Major depressive disorder (MDD) is a significant global health issue with increasing prevalence, causing substantial economic and social burdens. The pathogenesis of MDD is complex and involves multiple factors, including neurotransmitter imbalances, genetic and epigenetic anomalies, neuroinflammation, and social psychological stressors. Current hypotheses include the neurotransmitter hypothesis, HPA axis dysfunction, cytokine hypothesis, neuroplasticity, and systemic influence. These hypotheses, while providing insights, do not fully explain MDD's pathophysiology. Recent research has advanced understanding of MDD's pathogenesis, identifying novel therapeutic targets and multitarget strategies. New antidepressants and non-pharmacological treatments like phototherapy and acupuncture have shown promise. MDD is characterized by symptoms such as depression, anhedonia, and cognitive impairment, and is diagnosed using criteria from the DSM-5 and ICD-10. Genetic factors, environmental stress, and comorbid conditions contribute to MDD's development. The monoamine hypothesis suggests that deficiencies in serotonin, dopamine, and norepinephrine are key factors. Research on 5-HT receptors and their roles in MDD has led to the development of new antidepressants. Neurotransmitter systems like glutamate and dopamine are also involved in MDD's pathogenesis. The HPA axis hypothesis links stress and depression, with glucocorticoids playing a role. Thyroid hormones and estrogens also influence MDD. Cytokine hypothesis suggests that proinflammatory cytokines contribute to MDD. Oxidative stress and neuroinflammation are significant factors, with astrocytes playing a crucial role in MDD's pathogenesis. Inflammasomes, such as the NLRP3 inflammasome, are involved in neuroinflammation and MDD. Targeting these pathways offers potential therapeutic strategies for MDD.Major depressive disorder (MDD) is a significant global health issue with increasing prevalence, causing substantial economic and social burdens. The pathogenesis of MDD is complex and involves multiple factors, including neurotransmitter imbalances, genetic and epigenetic anomalies, neuroinflammation, and social psychological stressors. Current hypotheses include the neurotransmitter hypothesis, HPA axis dysfunction, cytokine hypothesis, neuroplasticity, and systemic influence. These hypotheses, while providing insights, do not fully explain MDD's pathophysiology. Recent research has advanced understanding of MDD's pathogenesis, identifying novel therapeutic targets and multitarget strategies. New antidepressants and non-pharmacological treatments like phototherapy and acupuncture have shown promise. MDD is characterized by symptoms such as depression, anhedonia, and cognitive impairment, and is diagnosed using criteria from the DSM-5 and ICD-10. Genetic factors, environmental stress, and comorbid conditions contribute to MDD's development. The monoamine hypothesis suggests that deficiencies in serotonin, dopamine, and norepinephrine are key factors. Research on 5-HT receptors and their roles in MDD has led to the development of new antidepressants. Neurotransmitter systems like glutamate and dopamine are also involved in MDD's pathogenesis. The HPA axis hypothesis links stress and depression, with glucocorticoids playing a role. Thyroid hormones and estrogens also influence MDD. Cytokine hypothesis suggests that proinflammatory cytokines contribute to MDD. Oxidative stress and neuroinflammation are significant factors, with astrocytes playing a crucial role in MDD's pathogenesis. Inflammasomes, such as the NLRP3 inflammasome, are involved in neuroinflammation and MDD. Targeting these pathways offers potential therapeutic strategies for MDD.