have attracted shocking numbers of our nation’s youth,” the organizations said in a statement.

The groups noted that “health authorities are investigating reports of severe respiratory illness associated with e-cigarette use in at least 215 people ... in 25 states,” adding that many are youth and young adults.

The U.S. Department of Health & Human Services Secretary Alex Azar said in an Aug. 30 statement that the federal government is “using every tool we have to get to the bottom of this deeply concerning outbreak of illness in Americans who use e-cigarettes. More broadly, we will continue using every regulatory and enforcement power we have to stop the epidemic of youth e-cigarette use.”

HHS noted that no single substance or e-cigarette product has been consistently associated with the reports of illness. The agency called upon clinicians to report any new cases as appropriate to their state and local health departments.

Gov. Whitmer earlier this year signed bills that clarify that it is illegal to sell nontraditional nicotine products to minors, but the governor’s statement notes her criticism that the bills did not go far enough to protect the state’s youth, necessitating this further action.

[email protected]

Michigan Governor Gretchen Whitmer (D) has ordered the state Department of Health and Human Services to issue emergency rules banning the sale of flavored nicotine vaping products in retail stores and online.

VlaDee/Getty Images

The state health agency is expected to issue rules outlining the ban within the next 30 days. The emergency ban will be in effect for 6 months, with the possibility of a 6-month extension while state health regulators craft rules to set in place a permanent ban.

The ban will also prohibit “misleading marketing of vaping products, including the use of terms like ‘clean,’ ‘safe,’ and ‘healthy,’ that perpetuate beliefs that these products are harmless,” according to a statement issued by Gov. Whitmer.

Companies selling vaping products “are using candy flavors to hook children on nicotine and misleading claims to promote the belief that these products are safe,” she said in a statement. “That ends today. Our kids deserve leaders who are going to fight to protect them. These bold steps will finally put an end to these irresponsible and deceptive practices and protect Michiganders’ public health.”

The ban also will cover mint- and menthol-flavors in addition to sweet flavors but will not ban tobacco-flavored e-cigarette products.

The American Academy of Pediatrics, American Heart Association, American Lung Association, American Cancer Society Cancer Action Network and other organizations praised the action taken by the state, calling the steps “necessary and appropriate.”

“The need for action is even more urgent in light of the recent outbreak of severe lung illness associated with e-cigarette use and the failure of the U.S. Food and Drug Administration to take strong regulatory action such as prohibiting the sale of the flavored products nationwide that have attracted shocking numbers of our nation’s youth,” the organizations said in a statement.

The groups noted that “health authorities are investigating reports of severe respiratory illness associated with e-cigarette use in at least 215 people ... in 25 states,” adding that many are youth and young adults.

The U.S. Department of Health & Human Services Secretary Alex Azar said in an Aug. 30 statement that the federal government is “using every tool we have to get to the bottom of this deeply concerning outbreak of illness in Americans who use e-cigarettes. More broadly, we will continue using every regulatory and enforcement power we have to stop the epidemic of youth e-cigarette use.”

HHS noted that no single substance or e-cigarette product has been consistently associated with the reports of illness. The agency called upon clinicians to report any new cases as appropriate to their state and local health departments.

Gov. Whitmer earlier this year signed bills that clarify that it is illegal to sell nontraditional nicotine products to minors, but the governor’s statement notes her criticism that the bills did not go far enough to protect the state’s youth, necessitating this further action.

[email protected]

Michigan Governor Gretchen Whitmer (D) has ordered the state Department of Health and Human Services to issue emergency rules banning the sale of flavored nicotine vaping products in retail stores and online.

VlaDee/Getty Images

The state health agency is expected to issue rules outlining the ban within the next 30 days. The emergency ban will be in effect for 6 months, with the possibility of a 6-month extension while state health regulators craft rules to set in place a permanent ban.

The ban will also prohibit “misleading marketing of vaping products, including the use of terms like ‘clean,’ ‘safe,’ and ‘healthy,’ that perpetuate beliefs that these products are harmless,” according to a statement issued by Gov. Whitmer.

Companies selling vaping products “are using candy flavors to hook children on nicotine and misleading claims to promote the belief that these products are safe,” she said in a statement. “That ends today. Our kids deserve leaders who are going to fight to protect them. These bold steps will finally put an end to these irresponsible and deceptive practices and protect Michiganders’ public health.”

The ban also will cover mint- and menthol-flavors in addition to sweet flavors but will not ban tobacco-flavored e-cigarette products.

The American Academy of Pediatrics, American Heart Association, American Lung Association, American Cancer Society Cancer Action Network and other organizations praised the action taken by the state, calling the steps “necessary and appropriate.”

“The need for action is even more urgent in light of the recent outbreak of severe lung illness associated with e-cigarette use and the failure of the U.S. Food and Drug Administration to take strong regulatory action such as prohibiting the sale of the flavored products nationwide that have attracted shocking numbers of our nation’s youth,” the organizations said in a statement.

The groups noted that “health authorities are investigating reports of severe respiratory illness associated with e-cigarette use in at least 215 people ... in 25 states,” adding that many are youth and young adults.

The U.S. Department of Health & Human Services Secretary Alex Azar said in an Aug. 30 statement that the federal government is “using every tool we have to get to the bottom of this deeply concerning outbreak of illness in Americans who use e-cigarettes. More broadly, we will continue using every regulatory and enforcement power we have to stop the epidemic of youth e-cigarette use.”

HHS noted that no single substance or e-cigarette product has been consistently associated with the reports of illness. The agency called upon clinicians to report any new cases as appropriate to their state and local health departments.

Gov. Whitmer earlier this year signed bills that clarify that it is illegal to sell nontraditional nicotine products to minors, but the governor’s statement notes her criticism that the bills did not go far enough to protect the state’s youth, necessitating this further action.

[email protected]

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease typically with childhood onset. In some cases, the condition persists, but AD usually resolves by the time a child reaches adulthood. Prevalence is difficult to estimate but, in developed countries, is approximately 15% to 30% among children and 2% to 10% among adults.¹

Atopic dermatitis is characterized by chronically itchy dry skin, weeping erythematous papules and plaques, and lichenification. Furthermore, AD often is associated with other atopic diseases, such as food allergy, allergic rhinitis, and bronchial asthma.

In this article, we review the literature on the quality of life (QOL) of patients with AD. Our goals are to discuss the most common methods for measuring QOL in AD and how to use them; highlight specific alterations of QOL in AD; and review data about QOL of children with AD, which is underrepresented in the medical literature, as studies tend to focus on adults. In addition, we address the importance of assessing QOL in patients with AD due to the psychological burden of the disease.

Quality of Life

The harmful effects of AD can include a range of areas, including emotional and mental health, physical activity, social functioning, sleep disturbance, decreased work productivity, financial expenditure, leisure activities, and family relationships. The impact varies by age of the patient, and there are specific instruments for measuring QOL in infants, children, adolescents, and adults.

Because QOL is an important instrument used in many AD studies, we call attention to the work of the Harmonising Outcome Measures for Eczema (HOME) initiative, which established a core outcome set for all AD clinical trials to enable comparison of results of individual studies.² Quality of life was identified in HOME as one of 4 basic outcome measures that should be included in every AD trial (the others are clinician-reported signs, patient-reported symptoms, and long-term control).³ According to the recent agreement, the following QOL instruments should be used: Dermatology Life Quality Index (DLQI) for adults, Children’s Dermatology Life Quality Index (CDLQI) for children, and Infants’ Dermatitis Quality of Life Index (IDQOL) for infants.⁴

In dermatology, these instruments can be divided into 3 basic categories: generic, dermatology specific, and disease specific.⁵ Generic QOL questionnaires are beneficial when comparing the QOL of an AD patient to patients with other conditions or to healthy individuals. On the other hand, dermatology-specific and AD-specific methods are more effective instruments for detecting impairments linked directly to the disease and, therefore, are more sensitive to changes in QOL.⁵ Some of the most frequently used QOL measures^5,6 for AD along with their key attributes are listed in the Table.

