Abstract
Abstract Myocardial infarction (MI) is a leading cause of long-term morbidity and mortality, significantly impacting health-related quality of life. Post-MI depression is increasingly recognized as a critical comorbidity, associated with a 2- to 3-fold increased risk of all-cause and cardiovascular mortality. While historically viewed through an event-centered lens, contemporary evidence suggests a disease-centered framework is more accurate: the trajectory of post-MI mortality and neuropsychiatric manifestations is frequently mediated by the development of left ventricular dysfunction and chronic heart failure. The association between depression and mortality is supported by behavioral, psychosocial, and physiological factors, though biological mechanisms such as altered platelet function and inflammation represent observational associations rather than established causal pathways. Despite its prognostic significance, post-MI depression remains underdiagnosed. Despite its profound prognostic significance, post-MI depression remains a critically neglected clinical entity, often overshadowed by traditional cardiovascular risk factors. This review synthesizes the complex interplay between structural cardiac decline and neuropsychiatric manifestations, exploring the “intervention paradox” of antidepressant therapies, and emphasizing comprehensive management strategies, including the iRT-ABCDEF program and E(e)SEEDi lifestyle interventions. Addressing post-MI depression through an integrated, multidisciplinary approach offers a vital opportunity to enhance outcomes in this high-risk population.