The paper explores the intricate bidirectional relationship between depression and obesity, emphasizing that each condition increases the risk of the other. Shared biologic mechanisms, such as neuroinflammation, dysregulation of the hypothalamic-pituitary-adrenal axis, and dysfunction of the gut-brain axis, contribute to the co-occurrence of these conditions. In addition, the emerging social withdrawal syndrome, hikikomori, is suggested as an associated socio-behavioral factor with the comorbidity of depression and obesity. Among antidepressants, selective serotonin reuptake inhibitors and bupropion (a norepinephrine/dopamine reuptake inhibitor), but not tricyclic antidepressants, are considered pharmacotherapeutic options for the co-occurrence of depression and obesity.