Inflammatory cytokines play a significant role in the development of depression, influencing brain neurocircuitry and neurotransmitter systems. Cytokines, which are crucial for brain development and function, can affect behavior by altering monoamine, glutamate, and neuropeptide systems, as well as reducing growth factors like brain-derived neurotrophic factor (BDNF). Chronic exposure to elevated cytokines and persistent neurotransmitter changes can lead to neuropsychiatric disorders and depression. Inflammatory cytokines may mediate environmental and genetic factors contributing to depression, such as childhood trauma, obesity, stress, and genetic polymorphisms. This review explores how specific gene polymorphisms and neurotransmitter systems can confer protection or vulnerability to cytokine-related depression. Potential therapeutic strategies targeting cytokine signaling or their effects on neurotransmitter systems are discussed. The role of cytokines in depression is evident in both medical illnesses and healthy individuals. Patients with idiopathic major depression often exhibit elevated levels of proinflammatory cytokines like IL-1, IL-6, and TNF-alpha. These cytokines are also associated with increased inflammation in chronic medical conditions such as cancer, autoimmune disorders, and HIV. Inflammation is linked to depression and other neuropsychiatric symptoms, and factors like stress, sleep disturbance, and gastrointestinal inflammation can contribute to this relationship. In healthy individuals, stress and the gut microbiome can influence cytokine production and inflammation, potentially leading to depression. Cytokines can access the brain through various pathways, including the blood-brain barrier and peripheral vagal nerve afferents, leading to local inflammatory responses. In the brain, cytokines can affect neurotransmitter systems, including serotonin (5-HT) and dopamine (DA), which are critical for mood regulation. Inflammatory cytokines can alter 5-HT metabolism and the function of the 5-HT transporter (5-HTT), influencing depressive symptoms. Similarly, cytokines can affect DA synthesis and function, contributing to fatigue and psychomotor slowing in depression. Exogenous cytokine administration, such as interferon-alpha, can induce depressive symptoms, highlighting the role of cytokines in behavioral changes. Genetic polymorphisms, such as those in the 5-HT transporter and IL-6 genes, may influence susceptibility to cytokine-induced depression. Understanding these mechanisms can lead to targeted therapeutic strategies for depression. Inflammatory pathways, including the metabolism of polyunsaturated fatty acids and the activity of indoleamine-2,3-dioxygenase (IDO), also play a role in cytokine-induced depression. These findings underscore the complex interplay between inflammation and depression, offering new insights into potential treatments.Inflammatory cytokines play a significant role in the development of depression, influencing brain neurocircuitry and neurotransmitter systems. Cytokines, which are crucial for brain development and function, can affect behavior by altering monoamine, glutamate, and neuropeptide systems, as well as reducing growth factors like brain-derived neurotrophic factor (BDNF). Chronic exposure to elevated cytokines and persistent neurotransmitter changes can lead to neuropsychiatric disorders and depression. Inflammatory cytokines may mediate environmental and genetic factors contributing to depression, such as childhood trauma, obesity, stress, and genetic polymorphisms. This review explores how specific gene polymorphisms and neurotransmitter systems can confer protection or vulnerability to cytokine-related depression. Potential therapeutic strategies targeting cytokine signaling or their effects on neurotransmitter systems are discussed. The role of cytokines in depression is evident in both medical illnesses and healthy individuals. Patients with idiopathic major depression often exhibit elevated levels of proinflammatory cytokines like IL-1, IL-6, and TNF-alpha. These cytokines are also associated with increased inflammation in chronic medical conditions such as cancer, autoimmune disorders, and HIV. Inflammation is linked to depression and other neuropsychiatric symptoms, and factors like stress, sleep disturbance, and gastrointestinal inflammation can contribute to this relationship. In healthy individuals, stress and the gut microbiome can influence cytokine production and inflammation, potentially leading to depression. Cytokines can access the brain through various pathways, including the blood-brain barrier and peripheral vagal nerve afferents, leading to local inflammatory responses. In the brain, cytokines can affect neurotransmitter systems, including serotonin (5-HT) and dopamine (DA), which are critical for mood regulation. Inflammatory cytokines can alter 5-HT metabolism and the function of the 5-HT transporter (5-HTT), influencing depressive symptoms. Similarly, cytokines can affect DA synthesis and function, contributing to fatigue and psychomotor slowing in depression. Exogenous cytokine administration, such as interferon-alpha, can induce depressive symptoms, highlighting the role of cytokines in behavioral changes. Genetic polymorphisms, such as those in the 5-HT transporter and IL-6 genes, may influence susceptibility to cytokine-induced depression. Understanding these mechanisms can lead to targeted therapeutic strategies for depression. Inflammatory pathways, including the metabolism of polyunsaturated fatty acids and the activity of indoleamine-2,3-dioxygenase (IDO), also play a role in cytokine-induced depression. These findings underscore the complex interplay between inflammation and depression, offering new insights into potential treatments.