Major Depressive Disorder organizes day-to-day treatment around what consistently helps patients reclaim function: precise assessment, sleep/circadian repair, matched psychotherapy, and medication choices that balance evidence with tolerability and goals. Begin with differentials—thyroid, anemia, pain syndromes, sleep apnea, medications, substance use—and a function-first map of energy, attention, and role participation (school, work, caregiving). Share a formulation that patients can see themselves in; set measurable targets and timelines for change. If you’re evaluating pathways at a depression conference, you’ll find stepped algorithms that start with activation, CBT/BA/ACT or IPT, and sleep anchors (fixed wake time, morning light, evening wind-down), then add or switch medications on schedule when progress stalls. We highlight choice by phenotype (anxious distress, melancholic, atypical, seasonal, peripartum) and by constraints (weight, sexual side effects, sedation). Because rumination and avoidance keep depression sticky, we pair skills practice with values-based actions and graded exposure to roles that matter.

Implementation is choreography, not guesswork. Registries track symptoms, sleep, and function; thresholds trigger augmentation, switching, or device steps without months of drift. We emphasize safety—means safety and crisis scripts—and equity features like interpreters, extended hours, and transport/tele options so care is usable. For partial responders, we outline augmentation with bupropion, mirtazapine, lithium, or atypicals, with metabolic monitoring and deprescribing plans that keep regimens simple. For perinatal, youth, and older adults, adapt consents, doses, and supports; coordinate with obstetrics/pediatrics/primary care. Digital tools (apps/SMS) nudge sleep, activity, and homework with privacy guardrails. When medical comorbidity or SUD complicates treatment, integrate care rather than referring progress away. For device strategies, see TMS/ECT for Depression; for individual-level tailoring, pair with Precision Psychiatry.