Evidence-Based Reviews

Antidepressants for pediatric patients

Jennifer B. Dwyer, MD, PhD
Assistant Professor
Child Study Center
Department of Radiology and Biomedical Imaging
Yale University
New Haven, Connecticut

Michael H. Bloch, MD, MS
Associate Professor
Child Study Center
Department of Psychiatry
Yale University
New Haven, Connecticut

Disclosures
Dr. Bloch receives grant or research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, Neurocrine Biosciences, and Therapix Biosciences. Dr. Dwyer received support from T32- MH018268 during the preparation of this manuscript.

Optimal prescribing depends on a thorough understanding of these agents’ efficacy and safety.


 

References

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.

Characteristics of commonly used 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.

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