Although no consensus favors a single definition of treatment-resistant depression (TRD), a helpful working definition assumes a lack of response in adults with major depressive disorder who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode. More than two-thirds of patients treated for major depression will not achieve remission following initial therapy. Up to 35% of patients with major depressive disorder may have TRD. Patients with treatment resistance generally report more somatic symptoms than those with responsive depressive illness. Identifying true resistance is facilitated by optimizing treatment trials-titrating a drug's dosage every 2 to 3 weeks until response is achieved, the maximum dosage is reached, or adverse effects require discontinuation.