Abstract
Intranasal esketamine has been available for treatment-resistant depression (TRD) since 2019, but the trials that led to its approval answer only some of the questions prescribers face. About 97% of trial participants had failed only one or two antidepressant classes, and patients with bipolar disorder, psychosis, obsessive–compulsive disorder, four personality disorders, moderate-to-severe substance use disorder, or recent suicidal intent were excluded, although such patients are common in practice. This review is meant as a practical guide for prescribers. We discuss the mechanism of action and its clinical implications, ideal and real-world candidates, patients with suicidal ideation, psychiatric comorbidity (including borderline personality disorder), dosing, concomitant medications, prevention and management of adverse effects, comorbid substance use disorder, treatment duration in responders and non-responders, and contraindications. Six tables summarise the drug’s characteristics, receptor pharmacology, patient selection, concomitant medications, adverse-event management and contraindications, including differences between the US and European labels. For each recommendation, we indicate whether it comes from the label, from expert consensus, or from untested practice. The evidence does not show that 84 mg is more effective than 56 mg; comorbidity has seldom predicted non-response in real-world cohorts; the standing benzodiazepine dose should be reviewed before induction; and response is often judged too early.