Neuro-inflammation has gained increasing recognition as a key element of the pathophysiology of Major Depressive Disorder, yet its exact mechanisms remain elusive. This study investigated the relationship between inflammatory biomarkers and depression severity, explored how neuro-inflammation contributes to neurotransmitter dysfunction, and examined the effectiveness of anti-inflammatory treatments for optimizing depressive symptoms. A mixed-methods approach was used, including biomarker analysis, neuroimaging studies, neurotransmitter assays, and a 12-week randomized controlled trial involving 100 MDD patients and 60 healthy controls. MDD patients had significantly higher levels of inflammatory markers (IL-6, TNF-alpha, IL-1beta, CRP) than healthy controls (p<0.001), while severity of depression remarkably positively correlated with inflammation (r=0.62, p<0.001). Neurotransmitter analysis revealed impaired serotonin and dopamine levels, elevated glutamate levels, and neuroimaging confirming heightened microglial activation and reduced serotonin receptor activity in MDD patients. The RCT indicated significant symptom improvement in the two patient groups receiving treatments, especially in the case of patients treated with cytokine inhibitors (p<0.001). Findings from qualitative in-depth interviews suggested that patients both experienced a number of physical ailments believed to contribute to a mental disorder and manifested positive improvements such as boosted mood, energy, and cognitive clarity after inflammation-targeted therapies. These data provide convincing evidence for the involvement of neuro-inflammation in MDD; accordingly, the dysfunction of neurotransmitters acts to incur depression severity. Moreover, the study suggests inflammation-targeted treatments guided by biomarkers represent a increasingly fruitful area for personalized psychiatry and improved management for depression.