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Effective treatment of severe or chronic unipolar depression requires the combination of pharmacological and psychotherapeutic interventions, and demands a theoretical paradigm integrating biological and psychosocial aspects of depression. Supported by recent research, we propose in our article a biopsychosocial diathesis-stress model of depression. Its basic aim is psychoeducational: to provide therapists, patients, and their environment a constructive conceptual framework to understand depressive complaints, vulnerability, and stress. The core of the model consists of the concept of psychobiological vulnerability, which is determined by risk factors—of a biogenetic, psychological, somatic, and societal nature—and by protective factors. Life events with an idiosyncratic, stress-inducing value interact with this vulnerability, triggering severe or chronic distress that affects the individual's resilience and leads to symptoms of depression. The pathogenesis of depression is symbolized by a negative downward loop, in which interactions among symptoms, vulnerability, and stressors drive the patient toward a depressive condition. Moreover, experiencing recurrent depression influences psychobiological vulnerability, the occurrence of stressors, and tremendously increases the risk of further relapse. The model stresses the self-evident integration of biological and psychological therapeutic interventions that need to focus on symptom reduction and on relapse prevention. Moreover, it offers the patient and therapist a psychoeducational context in which the individual's vulnerability and depressive symptoms can be treated. Finally, applications of the depression model as a therapeutic approach to severe depression in the phases of remoralization, symptom reduction, and relapse prevention are presented.