Editorial: Retuning the Adolescent Brain: Esketamine and Rapid Structural Change in the rACC.

Adolescent major depressive disorder is a leading cause of disability and a major risk factor for suicide. For 30% to 50% of patients who do not achieve remission after multiple treatments, consequences are substantial. Selective serotonin-reuptake inhibitors, though first-line, often take weeks to work and many adolescents do not respond, leaving a critical treatment gap. Esketamine, an NMDA receptor antagonist, may provide faster relief than conventional antidepressants, including as a monotherapy for treatment-resistant depression, but its neural mechanisms in the developing brain are not fully understood. Understanding these mechanisms is needed to guide clinical use and targeted prevention.

Study at a glance

Abstract

Adolescent major depressive disorder (MDD) is a leading cause of disability worldwide and a major, modifiable risk factor for suicide, which remains the second leading cause of death in this age group.1 For 30% to 50% of patients who fail to achieve remission despite multiple treatment steps, the clinical and psychosocial consequences are substantial.2 Although selective serotonin-reuptake inhibitors are widely used as first-line treatments, their therapeutic effects typically require several weeks to emerge, and a substantial proportion of adolescents do not respond to an initial antidepressant trial. Together, the delayed efficacy and incomplete response contribute to a critical treatment gap during which vulnerable youth remain at elevated risk. These limitations have driven growing interest in rapid-acting interventions such as the N-methyl-D-aspartate (NMDA) receptor antagonist esketamine. Multiple pieces of evidence suggest that esketamine can produce faster symptom relief than conventional antidepressants,2 including efficacy as a monotherapy in treatment-resistant depression3; however, its neural mechanisms remain incompletely understood. A clearer understanding of how esketamine acts on the developing brain is necessary to guide clinical use and to inform more targeted prevention strategies.