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To identify strategies for managing high-acuity-depressed adults in primary care settings. Patients who do not achieve remission with initial treatment, patients at risk for suicide, and patients with co-occurring substance use disorders are specifically addressed.Scientific literature and evidence-based practice guidelines.Accurate diagnosis is best accomplished using screening instruments as an adjunct to a thorough history and assessment. The goal of interventions is remission of symptoms as opposed to a partial response. Patient preferences regarding choice of intervention must be considered. Initial pharmacotherapy must include adequate doses and a trial of adequate duration. Patients who do not respond to two medication trials are at risk for suicide and/or have a co-occurring substance use disorder may require: (a) a combination of medications coupled with psychotherapy; or (b) referral to mental health specialists to achieve the best outcomes.High-acuity patients with mental health needs will continue to be seen in primary care settings. Through educational preparation and a patient-centered focus, advanced practice nurses in primary care settings are in an optimal position to set a high standard of care for complex mental health patients.