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Current treatment of major depressive disorder (MDD) warrants critical reexamination. Initial treatment response rates are modest and drop dramatically after 3 months. Meanwhile, MDD is emerging as the leading cause of disease burden worldwide. We searched PubMed (up to June 2021) for randomized controlled trials comparing antidepressant combinations versus monotherapy. We discuss findings from these studies in light of current treatment guidelines for MDD. These recommend a sequence of single, six-week-long, medication trials, before trying antidepressant combinations. The result leaves one third of patients still depressed after six months of treatment. Optimizing the first three months of MDD treatment is crucial because response rates during this period are five times better than in the second three months. We propose a new, evidence-based algorithm of sequential antidepressant treatment steps, termed Accelerated Sequential Antidepressant Protocol (ASAP), that may offer better response rates than current guidelines. ASAP involves shorter duration medication trials (2–4 weeks) and earlier use of antidepressant combinations, seeking additive antidepressant effects without worsening side effects. Future research should compare ASAP to current treatment guidelines. Research is also needed on the role of rapidly acting antidepressants like ketamine for acutely ill and suicidal depressed patients.

Rethinking the medication management of major depression