Inflammation plays a significant role in the pathophysiology of depression, with depressed patients showing elevated levels of proinflammatory cytokines, acute-phase proteins, chemokines, and adhesion molecules. Interferon-alpha treatment can induce depression in up to 50% of patients, suggesting a direct link between cytokines and depressive symptoms. Proinflammatory cytokines interact with key domains of depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and behavior. Stress, a common precipitant of depression, can promote inflammatory responses through the sympathetic and parasympathetic nervous systems. Depression may also be a behavioral byproduct of genes that promote inflammation, highlighting the complex interplay between immune responses and mental health. Evidence shows that individuals with major depression have activated inflammatory pathways, with increased levels of cytokines, acute-phase proteins, and chemokines. Inflammatory markers are associated with the severity of depressive symptoms, and genetic variants of IL-1β and TNF-α are linked to increased depression risk and reduced antidepressant response. Inflammation is evident across the adult lifespan and even in mild depressive symptoms. Recent studies indicate that abnormal IL-6 production is present in major depression across the circadian cycle. Inflammation is also linked to various medical conditions, including cardiovascular disease, cancer, and postviral infections. While some studies support the role of inflammation in depression, others have failed to find a clear association, suggesting that inflammation may contribute to some but not all cases of depression. Inflammation influences neurotransmitter function, HPA axis hormones, and CRH, which are central to depression's pathophysiology. Cytokines can access the brain through various routes, influencing brain function and behavior. Inflammatory cytokines induce a syndrome of sickness behavior with features similar to depression, including anhedonia, anorexia, and sleep disturbances. Interferon-alpha treatment in humans can induce a behavioral syndrome similar to depression, responsive to antidepressants and associated with changes in serotonin metabolism and CRH function. IFN-α also alters brain activity in regions involved in emotion regulation and reward. Stress activates proinflammatory cytokines and their signaling pathways, linking stress to depression. Stress-induced inflammation may explain reduced immune responses in stress and depression. Stress activates the sympathetic nervous system, promoting proinflammatory activation in the periphery and influencing CNS inflammation. Evolutionary perspectives suggest that depression may have evolved as a behavioral response to immune activation, aiding in energy conservation during pathogen exposure. Inflammation contributes to the pathogenesis of depression, and targeting proinflammatory cytokines may offer new treatment strategies. Antidepressants can inhibit proinflammatory cytokine production and stimulate anti-inflammatory cytokines, contributing to their therapeutic effects. Inflammatory markers are associated with treatment response in depression, and patients with non-response to antidepressants show increased inflammation. Inflammatory pathways may be a viable target for depression treatment, especially in patients withInflammation plays a significant role in the pathophysiology of depression, with depressed patients showing elevated levels of proinflammatory cytokines, acute-phase proteins, chemokines, and adhesion molecules. Interferon-alpha treatment can induce depression in up to 50% of patients, suggesting a direct link between cytokines and depressive symptoms. Proinflammatory cytokines interact with key domains of depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and behavior. Stress, a common precipitant of depression, can promote inflammatory responses through the sympathetic and parasympathetic nervous systems. Depression may also be a behavioral byproduct of genes that promote inflammation, highlighting the complex interplay between immune responses and mental health. Evidence shows that individuals with major depression have activated inflammatory pathways, with increased levels of cytokines, acute-phase proteins, and chemokines. Inflammatory markers are associated with the severity of depressive symptoms, and genetic variants of IL-1β and TNF-α are linked to increased depression risk and reduced antidepressant response. Inflammation is evident across the adult lifespan and even in mild depressive symptoms. Recent studies indicate that abnormal IL-6 production is present in major depression across the circadian cycle. Inflammation is also linked to various medical conditions, including cardiovascular disease, cancer, and postviral infections. While some studies support the role of inflammation in depression, others have failed to find a clear association, suggesting that inflammation may contribute to some but not all cases of depression. Inflammation influences neurotransmitter function, HPA axis hormones, and CRH, which are central to depression's pathophysiology. Cytokines can access the brain through various routes, influencing brain function and behavior. Inflammatory cytokines induce a syndrome of sickness behavior with features similar to depression, including anhedonia, anorexia, and sleep disturbances. Interferon-alpha treatment in humans can induce a behavioral syndrome similar to depression, responsive to antidepressants and associated with changes in serotonin metabolism and CRH function. IFN-α also alters brain activity in regions involved in emotion regulation and reward. Stress activates proinflammatory cytokines and their signaling pathways, linking stress to depression. Stress-induced inflammation may explain reduced immune responses in stress and depression. Stress activates the sympathetic nervous system, promoting proinflammatory activation in the periphery and influencing CNS inflammation. Evolutionary perspectives suggest that depression may have evolved as a behavioral response to immune activation, aiding in energy conservation during pathogen exposure. Inflammation contributes to the pathogenesis of depression, and targeting proinflammatory cytokines may offer new treatment strategies. Antidepressants can inhibit proinflammatory cytokine production and stimulate anti-inflammatory cytokines, contributing to their therapeutic effects. Inflammatory markers are associated with treatment response in depression, and patients with non-response to antidepressants show increased inflammation. Inflammatory pathways may be a viable target for depression treatment, especially in patients with