Commentary: Treatment failure and success: a commentary on defining and treating pediatric treatment-resistant depression - reflections on Dwyer et al. (2020).

Nearly two in five youth with major depressive disorder fail to respond to first-line interventions. As such, treatment-resistant depression represents a formidable challenge for clinicians and researchers. In fact, even considering the diagnosis of treatment-resistant depression in children and adolescents requires (a) defining treatment-resistant depression and, by extension, treatment failure; (b) defining recovery; (c) understanding its developmental trajectory; and in addition to (d) understanding the evidence for treatment interventions in this population. Accumulating data suggest that treatment-resistant depression is heterogeneous and that this heterogeneity may inform interventions. Additionally, these data suggest that substantially more nuance is needed in evaluating the 'adequacy' of prior treatments whether they are psychotherapeutic or psychopharmacologic. Last, adjunctive interventions that focus on neuromodulation, glutamatergic, GABAergic, and inflammatory pathways remain poorly understood in youth with treatment-resistant depression despite very significant advances in adults with treatment-resistant depression.