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.

Meta-Analysis: Hemodynamic Responses to Sub-anesthetic Doses of Ketamine in Patients With Psychiatric Disorders

“…Reduced norepinephrine reuptake may contribute to exaggerated ketamine-induced blood pressures increases in healthy participants (39), and thus, the impact of psychiatric medications that impact noradrenergic systems should be investigated. As ketamine is increasingly being studied and used clinically in broader patient populations with refractory mental illness (23,45), influences of age, medication regimen, and medical co-morbidities on risk for cardiovascular adverse events should be revisited as more data become available.…”

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

“…Although SSRI are clearly efficacious, in the case of non-responders, a switch to an antidepressant with a different mechanism (e.g., venlafaxine) and a cognitive behavioural therapy (CBT) resulted in a higher rate of clinical response than switching to another medication without CBT (Brent et al, 2008). Nonetheless, a consistent number of adolescent patients that do not respond even after two medications treatments with CBT, can be categorized as TRD; they require diagnostic careful evaluation, clinical attention and innovative therapies (Dwyer et al, 2020). Among new therapies, several studies investigated the efficacy of ketamine in children and adolescent with TRD (Papolos et al, 2013;Dwyer et al, 2017;Cullen et al, 2018;Zarrinnegar et al, 2019).…”

Editorial: Something new – what's next for child and adolescent psychiatry?

“…Although they cannot unambiguously attribute cross-national differences in suicide rates to differences in these risk factors for suicide, their findings provide important new leads for researchers interested in understanding the causes of suicide and potential targets for suicide prevention. Dwyer, Stringaris, Brent, and Bloch (2020) highlight a problem that, unfortunately, is related to high rates of suicide in young people. Approximately 20% of adolescents will experience an episode of major depressive disorder.…”