Objective: Adolescent depression is a heterogeneous disorder, with a wide variety of symptoms and inconsistent treatment response, and is not completely understood. A dysregulated stress system is a consistent finding, however, and exhaustion is a consistent trait in adolescent patients. The aim of this paper is to critically assess current hypotheses in adolescent depression research and reframe causes and treatment approaches. Methods: A mixed-method approach involved a review based on publications from PubMed, Embase and PsycInfo, and two exemplary adolescent cases. Results: Both cases show a spiral of stress and exhaustion, but with a different profile of symptoms and coping mechanisms. Reframing both cases from the perspective of coping behavior, searching for the sources of experienced stress and exhaustion, showed coping similarities. This proved essential in the successful personalized treatment and recovery process. In combination with recent evidence, both cases support the functional reframing of depression as the outcome of a stress-and exhaustion-related spiralling mechanism. Conclusions: We propose to open up a symptom-based, mood-centered view to a model in which adolescent depression is framed as a consecutive failure of stress coping mechanisms and chronic exhaustion. Addressing exhaustion and coping primarily as a treatment strategy in adolescents and young adults might work in synergy with existing treatments and improve overall outcomes. This perspective warrants further investigation.