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.

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.