Primary care nurse practitioners can manage antidepressant medications in a moderate amount of patients with major depression. Standardized depression screening instruments can identify symptom severity, engage patients and families, and monitor antidepressant treatment response. Medical conditions need to be ruled out before diagnosing a patient with major depression. It is critical to screen for substance use problems, suicidal ideation, and history of mania. Major depression care management includes knowing cytochrome P450 drug-to-drug interactions, improving medication adherence, developing follow-up plans, determining need for maintenance therapies, deciding when to augment antidepressants, and consulting or referring to mental health specialists.