Inflammation plays a critical role in depression, linking evolutionary mechanisms to modern treatment strategies. Depression, a major global health issue, is often resistant to conventional antidepressants, suggesting a need for new therapeutic approaches targeting the immune system. Recent research highlights the interaction between the immune system and neurocircuits, showing that inflammatory responses can influence depression risk and treatment outcomes. Evolutionary perspectives suggest that depressive behaviors may have provided survival advantages by enhancing immune responses to pathogens and stressors. Modern stressors, however, can trigger excessive inflammation, contributing to depression and treatment resistance. Inflammatory pathways, such as inflammasomes, are involved in stress-induced immune responses that affect the brain. Evidence shows that inflammation is linked to depressive symptoms, including anhedonia and anxiety, and that inflammatory biomarkers like CRP can predict treatment response. The immune system's role in depression is further supported by studies on cytokines, neurotransmitters, and neurocircuitry, with findings indicating that inflammation affects brain regions involved in motivation, reward, and emotional processing. Therapeutic strategies targeting inflammation, such as anti-cytokine therapies, show promise in treating depression, particularly in individuals with elevated inflammatory markers. However, the effectiveness of these treatments varies, and further research is needed to develop personalized approaches based on inflammatory biomarkers. Overall, the immune system's involvement in depression underscores the importance of integrating inflammatory mechanisms into the understanding and treatment of this complex disorder.Inflammation plays a critical role in depression, linking evolutionary mechanisms to modern treatment strategies. Depression, a major global health issue, is often resistant to conventional antidepressants, suggesting a need for new therapeutic approaches targeting the immune system. Recent research highlights the interaction between the immune system and neurocircuits, showing that inflammatory responses can influence depression risk and treatment outcomes. Evolutionary perspectives suggest that depressive behaviors may have provided survival advantages by enhancing immune responses to pathogens and stressors. Modern stressors, however, can trigger excessive inflammation, contributing to depression and treatment resistance. Inflammatory pathways, such as inflammasomes, are involved in stress-induced immune responses that affect the brain. Evidence shows that inflammation is linked to depressive symptoms, including anhedonia and anxiety, and that inflammatory biomarkers like CRP can predict treatment response. The immune system's role in depression is further supported by studies on cytokines, neurotransmitters, and neurocircuitry, with findings indicating that inflammation affects brain regions involved in motivation, reward, and emotional processing. Therapeutic strategies targeting inflammation, such as anti-cytokine therapies, show promise in treating depression, particularly in individuals with elevated inflammatory markers. However, the effectiveness of these treatments varies, and further research is needed to develop personalized approaches based on inflammatory biomarkers. Overall, the immune system's involvement in depression underscores the importance of integrating inflammatory mechanisms into the understanding and treatment of this complex disorder.