Annual Research Review: Defining and treating pediatric treatment-resistant depression

Abstract

Background: Adolescent major depressive disorder (MDD) is a significant health problem, associated with substantial morbidity, cost, and mortality. Depression is a significant risk factor for suicide, which is now the second leading cause of death in young people. Up to twenty per cent of adolescents will experience MDD before adulthood, and while a substantial proportion will improve with standard-of-care treatments (psychotherapy and medication), roughly one third will not.

Methods: Here, we have reviewed the literature in order to discuss the concept of treatment-resistant depression (TRD) in adolescence, examine risk factors, diagnostic difficulties, and challenges in evaluating symptom improvement, and providing guidance on how to define adequate medication and psychotherapy treatment trials.

Results: We propose a staging model for adolescent TRD and review the treatment literature. The evidence base for first- and second-line treatments primarily derives from four large pediatric clinical trials (TADS, TORDIA, ADAPT, and IMPACT). After two medications and a trial of evidence-based psychotherapy have failed to alleviate depressive symptoms, the evidence becomes quite thin for subsequent treatments. Here, we review the evidence for the effectiveness of medication switches, medication augmentation, psychotherapy augmentation, and interventional treatments (i.e., transcranial magnetic stimulation, electroconvulsive therapy, and ketamine) for adolescent TRD. Comparisons are drawn to the adult TRD literature, and areas for future pediatric depression research are highlighted.

Conclusions: As evidence is limited for treatments in this population, a careful consideration of the known risks and side effects of escalated treatments (e.g., mood stabilizers and atypical antipsychotics) is warranted and weighed against potential, but often untested, benefits.

Keywords: Depression; major depressive disorder; psychopharmacology; psychotherapy.

Figure 1

Differences in adult and pediatric depression diagnosis. A diagnosis requires fulfilling 5 of the 9 criteria listed, and at least one must be one of the two cardinal symptoms (listed first in the figure). These cardinal criteria serve as ports of entry to the diagnosis. A key difference between adult and pediatric diagnoses is the mood symptom, where sad or depressed mood is the criterion in adults, but sad, depressed, or irritable mood meets criteria in children. The allowance of irritability effectively creates a third port of entry to this diagnosis

Figure 2

Proposed stages of treatment resistance in pediatric depression. It depicts our proposed stages of treatment resistance in pediatric depression. These are extrapolated based on similar guidelines in adult depression but adjusted for the different levels of depression in pediatric depression (Ruhe, van Rooijen, Spijker, Peeters, & Schene, 2012; Sackeim et al., 2019). Based on clinical circumstances (e.g., acute suicidality and comorbidity), practitioners may want to skip or reorder certain treatment modalities. This table is meant for illustrative purposes and is not meant as an algorithm to guide treatment decisions for individual cases. Abbreviations: ECT, electroconvulsive therapy; FDA, Food and Drug Administration; rTMS, repetitive transcranial magnetic stimulation; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor

Figure 3

TORDIA study methods and findings. (A) It depicts the principal methodology of the TORDIA trial with SSRI-resistant patients randomized to an SSRI switch with or without CBT or a switch to the SNRI, venlafaxine, with or without CBT. (B) Three major take-home points are listed here, with a more detailed description listed in the text. *Paroxetine was discontinued midway through the TORDIA trial in favor of citalopram. Abbreviations: CBT, cognitive-behavioral therapy; MDD, major depressive disorder; SNRI, selective norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TORDIA, Treatment of SSRI-Resistant Depression in Adolescents