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NCT Number: NCT07088380

Ketamine Augmentation of ECT in Treatment-Resistant Depression

This is a randomized, double-blind, placebo-controlled phase 3 clinical trial evaluating the additive effect of intravenous ketamine in combination with electroconvulsive therapy (ECT) in patients with treatment-resistant major depressive disorder (MDD). The study aims to determine whether ketamine enhances the antidepressant efficacy of ECT and reduces associated cognitive side effects. Thirty hospitalized patients diagnosed with treatment-resistant MDD will be randomized to receive either ketamine or placebo (saline) during ECT sessions 2, 4, and 6. Primary outcome is the change in depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at 4 weeks.

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Key information

Conditions

Major Depressive Disorder Behavior Behavioral Symptoms Depression Depressive Disorder Depressive Disorder, Major Depressive Disorder, Treatment-Resistant Mental Disorders Mood Disorders Treatment Resistant Depression

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male and female subjects ages 18-70,
  • diagnosed with MDD (according to SCID5-CV interview)
  • treatment resistant (defined as at least 2 different antidepressant agents used without success),
  • ability to give informed consent,
  • adequacy of the score for anesthesia.

Exclusion criteria

  • Chronic neurological diseases,
  • Intellectual disability
  • Contraindications to the electroconvulsive therapy (severe aortic valve stenosis, implantable cardiac defibrillators, uncontrolled hypertension, clinically significant respiratory, renal or hepatic disease, abdominal aortic aneurysm, endocrine disorders, neuromuscular diseases, space occupying brain lesions, stroke in the last 6 months),
  • Patients with Alcohol Use Disorder or Substance Use Disorder or Substance Abuse history in the past year,
  • Pregnancy and lactation
  • Cardiovascular conditions,
  • Psychiatric Disorders,
  • Hepatic impairment,
  • Participants with a known hypersensitivity to ketamine or any of its excipients will be excluded from the study,
  • Participants with any contraindications to the use of ketamine, such as a history of severe cardiovascular conditions (e.g., uncontrolled hypertension, significant arrhythmias), intracranial hypertension, or severe liver impairment, will also be excluded to prevent potential adverse events.

Treatment and study plan

Ketamine Hydrochloride

Drug

Ketamine will be administered intravenously at a subanesthetic dose of 0.5 mg/kg after a bolus of Propofol, during ECT sessions 2, 4, and 6.

Placebo

Drug

Placebo will be administered intravenously at a subanesthetic dose of 0.5 mg/kg after a bolus of Propofol, during ECT sessions 2, 4, and 6.

Primary outcomes

  1. Mean change in depressive symptoms, as measured by MADRS scale

    Time frame: From baseline (day 0) to day 28 (7 days after the last ECT session). A follow-up assessment at Week 12 (90 days) will be included

    The primary efficacy endpoint will be assessed using the MADRS score (Montgomery-Åsberg Depression Rating Scale)

Secondary outcomes

  1. Change in Suicidal Ideation (Beck Scale for Suicide Ideation - BSSI)

    Time frame: Assessment will be performed at: baseline (day 0); Weekly during ECT treatment period (Weeks 1, 2, 3); Week 4 (1 week after last ECT session); Follow-up: Week 12 (3 months after last ECT session)

    To assess the effect of ketamine and ECT on suicidal ideation with Beck Scale for Suicide Ideation (BSSI)

  2. Change in Anxiety Symptoms (Hamilton Anxiety Rating Scale - HAM-A)

    Time frame: Assessment will be performed at: baseline (day 0); Weekly during ECT treatment period (Weeks 1, 2, 3); Week 4 (1 week after last ECT session); Follow-up: Week 12 (3 months after last ECT session)

    To evaluate the impact of ketamine and ECT on anxiety symptoms with Hamilton Anxiety Rating Scale (HAM-A)

  3. Change in Cognitive Function (Brief Assessment of Cognition in Affective Disorders - BAC-A)

    Time frame: Assessment will be performed at: baseline (day 0); Week 4 (1 week after last ECT session); Follow-up: Week 12 (3 months after last ECT session)

    To determine the cognitive effects of ketamine and ECT with Brief Assessment of Cognition in Affective Disorders (BAC-A)

  4. Change in Dissociative and Psychotic Symptoms (Clinician-Administered Dissociative States Scale - CADSS; Brief Psychiatric Rating Scale - BPRS)

    Time frame: Assessment will be performed at: Baseline (Day 0, before first ECT session); Week 1 (After ECT session 2); Week 2 (After ECT session 4); Week 3 (After ECT session 6); Week 4 (1 week after last ECT session); Follow-up: Week 12 (3 months after last ECT

    To assess the effects of ketamine and ECT on dissociative and psychotic symptoms with Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS)

  5. Change in Neurochemical Markers (Plasma Levels of Trp, 5-HT, 5-HIAA, Glutamate, Aspartate)

    Time frame: Assessment will be performed at: Baseline (Day 0, before first ECT session); Weekly during ECT treatment period (Weeks 1, 2, 3)

    To evaluate the neurochemical effects of ketamine and ECT with High-Performance Liquid Chromatography (HPLC) analysis of plasma samples. Change in plasma levels of Trp, 5-HT, 5-HIAA, glutamate, and aspartate from baseline to Week 3 will be assessed.

Study contacts

Contact information is provided by the study sponsor or research team.

Alberto AZ Zangrillo, MD

CONTACT

[email protected]

0226436154 ext. +39

Cristina CC Colombo, MD

CONTACT

[email protected]

0226435278 ext. +39

Sponsors and collaborators

Lead sponsor

Università Vita-Salute San Raffaele

Other

Registry information

Official study title

The Additive Effect of Ketamine in Combination With ElectroConvulsive Stimulation (ECS) in Major Depressive Disorder (MDD): a Translational Study

Acronym: Ketamina

Important dates

Study start
2025
Primary completion
2026
Study completion
2026
First posted
Jul 28, 2025
Registry last updated
May 11, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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