Clinical TrialDepressive DisordersTreatment-Resistant Depression (TRD)Major Depressive Disorder (MDD)Healthy VolunteersKetaminePlaceboNot yet recruiting

Neural Mechanisms of Ketamine Antidepressant Treatment 2.0: Exploring how ketamine affects the brain function in people with difficult-to-treat depression.

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.

Target Enrollment
90 participants
Study Type
Phase NA interventional
Design
Randomized, quadruple Blind

Detailed Description

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.

Study Arms & Interventions

Ketamine

experimental

Single subcutaneous injection of ketamine (0.75 mg/kg) at the Royal Melbourne Hospital Clinical Trials Centre.

Interventions

  • Ketamine0.75 mg/kg
    via subcutaneous• 1 doses total

    Single administration for neuroimaging study

Placebo

inactive

Matched placebo (0.9% saline) administered subcutaneously under double-blind conditions.

Interventions

  • Placebo
    via subcutaneous

    0.9% saline

Participants

Inclusion Criteria

  • Clinical Participants
  • Age 18 – 65 at the time of informed consent;
  • Meets DSM-5 criteria for major depressive disorder (MDD), with a current major depressive episode (MDE), confirmed via the MINI
  • Insufficient response to at least 2 adequate trials of antidepressant medications, as determined by study doctor;
  • Ability to provide written informed consent (including adequate intellectual capacity and fluency in the English language), as determined by the, study doctor or delegate.
  • Control Participants
  • Age 18-65;
  • Ability to provide written informed consent (including both adequate intellectual capacity and fluency in the English language) as determined by a study doctor or delegate; and
  • No diagnosis of major depressive disorder

Exclusion Criteria

  • Clinical Participants
  • Severe disturbance such that the patient would be unable to comply with study requirements
  • History or current diagnosis of a psychotic or bipolar disorder as assessed using the MINI
  • Any unstable medical condition, or medical or pharmaceutical contraindication to ketamine
  • Any history of a ketamine use disorder of any severity or moderate-to-severe substance use disorder (for other drugs) within the past 6 months
  • Contraindications to MRI
  • Control Participants (healthy controls)
  • Severe disturbances that the participant would be unable to comply with the requirements of informed consent or comply with the study protocol, as determined by a study doctor or delegate;
  • Any current or past mental health disorder diagnoses as assessed through the MINI;
  • Any unstable medical condition as determined by the study doctor that may be contraindicative to MRI (e.g., epilepsy);
  • Currently prescribed psychoactive medication;
  • Contraindications to MRI

Study Details

Locations

Unknown facility — Australia

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