In contrast, several other methods that also are administered by a parent/guardian assess how the parent perceives the QOL of their child with AD; these methods are essential for small children and infants who cannot answer questions themselves. The IDQOL⁹ was designed to assess the QOL of patients younger than 4 years using a parent-completed questionnaire. For older children and adolescents aged 4 to 16 years, the CDLQI¹⁰ is a widely used instrument; the questionnaire is completed by the child and is available in a cartoon format.¹⁰

For patients older than 16 years, 2 important instruments are the DLQI, a generic dermatology instrument, and the Quality of Life Index for Atopic Dermatitis (QoLIAD).¹¹

Clearly it can be troublesome for researchers and clinicians to find the most suitable instrument to evaluate QOL in AD patients. To make this task easier, the European Academy of Dermatology and Venereology Task Force released a position paper with the following recommendations: (1) only validated instruments should be used, and (2) their use should be based on the age of the patients for which the instruments were designed. It is reommended that researchers use a combination of a generic and a dermatology-specific or AD-specific instrument, whereas clinicians should apply a dermatology-specific or AD-specific method, or both.⁵

Alterations of QOL in AD

Sleep Disturbance in AD
Sleep disorders observed in AD include difficulty falling asleep, frequent waking episodes, shorter sleep duration, and feelings of inadequate sleep, which often result in impairment of daily activity.^12,13 Correlation has been found between sleep quality and QOL in both children and adults.¹⁴ Approximately 60% of children affected by AD experience a sleep disturbance,¹⁵ which seems to correlate well with disease severity.¹⁶ A US study found that adults with AD are more likely to experience a sleep disturbance, which often affects daytime functioning and work productivity.¹³

Financial Aspects and Impact on Work
The financial burden of AD is extensive.¹⁷ There are direct medical costs, including medication, visits to the physician, alternative therapies, and nonprescription products. Patients tend to spend relevant money on such items as moisturizers, bath products, antihistamines, topical steroids, and topical antibiotics.^18,19 However, it seems that most of the cost of AD is due to indirect and nonmedical costs, including transportation to medical visits; loss of work days; extra childcare; and expenditures associated with lifestyle changes,^19,20 such as modifying diet, wearing special clothes, using special bed linens, and purchasing special household items (eg, anti–dust mite vacuum cleaner, humidifier, new carpeting).^17,19

Absenteeism from work often is a consequence of physician appointments; in addition, parents/guardians of a child with AD often miss work due to medical care. Even at work, patients (or parents/guardians) often experience decreased work productivity (so-called presenteeism) due to loss of sleep and anxiety.²¹ In addressing the effects of AD on work life, a systematic literature review found that AD strongly affects sick leave and might have an impact on job choice and change or loss of job.²²

Furthermore, according to Su et al,²³ the costs of AD are related to disease severity. Moreover, their data suggest that among chronic childhood diseases, the financial burden of AD is greater than the cost of asthma and similar to the cost of diabetes mellitus.²³

Association Between QOL and Disease Severity

A large observational study found that improvement in AD severity was followed by an increase in QOL.²⁴ A positive correlation between disease severity and QOL has been found in other studies,^25,26 though no correlation or only moderate correlation also has been reported.²⁷ Apparently, in addition to QOL, disease severity scores are substantial parameters in the evaluation of distress caused by AD; the HOME initiative has identified clinician-reported signs and patient-reported symptoms as 2 of 4 core outcomes domains to include in all future AD clinical trials.³ For measuring symptoms, the Patient-Oriented Eczema Measure (POEM) is the recommended instrument.²⁸ Regarding clinical signs, the HOME group named the Eczema Area and Severity Index (EASI) as the preferred instrument.²⁹

Psychological Burden

Stress is a triggering factor for AD, but the connection between skin and mind appears bidirectional. The biological reaction to stress probably lowers the itch threshold and disrupts the skin barrier.³⁰ The Global Burden of Disease Study showed that skin diseases are the fourth leading cause of nonfatal disease burden.³¹ There are several factors—pruritus, scratch, and pain—that can all lead to sleep deprivation and daytime fatigue. Based on our experience, if lesions develop on visible areas, patients can feel stigmatized, which restricts their social life.

The most common psychological comorbidities of AD are anxiety and depression. In a cross-sectional, multicenter study, there was a significantly higher prevalence of depression (P<.001) and anxiety disorder (P=.02) among patients with common skin diseases compared to a control group.³² In a study that assessed AD patients, researchers found a higher risk of depression and anxiety.³³ Suicidal ideation also is more common in the population with AD^32,34; a study showed that the risk of suicidal ideation in adolescents was nearly 4-fold in patients with itching skin lesions compared to those without itch.³⁴

According to Linnet and Jemec,³⁵ mental and psychological comorbidities of AD are associated with lower QOL, not with clinical severity. As a result, to improve QOL in AD, one should take care of both dermatological and psychological problems. It has been demonstrated that psychological interventions, such as autogenic training, cognitive-behavioral therapy, relaxation techniques, habit reversal training,³⁶ and hypnotherapy³⁷ might be helpful in individual cases; educational interventions also are recommended.³⁶ With these adjuvant therapies, psychological status, unpleasant clinical symptoms, and QOL could be improved, though further studies are needed to confirm these benefits.

Conclusion

Atopic dermatitis places a notable burden on patients and their families. The degree of burden is probably related to disease severity. For measuring QOL, researchers and clinicians should use validated methods suited to the age of the patients for which they were designed. More studies are needed to assess the effects of different treatments on QOL. Besides pharmacotherapy, psychotherapy and educational programs might be beneficial for improving QOL, another important area to be studied.

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

SEATTLE – ICU transfers for acute bronchiolitis dropped 63% at Johns Hopkins All Children’s Hospital in St. Petersburg, Fla., after the high-flow nasal cannula limit on the floor was raised from 6 L/min to 12 L/min, and treatment was started in the emergency department, according to a presentation at Pediatric Hospital Medicine.

A year before the change was made in April 2018, there were 17 transfers among 249 bronchiolitis patients treated on the floor, a transfer rate of 6.8%. In the year after the change, there were eight among 319 patients, a transfer rate of 2.5%. Raising the limit to 12 L/min prevented an estimated 14 transfers, for a total savings of almost $250,000, said pediatric hospitalist and assistant professor Shaila Siraj, MD.

“As hospitalists, we felt we could safely take care of these patients,” Dr. Siraj said.

So she and her colleague pediatric critical care specialist Anthony Sochet, MD, also an assistant professor of pediatrics, reviewed over a year’s worth of data at All Children’s. They found that 12 L/min – roughly 1.5 L/kg/min – was the cutoff that best discriminated between patients who needed intubation and those who did not, “so that’s what we chose,” Dr. Sochet said.

For simplicity, they broke limits down by age: A maximum flow rate of 8 L/min for children up to 6 months old; 10 L for children aged 6-12 months; and up to 12 L/min for children age 12-24 months. The fraction of inspired oxygen remained the same at 50%. Children were started at maximum flows, then weaned down as they improved. Respiratory assessments were made at least every 4 hours.

The changes were part of a larger revision of the hospital’s pathway for uncomplicated bronchiolitis in children up to 2 years old; it was a joint effort involving nurses, respiratory therapists, and pediatric hospitalists, and ED and ICU teams.

