This article integrates psychoanalytic theory with contemporary neuroscience to explore depression. It contrasts Freud’s concept of melancholia with modern models emphasizing neurotransmitter imbalances and cortical-limbic dysregulation. Bridging classical ideas and current research, it highlights neuropsychoanalysis—drawing on Mark Solms’ and Jaak Panksepp’s work on affective circuits—and employs Karl Friston’s free energy principle to view depression as a failure in predictive coding. The discussion underscores the roles of unconscious conflict, internalized aggression, and existential despair, advocating for integrative treatments that combine pharmacological, neuromodulatory, and psychodynamic interventions to recalibrate both neural circuits and maladaptive internal narratives.