A Study Comparing Oral Ketamine With Oral Midazolam for the Treatment of Major Depressive Episodes

NCT07839338 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: JIP-IECIS-6/0826/89
• Study Type: interventional
• Target: 220
• Locations: 1 country
• Sites: 5

Brief Summary

Patients with depression are acutely distressed, often suicidal, and unable to meet the demands of everyday life. If proven effective in a rigorously conducted multicenter randomized controlled trial (RCT), oral ketamine would provide an affordable and scalable, intervention suitable for integration into routine psychiatric services.This study will establish an indigenous, cost-effective therapeutic strategy that could improve accessibility, hasten therapeutic response, and inform treatment guidelines, if found to be safe and effective.

Conditions

Major Depressive Episode

Keywords

oral ketamine; major depressive episodes; oral midazolam

Outcome Measures

Primary Outcomes (1)

• Hamilton Depression Rating Scale (HAM-D)

  Endpoint HAM-D scores. Minimum 0 and maximum 52. Higher scores denote worse outcomes.

  End of study week 3 (±2 days)

Secondary Outcomes (7)

• Hamilton Depression Rating Scale (HAM-D)

  Study day 2 (± 1 day), day 7 (± 1 day), and the end of study weeks 2 (± 1 day) and week 4 (±2 days)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)

• Patient Health Questionnaire (PHQ)-9

  End of study day 2 (± 1 day), day 7 (± 1 day), end of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)

• Hamilton Depression Rating Scale (HAM-D)/Montgomery-Asberg Depression Rating Scale (MADRS)

  End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)

• Visual Analogue Scale for self-rated functioning & quality of life

  End of study week 2 (±1 day), week 3 (± 2 days), and week 4 (± 2 days)

Study Arms (2)

Oral midazolam

PLACEBO COMPARATOR

The comparator arm will receive flexibly-dosed oral midazolam (5-7.5mg across all nine sessions, guided based on psychophysiological response to preserve the integrity of blinding), which will also be administered in approximately 200 mL of water, and sipped across 20-30 minutes

Drug: Oral midazolam

Oral ketamine

EXPERIMENTAL

In the first session, oral ketamine will be administered as a fixed 150 mg dose diluted in approximately 200 mL water and sipped across 20-30 minutes. In sessions 2-9 for oral ketamine, the dose will be lowered to 100-125mg in those who do not tolerate 150mg. If patients tolerate the first session well, the dose of ketamine will be increased to 175mg in the second session. If there is a negligible benefit and the intervention is tolerated, the dose of ketamine will be increased to 200 mg in the third session. Further increase in ketamine will be done in the last week to 250mg, if deemed necessary, due to suboptimal response. Participants will remain nil per oral from one hour before until two hours after each session. Blood pressure and pulse rate will be monitored every 15 minutes for one hour or until normalization. Benzodiazepines such as clonazepam will be permitted for anxiety or agitation

Drug: Oral ketamine

Interventions

Oral ketamine DRUG

Nine sessions of oral ketamine

Oral ketamine

Oral midazolam DRUG

Nine sessions of oral midazolam

Oral midazolam

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Consenting adult outpatients or inpatients with at least moderately severe major depressive episode (MDE), denoted by HAM- D more than or equal to 20, associated with major depressive disorder or bipolar disorder, with diagnosis confirmed using a structured diagnostic interview.

You may not qualify if:

• Patients with co-morbid obsessive-compulsive disorder or intellectual disability disorder or co-morbid substance dependence other than nicotine or patients concurrently receiving neuromodulation treatments or those with psychotic symptoms. Patients with current or ongoing suicide risk, such as active suicidal ideation with a specific plan or some intent in the last 3 days, will be excluded if they are treated as outpatients. Patients in whom, in the subjective opinion of the PI, the MDE symptoms appear to be significantly driven by acute life events or circumstances. Patients with abnormalities of concern detected in the electrocardiogram, or with uncontrolled hypertension or those with ongoing pregnancy or lactation

Sponsors & Collaborators

• Jawaharlal Institute of Postgraduate Medical Education & Research: lead
• Indian Council of Medical Research: collaborator

Study Sites (5)

NIMHANS

Bangalore, Karnataka, India

Location

Kasturba Medical College

Udupi, Karnataka, India

Location

MGM Medical College, Mumbai

Mumbai, Maharashtra, India

Location

AIIMS, Bhubaneswar

Bhubaneswar, Odisha, India

Location

Jawaharlal Institute of Postgraduate Medical Education and Research

Puducherry, Puducherry, India

Location

Related Publications (3)

• Kaur S, Parmar C, Gaur V, Chauhan A, Andrade C. The efficacy of oral ketamine in severely depressed patients at high risk of suicide. Asian J Psychiatr. 2023 Aug;86:103678. doi: 10.1016/j.ajp.2023.103678. Epub 2023 Jun 12.

  PMID: 37352755 BACKGROUND

• Kumar PS, Menon V, Andrade C. A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression. Asian J Psychiatr. 2024 Sep;99:104171. doi: 10.1016/j.ajp.2024.104171. Epub 2024 Jul 23.

  PMID: 39068714 BACKGROUND

• Silberbauer LR, Eggerstorfer B, Michenthaler P, Reichel S, Stimpfl T, Vanicek T, Naderi-Heiden A, Kasper S, Lanzenberger R, Gryglewski G. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. J Affect Disord. 2026 Feb 1;394(Pt A):120466. doi: 10.1016/j.jad.2025.120466. Epub 2025 Oct 14.

  PMID: 41101490 BACKGROUND

MeSH Terms

Interventions

Ketamine; Midazolam

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Central Study Contacts

Vikas Menon, MD

CONTACT

+91 8098158528; drvmenon@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: September 18, 2026
• First Posted: September 24, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): October 1, 2029
• Study Completion (Estimated): October 1, 2029
• Last Updated: October 1, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

IN (5)