Early initiation in the ED was “probably one of the most important” changes; it kept children from wearing out as they struggled to breath. Kids often start to improve right away, but when then don’t after 30-60 minutes, it’s an indication that they should probably be triaged to the ICU for possible intubation, Dr. Siraj said.

Dr. Sochet was careful to note that institutions have to assess their own situations before taking similar steps. “Not everyone has a tertiary care ICU staffed 24 and 7,” he said.

“You have to ask what floor resources you have, what’s your ability to escalate when you need to. Use data from your own institution to guide where you pick your cutoffs. Adequate staffing is really about respiratory [therapist]/nursing ratios, not the physicians,” he said.

In addition, “in an otherwise healthy child that just has [HFNC] for bronchiolitis, there is absolutely no reason why you should be withholding feeds.” Fed children will feel better and do better, he said.

The presenters had no disclosures.

[email protected]

SEATTLE – ICU transfers for acute bronchiolitis dropped 63% at Johns Hopkins All Children’s Hospital in St. Petersburg, Fla., after the high-flow nasal cannula limit on the floor was raised from 6 L/min to 12 L/min, and treatment was started in the emergency department, according to a presentation at Pediatric Hospital Medicine.

A year before the change was made in April 2018, there were 17 transfers among 249 bronchiolitis patients treated on the floor, a transfer rate of 6.8%. In the year after the change, there were eight among 319 patients, a transfer rate of 2.5%. Raising the limit to 12 L/min prevented an estimated 14 transfers, for a total savings of almost $250,000, said pediatric hospitalist and assistant professor Shaila Siraj, MD.

“As hospitalists, we felt we could safely take care of these patients,” Dr. Siraj said.

So she and her colleague pediatric critical care specialist Anthony Sochet, MD, also an assistant professor of pediatrics, reviewed over a year’s worth of data at All Children’s. They found that 12 L/min – roughly 1.5 L/kg/min – was the cutoff that best discriminated between patients who needed intubation and those who did not, “so that’s what we chose,” Dr. Sochet said.

For simplicity, they broke limits down by age: A maximum flow rate of 8 L/min for children up to 6 months old; 10 L for children aged 6-12 months; and up to 12 L/min for children age 12-24 months. The fraction of inspired oxygen remained the same at 50%. Children were started at maximum flows, then weaned down as they improved. Respiratory assessments were made at least every 4 hours.

The changes were part of a larger revision of the hospital’s pathway for uncomplicated bronchiolitis in children up to 2 years old; it was a joint effort involving nurses, respiratory therapists, and pediatric hospitalists, and ED and ICU teams.

Early initiation in the ED was “probably one of the most important” changes; it kept children from wearing out as they struggled to breath. Kids often start to improve right away, but when then don’t after 30-60 minutes, it’s an indication that they should probably be triaged to the ICU for possible intubation, Dr. Siraj said.

Dr. Sochet was careful to note that institutions have to assess their own situations before taking similar steps. “Not everyone has a tertiary care ICU staffed 24 and 7,” he said.

“You have to ask what floor resources you have, what’s your ability to escalate when you need to. Use data from your own institution to guide where you pick your cutoffs. Adequate staffing is really about respiratory [therapist]/nursing ratios, not the physicians,” he said.

In addition, “in an otherwise healthy child that just has [HFNC] for bronchiolitis, there is absolutely no reason why you should be withholding feeds.” Fed children will feel better and do better, he said.

The presenters had no disclosures.

[email protected]

SEATTLE – ICU transfers for acute bronchiolitis dropped 63% at Johns Hopkins All Children’s Hospital in St. Petersburg, Fla., after the high-flow nasal cannula limit on the floor was raised from 6 L/min to 12 L/min, and treatment was started in the emergency department, according to a presentation at Pediatric Hospital Medicine.

A year before the change was made in April 2018, there were 17 transfers among 249 bronchiolitis patients treated on the floor, a transfer rate of 6.8%. In the year after the change, there were eight among 319 patients, a transfer rate of 2.5%. Raising the limit to 12 L/min prevented an estimated 14 transfers, for a total savings of almost $250,000, said pediatric hospitalist and assistant professor Shaila Siraj, MD.

“As hospitalists, we felt we could safely take care of these patients,” Dr. Siraj said.

So she and her colleague pediatric critical care specialist Anthony Sochet, MD, also an assistant professor of pediatrics, reviewed over a year’s worth of data at All Children’s. They found that 12 L/min – roughly 1.5 L/kg/min – was the cutoff that best discriminated between patients who needed intubation and those who did not, “so that’s what we chose,” Dr. Sochet said.

For simplicity, they broke limits down by age: A maximum flow rate of 8 L/min for children up to 6 months old; 10 L for children aged 6-12 months; and up to 12 L/min for children age 12-24 months. The fraction of inspired oxygen remained the same at 50%. Children were started at maximum flows, then weaned down as they improved. Respiratory assessments were made at least every 4 hours.

The changes were part of a larger revision of the hospital’s pathway for uncomplicated bronchiolitis in children up to 2 years old; it was a joint effort involving nurses, respiratory therapists, and pediatric hospitalists, and ED and ICU teams.

Early initiation in the ED was “probably one of the most important” changes; it kept children from wearing out as they struggled to breath. Kids often start to improve right away, but when then don’t after 30-60 minutes, it’s an indication that they should probably be triaged to the ICU for possible intubation, Dr. Siraj said.

Dr. Sochet was careful to note that institutions have to assess their own situations before taking similar steps. “Not everyone has a tertiary care ICU staffed 24 and 7,” he said.

“You have to ask what floor resources you have, what’s your ability to escalate when you need to. Use data from your own institution to guide where you pick your cutoffs. Adequate staffing is really about respiratory [therapist]/nursing ratios, not the physicians,” he said.

In addition, “in an otherwise healthy child that just has [HFNC] for bronchiolitis, there is absolutely no reason why you should be withholding feeds.” Fed children will feel better and do better, he said.

The presenters had no disclosures.

[email protected]

A new study has reaffirmed that, as methicillin‐sensitive Staphylococcus aureus (MSSA) remains the most common skin infection in pediatric atopic dermatitis (AD) patients, first‐generation cephalosporins remain the appropriate empiric therapy.

“Clindamycin, tetracyclines, or TMP‐SMX can be considered in patients suspected to have, or with a history of, MRSA [methicillin‐resistant S. aureus] infection,” wrote Cristopher C. Briscoe, MD, of the Washington University School of Medicine in St. Louis, Missouri, and his coauthors. The study was published in Pediatric Dermatology.

To determine the optimal empiric antibiotic for pediatric AD patients with skin infections, the researchers analyzed skin cultures from 106 patients seen at Saint Louis Children’s Hospital (SLCH). The results were also compared to cultures from pediatric patients who presented at the SLCH emergency department (ED) with S. aureus skin abscesses.

Of the 170 cultures that grew S. aureus, 130 (77.8%) grew MSSA, and 37 (22.2%) grew MRSA. Three of the cultures grew both. The prevalence of MRSA in the cohort differed from the prevalence in the ED patients (44%). The prevalence of either infection did not differ significantly by age, sex or race, though the average number of cultures in African American patients topped the average for Caucasian patients (1.8 vs. 1.2, P less than .003).

All patients with MSSA – in both the cohort and the ED – proved 100% susceptible to cefazolin. Cohort patients with MSSA saw lower susceptibility to doxycycline compared to the ED patients (89.4% vs. 97%), as did MRSA cohort patients to trimethoprim‐sulfamethoxazole (92% vs. 98%).

“When a patient with AD walks into your office and looks like they have an infection of their eczema, your go-to antibiotic is going to be one that targets MSSA,” said coauthor Carrie Coughlin, MD, of the Washington University School of Medicine in an interview. “You’ll still do a culture to prove or disprove that assumption, but it gives you a guide to help make that patient better in the short term while you work things up.”

