This is a randomised, quadruple‑blind, placebo‑controlled mechanistic clinical trial enrolling 90 participants (60 adults with major depressive disorder, including treatment‑resistant cases, and 30 healthy controls) at the Royal Melbourne Hospital, Australia, with recruitment from February 2026 and completion expected December 2027. Participants receive a single subcutaneous administration of ketamine 0.75 mg/kg versus placebo (0.9% saline). The primary outcome is change in habenula activity measured using ultra‑high‑field 7T MRI at baseline and 24–48 hours after dosing, designed to probe rapid neural mechanisms underlying ketamine’s antidepressant effects. Secondary outcomes assess clinical and behavioural effects using the Montgomery–Åsberg Depression Rating Scale (MADRS), QIDS‑C, Snaith–Hamilton Pleasure Scale (SHAPS), GAD‑7, and objective activity monitoring by actigraphy. The protocol includes healthy controls to facilitate mechanistic comparisons between clinical and non‑clinical neural responses. The study phase is not specified in the available data. The quadruple‑blind design and saline comparator aim to isolate drug‑specific neural changes and early clinical signal following a single subcutaneous ketamine exposure in treatment‑resistant and broader MDD populations.
The proposed intervention involves a single subcutaneous injection of ketamine (0.75 mg/kg) or a matched placebo (0.9% saline) administered to participants with difficult-to-treat depression (DTD). The intervention is delivered under double-blind conditions at the Royal Melbourne Hospital Clinical Trials Centre. The ketamine dose is administered once only and is not part of any ongoing therapeutic protocol.
The intervention is designed to investigate neural and clinical changes following ketamine administration, with a particular focus on the habenula (Hb) - a subcortical region implicated in reward processing and mood regulation. The intervention is
embedded within a case-control, pre-post imaging study framework. Participants undergo ultra-high field 7-Tesla MRI scans before and 24-48 hours after the injection to assess changes in Hb activity and connectivity. Secondary behavioural and clinical
assessments (e.g., MADRS, QIDS-C, SHAPS, GAD-7, actigraphy, and mobile sensing) will evaluate treatment response, mood, circadian regulation, and anhedonia.
This intervention is not intended as a clinical treatment but rather as a mechanism-focused investigation. Participants are fully informed that the intervention is experimental and not part of routine care. Safety monitoring includes cardiorespiratory assessment, adverse event screening, and psychiatric review before and after the injection, following established ketamine research protocol.
Single subcutaneous injection of ketamine (0.75 mg/kg) at the Royal Melbourne Hospital Clinical Trials Centre.
Single administration for neuroimaging study
Matched placebo (0.9% saline) administered subcutaneously under double-blind conditions.
0.9% saline