Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression

Introduction

Major depressive disorder (MDD) with psychotic features carries a worse prognosis than non-psychotic MDD, with heavier symptom burden, greater relapse risk, and frequent misdiagnosis. Standard treatments endorsed in clinical guidelines prioritise combined antidepressant and antipsychotic therapy or electroconvulsive therapy (ECT), yet a subset of patients remain treatment-resistant. Ketamine and its enantiomers have emerged as rapid-acting antidepressant agents, and esketamine nasal spray has regulatory approval as an add-on in treatment-resistant depression (TRD) and certain acute indications. Nevertheless, most clinical trials exclude patients with psychotic features because of concerns that ketamine could exacerbate psychosis; consequently, evidence on safety and efficacy in psychotic MDD is limited. Siwek and colleagues set out to contribute data on the safety and tolerability of intravenous ketamine as an add-on to standard of care in psychotic TRD. The paper reports four hospitalised patients with MDD and psychotic features drawn from a naturalistic observational registry at a tertiary mood disorders unit (NCT04226963), describing clinical course during a standardised course of ketamine infusions and short- to longer-term follow-up. The authors frame the report as addressing a gap in the literature on whether ketamine precipitates psychotic worsening and on its antidepressant and antisuicidal effects in this subgroup.