“Also, remember that MSSA is not ‘better’ to have than MRSA,” she added. “You can now see some of the virulence factors from MRSA strains in MSSA strains, so treating both of them is important.”

The authors acknowledged their study’s limitations, including the limited generalizability of a single-center design and a lack of information as to the body sites from which the cultures were obtained. They were also unable to reliably determine prior antibiotic exposure, noting that “future work could examine whether prior exposure differed significantly in the MRSA and MSSA groups.”

The study was funded by grants from the Agency for Healthcare Research and Quality. The authors reported no conflicts of interest.


SOURCE: Briscoe CC et al. Pediatr Dermatol. 2019 May 24. doi: 10.1111/pde.13867.

A new study has reaffirmed that, as methicillin‐sensitive Staphylococcus aureus (MSSA) remains the most common skin infection in pediatric atopic dermatitis (AD) patients, first‐generation cephalosporins remain the appropriate empiric therapy.

“Clindamycin, tetracyclines, or TMP‐SMX can be considered in patients suspected to have, or with a history of, MRSA [methicillin‐resistant S. aureus] infection,” wrote Cristopher C. Briscoe, MD, of the Washington University School of Medicine in St. Louis, Missouri, and his coauthors. The study was published in Pediatric Dermatology.

To determine the optimal empiric antibiotic for pediatric AD patients with skin infections, the researchers analyzed skin cultures from 106 patients seen at Saint Louis Children’s Hospital (SLCH). The results were also compared to cultures from pediatric patients who presented at the SLCH emergency department (ED) with S. aureus skin abscesses.

Of the 170 cultures that grew S. aureus, 130 (77.8%) grew MSSA, and 37 (22.2%) grew MRSA. Three of the cultures grew both. The prevalence of MRSA in the cohort differed from the prevalence in the ED patients (44%). The prevalence of either infection did not differ significantly by age, sex or race, though the average number of cultures in African American patients topped the average for Caucasian patients (1.8 vs. 1.2, P less than .003).

All patients with MSSA – in both the cohort and the ED – proved 100% susceptible to cefazolin. Cohort patients with MSSA saw lower susceptibility to doxycycline compared to the ED patients (89.4% vs. 97%), as did MRSA cohort patients to trimethoprim‐sulfamethoxazole (92% vs. 98%).

“When a patient with AD walks into your office and looks like they have an infection of their eczema, your go-to antibiotic is going to be one that targets MSSA,” said coauthor Carrie Coughlin, MD, of the Washington University School of Medicine in an interview. “You’ll still do a culture to prove or disprove that assumption, but it gives you a guide to help make that patient better in the short term while you work things up.”

“Also, remember that MSSA is not ‘better’ to have than MRSA,” she added. “You can now see some of the virulence factors from MRSA strains in MSSA strains, so treating both of them is important.”

The authors acknowledged their study’s limitations, including the limited generalizability of a single-center design and a lack of information as to the body sites from which the cultures were obtained. They were also unable to reliably determine prior antibiotic exposure, noting that “future work could examine whether prior exposure differed significantly in the MRSA and MSSA groups.”

The study was funded by grants from the Agency for Healthcare Research and Quality. The authors reported no conflicts of interest.


SOURCE: Briscoe CC et al. Pediatr Dermatol. 2019 May 24. doi: 10.1111/pde.13867.

A new study has reaffirmed that, as methicillin‐sensitive Staphylococcus aureus (MSSA) remains the most common skin infection in pediatric atopic dermatitis (AD) patients, first‐generation cephalosporins remain the appropriate empiric therapy.

“Clindamycin, tetracyclines, or TMP‐SMX can be considered in patients suspected to have, or with a history of, MRSA [methicillin‐resistant S. aureus] infection,” wrote Cristopher C. Briscoe, MD, of the Washington University School of Medicine in St. Louis, Missouri, and his coauthors. The study was published in Pediatric Dermatology.

To determine the optimal empiric antibiotic for pediatric AD patients with skin infections, the researchers analyzed skin cultures from 106 patients seen at Saint Louis Children’s Hospital (SLCH). The results were also compared to cultures from pediatric patients who presented at the SLCH emergency department (ED) with S. aureus skin abscesses.

Of the 170 cultures that grew S. aureus, 130 (77.8%) grew MSSA, and 37 (22.2%) grew MRSA. Three of the cultures grew both. The prevalence of MRSA in the cohort differed from the prevalence in the ED patients (44%). The prevalence of either infection did not differ significantly by age, sex or race, though the average number of cultures in African American patients topped the average for Caucasian patients (1.8 vs. 1.2, P less than .003).

All patients with MSSA – in both the cohort and the ED – proved 100% susceptible to cefazolin. Cohort patients with MSSA saw lower susceptibility to doxycycline compared to the ED patients (89.4% vs. 97%), as did MRSA cohort patients to trimethoprim‐sulfamethoxazole (92% vs. 98%).

“When a patient with AD walks into your office and looks like they have an infection of their eczema, your go-to antibiotic is going to be one that targets MSSA,” said coauthor Carrie Coughlin, MD, of the Washington University School of Medicine in an interview. “You’ll still do a culture to prove or disprove that assumption, but it gives you a guide to help make that patient better in the short term while you work things up.”

“Also, remember that MSSA is not ‘better’ to have than MRSA,” she added. “You can now see some of the virulence factors from MRSA strains in MSSA strains, so treating both of them is important.”

The authors acknowledged their study’s limitations, including the limited generalizability of a single-center design and a lack of information as to the body sites from which the cultures were obtained. They were also unable to reliably determine prior antibiotic exposure, noting that “future work could examine whether prior exposure differed significantly in the MRSA and MSSA groups.”

The study was funded by grants from the Agency for Healthcare Research and Quality. The authors reported no conflicts of interest.


SOURCE: Briscoe CC et al. Pediatr Dermatol. 2019 May 24. doi: 10.1111/pde.13867.

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

Major depressive disorder (MDD) is a significant pediatric health problem, with a lifetime prevalence as high as 20% by the end of adolescence.^1-3 Major depressive disorder in adolescence is associated with significant morbidity, including poor social functioning, school difficulties, early pregnancy, and increased risk of physical illness and substance abuse.^4-6 It is also linked with significant mortality, with increased risk for suicide, which is now the second leading cause of death in individuals age 10 to 24 years.^1,7,8

As their name suggests, antidepressants comprise a group of medications that are used to treat MDD; they are also, however, first-line agents for generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD) in adults. Anxiety disorders (including GAD and other anxiety diagnoses) and PTSD are also common in childhood and adolescence with a combined lifetime prevalence ranging from 15% to 30%.^9,10 These disorders are also associated with increased risk of suicide.¹¹ For all of these disorders, depending on the severity of presentation and the preference of the patient, treatments are often a combination of psychotherapy and psychopharmacology.

Clinicians face several challenges when considering antidepressants for pediatric patients. Pediatricians and psychiatrists need to understand whether these medications work in children and adolescents, and whether there are unique developmental safety and tolerability issues. The evidence base in child psychiatry is considerably smaller compared with that of adult psychiatry. From this more limited evidence base also came the controversial “black-box” warning regarding a risk of emergent suicidality when starting antidepressants that accompanies all antidepressants for pediatric, but not adult, patients. This warning has had major effects on clinical encounters with children experiencing depression, including altering clinician prescribing behavior.¹²

In this article, we review the current evidence for antidepressant efficacy, tolerability, and safety in pediatric patients. We also suggest ways in which clinicians might choose, start, and stop antidepressants in children, as well as how to talk with parents about benefits, risks, and the black-box warning.

