Pediatrics

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.

BANGKOK – The current gold standard for treatment of West syndrome remains hormonal therapy with either adrenocorticotropic hormone (ACTH) or high-dose prednisone as monotherapy rather than in combination with vigabatrin, Hiroki Nariai, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).

However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.

“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.

He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.

The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).

The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.

Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.

“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.

The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.

[email protected]

BANGKOK – The current gold standard for treatment of West syndrome remains hormonal therapy with either adrenocorticotropic hormone (ACTH) or high-dose prednisone as monotherapy rather than in combination with vigabatrin, Hiroki Nariai, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).

However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.

“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.

He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.

The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).

The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.

Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.

“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.

The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.

[email protected]

BANGKOK – The current gold standard for treatment of West syndrome remains hormonal therapy with either adrenocorticotropic hormone (ACTH) or high-dose prednisone as monotherapy rather than in combination with vigabatrin, Hiroki Nariai, MD, declared at the International Epilepsy Congress.

Bruce Jancin/MDedge News

West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).

However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.

“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.

He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.

The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).

The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.

Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.

“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.

The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.

[email protected]

Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.

MarianVejcik/Getty Images

For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.

Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.

The investigators noted that vaccine deniers tended to rely on anecdotal evidence, while the deliberation that partial accepters undertook was both time consuming and difficult. This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.

“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.

The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.

[email protected]

SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.

Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.

MarianVejcik/Getty Images

For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.

Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.

The investigators noted that vaccine deniers tended to rely on anecdotal evidence, while the deliberation that partial accepters undertook was both time consuming and difficult. This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.

“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.

The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.

[email protected]

SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.

Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.

MarianVejcik/Getty Images

For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.

Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.

The investigators noted that vaccine deniers tended to rely on anecdotal evidence, while the deliberation that partial accepters undertook was both time consuming and difficult. This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.

“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.

The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.

[email protected]

SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.

Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.

“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.

But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.

Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.

Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.

For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.

Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.

Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.

A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.

As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).

The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.

A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.

The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.

SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.

When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.

michaeljung/iStock/Getty Images Plus

If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.

With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.

The Harvard article quotes Dr. Hendren as saying, “The policies that have historically invested in kids tend to be the biggest bang for the buck.” This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.

Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.

However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.

The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.

michaeljung/iStock/Getty Images Plus

If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.

With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.

The Harvard article quotes Dr. Hendren as saying, “The policies that have historically invested in kids tend to be the biggest bang for the buck.” This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.

Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.

However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.

The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.

michaeljung/iStock/Getty Images Plus

If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.

With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.

The Harvard article quotes Dr. Hendren as saying, “The policies that have historically invested in kids tend to be the biggest bang for the buck.” This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.

Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.

However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.

The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.

Steve Mann/Thinkstock

In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.

The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.

In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.

“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.

The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.

[email protected]

SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.

While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.

Steve Mann/Thinkstock

In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.

The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.

In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.

“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.

The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.

[email protected]

SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.

While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.

Steve Mann/Thinkstock

In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.

The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.

In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.

“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.

The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.

[email protected]

SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.