The nurse managing MDD must independently perform comprehensive suicide risk assessment, implement safety interventions, manage complex medication regimens, and recognize treatment-resistant depression. Advanced neurobiology of MDD includes the stress-diathesis model: genetic vulnerability (serotonin transporter gene 5-HTTLPR short allele, BDNF Val66Met polymorphism) combined with environmental stressors activates the HPA axis, causing sustained cortisol elevation that is neurotoxic to hippocampal neurons. Neuroimaging findings in MDD include: decreased prefrontal cortex activity (impaired executive function and emotion regulation), increased amygdala reactivity (heightened negative emotional processing), decreased hippocampal volume (impaired memory and contextual processing), and disrupted default mode network connectivity (rumination). The glutamate system is increasingly recognized: NMDA receptor antagonism (ketamine mechanism) produces rapid antidepressant effects within hours, suggesting that glutamatergic dysfunction contributes to depression beyond monoamine deficiency alone. The nurse performs structured suicide risk assessment using evidence-based tools, implements graduated levels of observation, manages medication titration and switching, monitors for treatment response using validated scales (PHQ-9 trending), and coordinates the multidisciplinary treatment team including psychiatry, psychology, social work, and case management.