Do antidepressants work in children?

Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants in both children and adults.¹³ While only a few SSRIs are FDA-approved for pediatric indications, the lack of FDA approval is typically related to a lack of sufficient testing in randomized controlled trials (RCTs) for specific pediatric indications, rather than to demonstrable differences in efficacy between antidepressant agents. Since there is currently no data to suggest inferiority of one agent compared to another in children or adults,^14,15 efficacy data will be discussed here as applied to the class of SSRIs, generalizing from RCTs conducted on individual drugs. Table 1 lists FDA indications and dosing information for individual antidepressants.

There is strong evidence that SSRIs are effective for treating pediatric anxiety disorders (eg, social anxiety disorder and GAD)¹⁶ and OCD,¹⁷ with numbers needed to treat (NNT) between 3 and 5. For both of these disorders, SSRIs combined with cognitive-behavioral therapy (CBT) have the highest likelihood of improving symptoms or achieving remission.^17,18

Selective serotonin reuptake inhibitors are also effective for treating pediatric MDD; however, the literature is more complex for this disorder compared to GAD and OCD as there are considerable differences in effect sizes between National Institute of Mental Health (NIMH)–funded studies and industry-sponsored trials.¹³ The major NIMH-sponsored adolescent depression trial, TADS (Treatment for Adolescents and Depression Study), showed that SSRIs (fluoxetine in this case) were quite effective, with an NNT of 4 over the acute phase (12 weeks).¹⁹ Ultimately, approximately 80% of adolescents improved over 9 months. Many industry-sponsored trials for MDD in pediatric patients had large placebo response rates (approximately 60%), which resulted in smaller between-group differences, and estimates of an NNT closer to 12,¹³ which has muddied the waters in meta-analyses that include all trials.²⁰ Improvement in depressive symptoms also appears to be bolstered by concomitant CBT in MDD,¹⁹ but not as robustly as in GAD and OCD. While the full benefit of SSRIs for depression may take as long as 8 weeks, a meta-analysis of depression studies of pediatric patients suggests that significant benefits from placebo are observed as early as 2 weeks, and that further treatment gains are minimal after 4 weeks.¹⁵ Thus, we recommend at least a 4- to 6-week trial at therapeutic dosing before deeming a medication a treatment failure.

Continue to: Posttraumatic stress disorder...

Posttraumatic stress disorder is a fourth disorder in which SSRIs are a first-line treatment in adults. The data for using SSRIs to treat pediatric patients with PTSD is scant, with only a few RCTs, and no large NIMH-funded trials. Randomized controlled trials have not demonstrated significant differences between SSRIs and placebo^21,22 and thus the current first-line recommendation in pediatric PTSD remains trauma-focused therapy, with good evidence for trauma-focused CBT.²³ Practically speaking, there can be considerable overlap of PTSD, depression, and anxiety symptoms in children,²³ and children with a history of trauma who also have comorbid MDD may benefit from medication if their symptoms persist despite an adequate trial of psychotherapy.

Taken together, the current evidence suggests that SSRIs are often effective in pediatric GAD, OCD, and MDD, with low NNTs (ranging from 3 to 5 based on NIMH-funded trials) for all of these disorders; there is not yet sufficient evidence of efficacy in pediatric patients with PTSD.

Fluoxetine has been studied more intensively than other SSRIs (for example, it was the antidepressant used in the TADS trial), and thus has the largest evidence base. For this reason, fluoxetine is often considered the first of the first-line options. Additionally, fluoxetine has a longer half-life than other antidepressants, which may make it more effective in situations where patients are likely to miss doses, and results in a lower risk of withdrawal symptoms when stopped due to “self-tapering.”

SNRIs and atypical antidepressants. Other antidepressants commonly used in pediatric patients but with far less evidence of efficacy include serotonin-norepinephrine reuptake inhibitors (SNRIs) and the atypical antidepressants bupropion and mirtazapine. The SNRI duloxetine is FDA-approved for treating GAD in children age 7 to 17, but there are no other pediatric indications for duloxetine, or for the other SNRIs.

In general, adverse effect profiles are worse for SNRIs compared to SSRIs, further limiting their utility. While there are no pediatric studies demonstrating SNRI efficacy for neuropathic pain, good data exists in adults.²⁴ Thus, an SNRI could be a reasonable option if a pediatric patient has failed prior adequate SSRI trials and also has comorbid neuropathic pain.

Continue to: Neither bupropion nor mirtazapine...

Neither bupropion nor mirtazapine have undergone rigorous testing in pediatric patients, and therefore these agents should generally be considered only once other first-line treatments have failed. Bupropion has been evaluated for attention-deficit/hyperactivity disorder (ADHD)²⁵ and for adolescent smoking cessation.²⁶ However, the evidence is weak, and bupropion is not considered a first-line option for children and adolescents.

Tricyclic antidepressants. Randomized controlled trials have demonstrated that tricyclic antidepressants (TCAs) are efficacious for treating several pediatric conditions; however, their significant side effect profile, their monitoring requirements, as well as their lethality in overdose has left them replaced by SSRIs in most cases. That said, they can be appropriate in refractory ADHD (desipramine^27,28) and refractory OCD (clomipramine is FDA-approved for this indication²⁹); they are considered a third-line treatment for enuresis.³⁰

Why did my patient stop the medication?

Common adverse effects. Although the greatest benefit of antidepressant medications compared with placebo is achieved relatively early on in treatment, it generally takes time for these benefits to accrue and become clinically apparent.^15,31 By contrast, most adverse effects of antidepressants present and are at their most severe early in treatment. The combination of early adverse effects and delayed efficacy leads many patients, families, and clinicians to discontinue medications before they have an adequate chance to work. Thus, it is imperative to provide psychoeducation before starting a medication about the typical time-course of improvement and adverse effects (Table 2).

Adverse effects of SSRIs often appear or worsen transiently during initiation of a medication, during a dose increase,³² or, theoretically, with the addition of a medication that interferes with SSRI metabolism (eg, cimetidine inhibition of cytochrome P450 2D6).³³ If families are prepared for this phenomenon and the therapeutic alliance is adequate, adverse effects can be tolerated to allow for a full medication trial. Common adverse effects of SSRIs include sleep problems (insomnia/sedation), gastrointestinal upset, sexual dysfunction, dry mouth, and hyperhidrosis. Although SSRIs differ somewhat in the frequency of these effects, as a class, they are more similar than different. Adequate psychoeducation is especially imperative in the treatment of OCD and anxiety disorders, where there is limited evidence of efficacy for any non-serotonergic antidepressants.

Serotonin-norepinephrine reuptake inhibitors are not considered first-line medications because of the reduced evidence base compared to SSRIs and their enhanced adverse effect profiles. Because SNRIs partially share a mechanism of action with SSRIs, they also share portions of the adverse effects profile. However, SNRIs have the additional adverse effect of hypertension, which is related to their noradrenergic activity. Thus, it is reasonable to obtain a baseline blood pressure before initiating an SNRI, as well as periodically after initiation and during dose increases, particularly if the patient has other risk factors for hypertension.³⁴

Continue to: Although TCAs have efficacy...

Although TCAs have efficacy in some pediatric disorders,^27-29,35 their adverse effect profile limits their use. Tricyclic antidepressants are highly anticholinergic (causing dizziness secondary to orthostatic hypotension, dry mouth, and urinary retention) and antihistaminergic (causing sedation and weight gain). Additionally, TCAs lower the seizure threshold and have adverse cardiac effects relating to their anti-alpha-1 adrenergic activity, resulting in dose-dependent increases in the QTc and cardiac toxicity in overdose that could lead to arrhythmia and death. These medications have their place, but their use requires careful informed consent, clear treatment goals, and baseline and periodic cardiac monitoring (via electrocardiogram).

