Antianhedonic Effect of Repeated Ketamine Infusions in Patients With Treatment Resistant Depression

Introduction

Anhedonia, defined as reduced ability to experience pleasure, is a core symptom of depressive episodes that correlates with suicidality and predicts poor antidepressant outcomes. Previous research implicates dopaminergic and glutamatergic circuits in anhedonia, and mechanistic data suggest ketamine—a rapid-acting N-methyl-D-aspartate receptor (NMDAR) antagonist—may exert antidepressant and antisuicidal effects via disinhibition of glutamate transmission, AMPA receptor activation, and downstream BDNF–TrkB signalling. Human and preclinical studies provide limited and sometimes inconsistent evidence that ketamine increases dopaminergic activity in reward-related brain regions, suggesting a plausible route for an antianhedonic effect. Strzelecki and colleagues set out to examine changes in anhedonia during a course of eight intravenous ketamine infusions delivered as an add-on in patients with treatment-resistant depression (TRD). The primary aim was to assess change in anhedonia measured by the Snaith–Hamilton Pleasure Scale (SHAPS). Secondary aims were to evaluate how change in anhedonia related to overall depressive symptoms (IDS‑SR 30) and to suicidal ideation (item 18 of IDS‑SR 30). The investigators also tested whether concomitant benzodiazepine (BDZ) use moderated ketamine’s effects, hypothesising that ketamine would reduce both depressive symptoms and anhedonia and that BDZ co‑treatment would attenuate these effects.