The NP approaches major depressive disorder (MDD) through systematic diagnostic formulation, differential diagnosis, and evidence-based pharmacotherapy selection. DSM-5-TR requires ≥5 of 9 symptoms for ≥2 weeks, with at least one being depressed mood or anhedonia. The nine criteria (SIG E CAPS): Sleep disturbance, Interest loss (anhedonia), Guilt/worthlessness, Energy loss, Concentration impairment, Appetite/weight change, Psychomotor agitation or retardation, Suicidal ideation. The NP must differentiate MDD from bipolar depression (screen with MDQ — Mood Disorder Questionnaire — before starting antidepressants, as SSRIs can precipitate mania), persistent depressive disorder (dysthymia — depressed mood more days than not for ≥2 years), adjustment disorder with depressed mood (symptoms within 3 months of identifiable stressor, not meeting full MDD criteria), and medical causes of depression (hypothyroidism, Cushing syndrome, vitamin D deficiency, anemia, medication-induced from beta-blockers, corticosteroids, interferon). Treatment-resistant depression (TRD) is defined as failure to respond to ≥2 adequate antidepressant trials (adequate dose for ≥6-8 weeks). The STAR*D trial demonstrated that after first SSRI failure, switching classes (SNRI) or augmenting (with bupropion, lithium, or atypical antipsychotic) are evidence-based strategies. Esketamine nasal spray (Spravato) is FDA-approved for...