Serious adverse effects. Clinicians may be hesitant to prescribe antidepressants for pediatric patients because of the potential for more serious adverse effects, including severe behavioral activation syndromes, serotonin syndrome, and emergent suicidality. However, current FDA-approved antidepressants arguably have one of the most positive risk/benefit profiles of any orally-administered medication approved for pediatric patients. Having a strong understanding of the evidence is critical to evaluating when it is appropriate to prescribe an antidepressant, how to properly monitor the patient, and how to obtain accurate informed consent.

Pediatric behavioral activation syndrome. Many clinicians report that children receiving antidepressants experience a pediatric behavioral activation syndrome, which exists along a spectrum from mild activation, increased energy, insomnia, or irritability up through more severe presentations of agitation, hyperactivity, or possibly mania. A recent meta-analysis suggested a positive association between antidepressant use and activation events on the milder end of this spectrum in pediatric patients with non-OCD anxiety disorders,¹⁶ and it is thought that compared with adolescents, younger children are more susceptible to activation adverse effects.³⁶ The likelihood of activation events has been associated with higher antidepressant plasma levels,³⁷ suggesting that dose or individual differences in metabolism may play a role. At the severe end of the spectrum, the risk of induction of mania in pediatric patients with depression or anxiety is relatively rare (<2%) and not statistically different from placebo in RCTs of pediatric participants.³⁸ Meta-analyses of larger randomized, placebo-controlled trials of adults do not support the idea that SSRIs and other second-generation antidepressants carry an increased risk of mania compared with placebo.^39,40 Children or adolescents with bona fide bipolar disorder (ie, patients who have had observed mania that meets all DSM-5 criteria) should be treated with a mood-stabilizing agent or antipsychotic if prescribed an antidepressant.⁴¹ These clear-cut cases are, however, relatively rare, and more often clinicians are confronted with ambiguous cases that include a family history of bipolar disorder along with “softer” symptoms of irritability, intrusiveness, or aggression. In these children, SSRIs may be appropriate for depressive, OCD, or anxiety symptoms, and should be strongly considered before prescribing antipsychotics or mood stabilizers, as long as initiated with proper monitoring.

Serotonin syndrome is a life-threatening condition caused by excess synaptic serotonin. It is characterized by confusion, sweating, diarrhea, hypertension, hyperthermia, and tachycardia. At its most severe, serotonin syndrome can result in seizures, arrhythmias, and death. The risk of serotonin syndrome is very low when using an SSRI as monotherapy. Risk increases with polypharmacy, particularly unexamined polypharmacy when multiple serotonergic agents are inadvertently on board. Commonly used serotonergic agents include other antidepressants, migraine medications (eg, triptans), some pain medications, and the cough suppressant dextromethorphan.

The easiest way to mitigate the risk of serotonin syndrome is to use an interaction index computer program, which can help ensure that the interacting agents are not prescribed without first discussing the risks and benefits. It is important to teach adolescents that certain recreational drugs are highly serotonergic and can cause serious interactions with antidepressants. For example, recreational use of dextrometh­orphan or 3,4-methylenedioxymethamphetamine (MDMA; commonly known as “ecstasy”) has been associated with serotonin syndrome in adolescents taking antidepressant medications.^42,43

Continue to: Suicidality

Suicidality. The black-box warning regarding a risk of emergent suicidality when starting antidepressant treatment in children is controversial.⁴⁴ The prospect that a medication intended to ameliorate depression might instead risk increasing suicidal thinking is alarming to parents and clinicians alike. To appropriately weigh and discuss the risks and benefits with families, it is important to understand the data upon which the warning is based.

In 2004, the FDA commissioned a review of 23 antidepressant trials, both published and unpublished, pooling studies across multiple indications (MDD, OCD, anxiety, and ADHD) and multiple antidepressant classes. This meta-analysis, which included nearly 4,400 pediatric patients, found a small but statistically significant increase in spontaneously-reported suicidal thoughts or actions, with a risk difference of 1% (95% confidence interval [CI], 1% to 2%).⁴⁵ These data suggest that if one treats 100 pediatric patients, 1 to 2 of them may experience short-term increases in suicidal thinking or behavior.⁴⁵ There were no differences in suicidal thinking when assessed systematically (ie, when all subjects reported symptoms of suicidal ideation on structured rating scales), and there were no completed suicides.⁴⁵ A subsequent analysis that included 27 pediatric trials suggested an even lower, although still significant, risk difference (<1%), yielding a number needed to harm (NNH) of 143.⁴⁶ Thus, with low NNT for efficacy (3 to 6) and relatively high NNH for emergent suicidal thoughts or behaviors (100 to 143), for many patients the benefits will outweigh the risks.

Figure 1, Figure 2, and Figure 3 are Cates plots that depict the absolute benefits of antidepressants compared with the risk of suicidality for pediatric patients with MDD, OCD, and anxiety disorders. Recent meta-analyses have suggested that the increased risk of suicidality in antidepressant trials is specific to studies that included children and adolescents, and is not observed in adult studies. A meta-analysis of 70 trials involving 18,526 participants suggested that the odds ratio of suicidality in trials of children and adolescents was 2.39 (95% CI, 1.31 to 4.33) compared with 0.81 (95% CI, 0.51 to 1.28) in adults.⁴⁷ Additionally, a network meta-analysis exclusively focusing on pediatric antidepressant trials in MDD reported significantly higher suicidality-related adverse events in venlafaxine trials compared with placebo, duloxetine, and several SSRIs (fluoxetine, paroxetine, and escitalopram).²⁰ These data should be interpreted with caution as differences in suicidality detected between agents is quite possibly related to differences in the method of assessment between trials, as opposed to actual differences in risk between agents.

Epidemiologic data further support the use of antidepressants in pediatric patients, showing that antidepressant use is associated with decreased teen suicide attempts and completions,⁴⁸ and the decline in prescriptions that occurred following the black-box warning was accompanied by a 14% increase in teen suicides.⁴⁹ Multiple hypotheses have been proposed to explain the pediatric clinical trial findings. One idea is that potential adverse effects of activation, or the intended effects of restoring the motivation, energy, and social engagement that is often impaired in depression, increases the likelihood of thinking about suicide or acting on thoughts. Another theory is that reporting of suicidality may be increased, rather than increased de novo suicidality itself. Antidepressants are effective for treating pediatric anxiety disorders, including social anxiety disorder,¹⁶ which could result in more willingness to report. Also, the manner in which adverse effects are generally ascertained in trials might have led to increased spontaneous reporting. In many trials, investigators ask whether participants have any adverse effects in general, and inquire about specific adverse effects only if the family answers affirmatively. Thus, the increased rate of other adverse effects associated with antidepressants (sleep problems, gastrointestinal upset, dry mouth, etc.) might trigger a specific question regarding suicidal ideation, which the child or family then may be more likely to report. Alternatively, any type of psychiatric treatment could increase an individual’s propensity to report; in adolescent psychotherapy trials, non-medicated participants have reported emergent suicidality at similar frequencies as those described in drug trials.⁵⁰ Regardless of the mechanism, the possibility of treatment-emergent suicidality is a low-frequency but serious event that necessitates careful monitoring when starting medication. Current guidelines suggest seeing children weekly for the first month after medication initiation, every 2 weeks for the following month, and monthly thereafter.⁵¹

Continue to: How long should the antidepressant be continued?

How long should the antidepressant be continued?

