TREATMENT-RESISTANT DEPRESSION: WHEN TO ESCALATE THERAPY AND RETHINK THE DIAGNOSIS

Abstract

Failure to achieve remission after successive antidepressant trials is a common outcome in major depressive disorder and is usually labelled treatment-resistant depression, a category that gathers heterogeneous and not always equivalent clinical situations. This critical narrative review aimed to discuss two decisions arising when the response is insufficient: when to intensify treatment and when to suspect an incorrect or incomplete diagnosis. Drawing on literature retrieved from biomedical databases and recent guidelines, it examines the conceptual limits of resistance and staging models, the need to rule out pseudoresistance arising from insufficient dose, inadequate duration and poor adherence, and diagnostic reappraisal with attention to unrecognised bipolarity, comorbidities and medical conditions that mimic depression. A scenario-based decision algorithm is proposed, and escalation strategies and rapid-acting and somatic interventions are discussed, distinguishing intranasal esketamine from intravenous racemic ketamine. We conclude that the decision to escalate is only rational after diagnosis and treatment adequacy have been reconfirmed, except in severe situations requiring rapid intervention.