Many patients are concerned about how long they may be taking medication, and whether they will be taking an antidepressant “forever.” A treatment course can be broken into an acute phase, wherein remission is achieved and maintained for 6 to 8 weeks. This is followed by a continuation phase, with the goal of relapse prevention, lasting 16 to 20 weeks. The length of the last phase—the maintenance phase—depends both on the child’s history, the underlying therapeutic indication, the adverse effect burden experienced, and the family’s preferences/values. In general, for a first depressive episode, after treating for 1 year, a trial of discontinuation can be attempted with close monitoring. For a second depressive episode, we recommend 2 years of remission on antidepressant therapy before attempting discontinuation. In patients who have had 3 depressive episodes, or have had episodes of high severity, we recommend continuing antidepressant treatment indefinitely. Although much less well studied, the risk of relapse following SSRI discontinuation appears much more significant in OCD, whereas anxiety disorders and MDD have a relatively comparable risk.⁵²

In general, stopping an antidepressant should be done carefully and slowly. The speed with which a specific antidepressant can be stopped is largely related to its half-life. Agents with very long half-lives, such as fluoxetine (half-life of 5 days for the parent compound and 9 days for active metabolite), can often be stopped altogether, being “auto-tapered” by the long half-life. One might still consider a taper if the patient were taking high doses. Medications with shorter half-lives must be more carefully tapered to avoid discontinuation syndromes. Discontinuation syndromes are characterized by flu-like symptoms (nausea, myalgias, fatigue, dizziness) and worsening mood. Medications with short half-lives (eg, paroxetine and venlafaxine) have the highest potential for this syndrome in children,⁵³ and thus are used less frequently.

What to do when first-line treatments fail

When a child does not experience sufficient improvement from first-line treatments, it is crucial to determine whether they have experienced an adequate dosing, duration, and quality of medication and psychotherapy.

Adequate psychotherapy? To determine whether children are receiving adequate CBT, ask:

1. if the child receives homework from psychotherapy
2. if the parents are included in treatment
3. if therapy has involved identifying thought patterns that may be contributing to the child’s illness, and
4. if the therapist has ever exposed the child to a challenge likely to produce anxiety or distress in a supervised environment and has developed an exposure hierarchy (for conditions with primarily exposure-based therapies, such as OCD or anxiety disorders).

If a family is not receiving most of these elements in psychotherapy, this is a good indicator that they may not be receiving evidence-based CBT.

Continue to: Adequate pharmacotherapy?

Adequate pharmacotherapy? Similarly, when determining the adequacy of previous pharmacotherapy, it is critical to determine whether the child received an adequate dose of medications (at least the FDA-recommended minimum dose) for an adequate duration of time at therapeutic dosing (at least 6 weeks for MDD, 8 weeks for anxiety disorders, and 8 to 12 weeks for pediatric patients with OCD), and that the child actually took the medication regularly during that period. Patient compliance can typically be tracked through checking refill requests or intervals through the patient’s pharmacy. Ensuring proper delivery of first-line treatments is imperative because (1) the adverse effects associated with second-line treatments are often more substantial; (2) the cost in terms of time and money is considerably higher with second-line treatments, and; (3) the evidence regarding the benefits of these treatments is much less certain.

Inadequate dosing is a common reason for non-response in pediatric patients. Therapeutic dose ranges for common antidepressants are displayed in Table 1. Many clinicians underdose antidepressants for pediatric patients initially (and often throughout treatment) because they fear that the typical dose titration used in clinical trials will increase the risk of adverse effects compared with more conservative dosing. There is limited evidence to suggest that this underdosing strategy is likely to be successful; adverse effects attributable to these medications are modest, and most that are experienced early in treatment (eg, headache, increased anxiety or irritability, sleep problems, gastrointestinal upset) are self-limiting and may be coincidental rather than medication-induced. Furthermore, there is no evidence for efficacy of subtherapeutic dosing in children in the acute phase of treatment or for preventing relapse.¹⁴ Thus, from an efficacy standpoint, a medication trial has not officially begun until the therapeutic dose range is reached.

Once dosing is within the therapeutic range, however, pediatric data differs from the adult literature. In most adult psychi­atric conditions, higher doses of SSRIs within the therapeutic range are associated with an increased response rate.^14,54 In pediatrics, there are few fixed dose trials, and once within the recommended therapeutic range, minimal data supports an association between higher dosing and higher efficacy.¹⁴ In general, pediatric guidelines are silent regarding optimal dosing of SSRIs within the recommended dose range, and higher antidepressant doses often result in a more significant adverse effect burden for children. One exception is pediatric OCD, where, similar to adults, the guidelines suggest that higher dosing of SSRIs often is required to induce a therapeutic response as compared to MDD and GAD.^31,55

If a child does not respond to adequate first-line treatment (or has a treatment history that cannot be fully verified), repeating these first-line interventions carries little risk and can be quite effective. For example, 60% of adolescents with MDD who did not initially respond to an SSRI demonstrated a significant response when prescribed a second SSRI or venlafaxine (with or without CBT).⁵⁶

When pediatric patients continue to experience significantly distressing and/or debilitating symptoms (particularly in MDD) despite multiple trials of antidepressants and psychotherapy, practitioners should consider a careful referral to interventional psychiatry services, which can include the more intensive treatments of electroconvulsive therapy, repetitive transcranial magnetic stimulation, or ketamine (see Box 1). Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and under-utilized clinically in pediatric populations.

Continue to: Antidepressants in general...

Antidepressants in general, and SSRIs in particular, are the first-line pharmacotherapy for pediatric anxiety, OCD, and MDD. For PTSD, although they are a first-line treatment in adults, their efficacy has not been demonstrated in children and adolescents. Antidepressants are generally safe, well-tolerated, and effective, with low NNTs (3 to 5 for anxiety and OCD; 4 to 12 in MDD, depending on whether industry trials are included). It is important that clinicians and families be educated about possible adverse effects and their time course in order to anticipate difficulties, ensure adequate informed consent, and monitor appropriately. The black-box warning regarding treatment-emergent suicidal thoughts or behaviors must be discussed (for suggested talking points, see Box 2). The NNH is large (100 to 143), and for many patients, the benefits will outweigh the risks. For pediatric patients who fail to respond to multiple adequate trials of antidepressants and psychotherapy, referrals for interventional psychiatry consultation should be considered.

Bottom Line

Although the evidence base for prescribing antidepressants for children and adolescents is smaller compared to the adult literature, properly understanding and prescribing these agents, and explaining their risks and benefits to families, can make a major difference in patient compliance, satisfaction, and outcomes. Antidepressants (particularly selective serotonin reuptake inhibitors) are the firstline pharmacologic intervention for pediatric patients with anxiety disorders, obsessive-compulsive disorder, or major depressive disorder.

Related Resource

• Bonin L, Moreland CS. Overview of prevention and treatment for pediatric depression. https://www.uptodate.com/contents/overview-of-prevention-and-treatment-for-pediatric-depression. Last reviewed July 2019.

Drug Brand Names

Bupropion • Wellbutrin, Zyban
Cimetidine • Tagamet
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Fluvoxamine • Luvox
Imipramine • Tofranil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor
Vilazodone • Viibryd
Vortioxetine • Trintellix

Box 1

Box 2

AUSTIN, TEX. – For children and adolescents with severe, refractory atopic dermatitis, Peter A. Lio, MD, often turns to cyclosporine as his systemic treatment of choice.

Doug Brunk/MDedge News

Cyclosporine “works quickly, and it’s very reliable,” Dr. Lio said at the annual meeting of the Society for Pediatric Dermatology. “In my experience, more than 90% of patients will see significant improvement, but there are real risks, including hypertension, kidney damage, monthly blood work, tremor, hypertrichosis, gum hypertrophy, and cancer/infection risk.”

To mitigate those risks, Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago, prescribes cyclosporine for 3-6 months at a dose of 5 mg/kg per day with a cap of 300 mg per day to “to cool things down.” He then transitions patients to phototherapy or mycophenolate right away. “Those are my two favorites,” he said. “Methotrexate can also be used, but I rarely use azathioprine.

“If you do this, you avoid most of the major risks and you can put people in a remission. More than half of the time, maybe two-thirds of the time, I get them into at least a relative remission,” Dr. Lio said.

While patients are on cyclosporine, blood pressure should be monitored each week for 4 weeks, and then monthly, he said. Draws for complete blood count, liver function tests, comprehensive metabolic panel, uric acid, and lipids should be performed monthly for 3 months, then every 8 weeks, he advised. Dr. Lio typically maintains the cyclosporine for 3 months, then tapers patients off the drug.

Patients who continue to struggle for relief might try taking cyclosporine on weekends only, a concept reported by Spanish investigators in 2015 (Pediatr Dermatol 2015 32[4]:551-2). “This involves twice-daily full dosing just on Saturdays and Sundays,” Dr. Lio said. “I now have quite a few patients doing well with this approach.”

Dr. Lio disclosed having financial ties to numerous pharmaceutical companies but none related to cyclosporine.

[email protected]

AUSTIN, TEX. – For children and adolescents with severe, refractory atopic dermatitis, Peter A. Lio, MD, often turns to cyclosporine as his systemic treatment of choice.

Doug Brunk/MDedge News

Cyclosporine “works quickly, and it’s very reliable,” Dr. Lio said at the annual meeting of the Society for Pediatric Dermatology. “In my experience, more than 90% of patients will see significant improvement, but there are real risks, including hypertension, kidney damage, monthly blood work, tremor, hypertrichosis, gum hypertrophy, and cancer/infection risk.”

To mitigate those risks, Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago, prescribes cyclosporine for 3-6 months at a dose of 5 mg/kg per day with a cap of 300 mg per day to “to cool things down.” He then transitions patients to phototherapy or mycophenolate right away. “Those are my two favorites,” he said. “Methotrexate can also be used, but I rarely use azathioprine.

“If you do this, you avoid most of the major risks and you can put people in a remission. More than half of the time, maybe two-thirds of the time, I get them into at least a relative remission,” Dr. Lio said.

While patients are on cyclosporine, blood pressure should be monitored each week for 4 weeks, and then monthly, he said. Draws for complete blood count, liver function tests, comprehensive metabolic panel, uric acid, and lipids should be performed monthly for 3 months, then every 8 weeks, he advised. Dr. Lio typically maintains the cyclosporine for 3 months, then tapers patients off the drug.

Patients who continue to struggle for relief might try taking cyclosporine on weekends only, a concept reported by Spanish investigators in 2015 (Pediatr Dermatol 2015 32[4]:551-2). “This involves twice-daily full dosing just on Saturdays and Sundays,” Dr. Lio said. “I now have quite a few patients doing well with this approach.”

Dr. Lio disclosed having financial ties to numerous pharmaceutical companies but none related to cyclosporine.

[email protected]

AUSTIN, TEX. – For children and adolescents with severe, refractory atopic dermatitis, Peter A. Lio, MD, often turns to cyclosporine as his systemic treatment of choice.

Doug Brunk/MDedge News

Cyclosporine “works quickly, and it’s very reliable,” Dr. Lio said at the annual meeting of the Society for Pediatric Dermatology. “In my experience, more than 90% of patients will see significant improvement, but there are real risks, including hypertension, kidney damage, monthly blood work, tremor, hypertrichosis, gum hypertrophy, and cancer/infection risk.”

To mitigate those risks, Dr. Lio, of the departments of dermatology and pediatrics at Northwestern University, Chicago, prescribes cyclosporine for 3-6 months at a dose of 5 mg/kg per day with a cap of 300 mg per day to “to cool things down.” He then transitions patients to phototherapy or mycophenolate right away. “Those are my two favorites,” he said. “Methotrexate can also be used, but I rarely use azathioprine.

“If you do this, you avoid most of the major risks and you can put people in a remission. More than half of the time, maybe two-thirds of the time, I get them into at least a relative remission,” Dr. Lio said.

While patients are on cyclosporine, blood pressure should be monitored each week for 4 weeks, and then monthly, he said. Draws for complete blood count, liver function tests, comprehensive metabolic panel, uric acid, and lipids should be performed monthly for 3 months, then every 8 weeks, he advised. Dr. Lio typically maintains the cyclosporine for 3 months, then tapers patients off the drug.

Patients who continue to struggle for relief might try taking cyclosporine on weekends only, a concept reported by Spanish investigators in 2015 (Pediatr Dermatol 2015 32[4]:551-2). “This involves twice-daily full dosing just on Saturdays and Sundays,” Dr. Lio said. “I now have quite a few patients doing well with this approach.”

Dr. Lio disclosed having financial ties to numerous pharmaceutical companies but none related to cyclosporine.

[email protected]

BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.

Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.

When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.

Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.

At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.

Side effects included several cases of device failure, infection, and hypersensitivity reactions.

In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).

The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.

[email protected]

SOURCE: Trivisano M et al. IEC 2019, Abstract P333.

BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.

Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.

When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.

Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.

At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.

Side effects included several cases of device failure, infection, and hypersensitivity reactions.

In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).

The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.

[email protected]

SOURCE: Trivisano M et al. IEC 2019, Abstract P333.

BANGKOK – Biweekly cerliponase alfa continued to show durable and clinically important therapeutic benefit in children with neuronal ceroid lipofuscinosis type 2 (CLN2) disease at the 3-year mark in an ongoing international study, Marina Trivisano, MD, reported at the International Epilepsy Congress.

Cerliponase alfa, approved under the trade name Brineura by the Food and Drug Administration and European Commission, is a recombinant human tripeptidyl peptidase 1 designed as enzyme replacement therapy delivered by a surgically implanted intraventricular infusion device in children with this rare lysosomal storage disease, a form of Batten disease, she explained at the congress sponsored by the International League Against Epilepsy.

When both healthy parents carry one defective gene, each of their children has a one in four chance of inheriting this devastating disease that causes rapidly progressive dementia. CLN2 disease typically reveals itself when a child reaches about 3 years of age, with seizures, language delay, or loss of acquired language being the most common first indications.

Of 23 patients enrolled in the open-label study, 21 remained participants at 3 years of follow-up. The two dropouts weren’t caused by treatment-related adverse events, but rather by the formidable logistic challenges posed because the treatment – 300 mg of cerliponase alfa delivered by intraventricular infusion over a 4-hour period every 2 weeks – was available only at five medical centers located in Rome; London; New York; Hamburg, Germany; and Columbus, Ohio.

At 3 years of follow-up, 83% of patients met the primary study endpoint, defined as the absence of a 2-point or greater decline in the motor-language score on the 0-6 CLN2 Clinical Rating Scale. This was a success rate 12 times greater than in 42 historical controls. Indeed, at 3 years the cerliponase alfa–treated patients had an average CLN2 Clinical Rating Scale motor-language score 3.8 points better than the historical controls, reported Dr. Trivisano, a pediatric neurologist at Bambino Gesu Children’s Hospital in Rome.

Side effects included several cases of device failure, infection, and hypersensitivity reactions.

In an earlier report based upon 96 weeks of follow-up, the mean rate of decline in the motor-language score was 0.27 points per 48 weeks in treated patients, compared with 2.12 points in the historical controls (N Engl J Med. 2018 May 17;378[20]:1898-1907).

The study was funded by BioMarin Pharmaceutical, which markets Brineura. Dr. Trivisano was a subinvestigator in the trial.

[email protected]

SOURCE: Trivisano M et al. IEC 2019, Abstract P333.