i-CBT and IV Ketamine for Suicidality in Treatment-Resistant Depression: A Randomized, Midazolam-Controlled Clinical Trial

NCT06480500 | Recruiting Phase 2 DMC

• 1 other identifier: 21-6000
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

Approximately four thousand Canadians die by suicide every year, and suicide is the second leading cause of death in youth and young adults (15-34 years). Most people with depression experience thoughts of suicide and many will also plan and/or attempt suicide at some time in their life. There is an urgent need for new scalable treatments that can effectively reduce suicidality in people with depression. Cognitive behavioural therapy (CBT) reduces suicidal thoughts and behaviours, and can be delivered through the internet (i-CBT) making it more accessible and scalable. However, i-CBT has not been shown to rapidly reduce suicidal thoughts and behaviours (suicidality), such as within 24 hours. IV ketamine on the other hand has been shown to rapidly reduce thoughts of suicide, but not suicidal behaviours. Therefore, combining i-CBT with IV ketamine may be more effective reducing suicidality than i-CBT treatment with a control treatment. The investigators propose a 13-week, multi-site, study that looks at how combining i-CBT and IV ketamine treatment will affect suicidality in individuals with depression who have recently experienced suicidal thoughts and/or behaviours, but have not responded to previous treatment. All 110 participants will receive a weekly session of i-CBT for 13 weeks, but half will be randomly assigned to also receive six IV ketamine treatments or six IV midazolam treatments (control treatment) over the first initial 30 days. The investigators will measure changes in suicidal thoughts and behaviours before drug treatment and at the primary endpoint (i.e.,day 30), and after 3 months (i.e. Day 91) of the starting treatment.

Conditions

Major Depressive Disorder; Suicide; Treatment Resistant Depression

Keywords

MDD; Ketamine; Internet-Based Cognitive Behavioural Therapy; Suicide

Outcome Measures

Primary Outcomes (1)

• Suicidality severity using the Columbia-Suicide Severity Rating Scale (C-SSRS)

  The CSSRS evaluates suicidal ideation and behaviour. The CSSRS evaluates suicidal ideation and behaviour. The suicidal ideation score ranges from 0 (no ideation) to 5 (active suicidal ideation with specific plan and intent). Suicidal ideation intensity score ranges from 0 (no ideation) to 25 (most severe). The presence of suicidal behaviour is rated as a binary response; the lethality of actual attempts are rated on a scale of 0 (no or very minor physical damage) to 5 (death) and the potential lethality of actual attempts are rated on a scale of 0 (behaviour not likely to result in injury) to 2 (behaviour likely to result in death despite available medical care).

  30 Days, up to 91 Days.

Secondary Outcomes (32)

• Objective Depressive Symptom Severity using the Montgomery-Asberg Depression Rating Scale (MADRS)

  Day 30, Day 91

• Subjective Depressive Symptom Severity using the McIntyre and Rosenblat Rapid Response Scale (MARRRS)

  Day 30, Day 91

• Subjective Depressive Symptom Severity using Quick Inventory for Depressive Symptomatology, Self-Report, 16-item (QIDS-SR-16)

  Day 30, Day 91

• Symptom Severity and Treatment response using the Clinical Global Impressions Scale (CGI)

  Day 30, Day 91

• Dissociative Symptom Severity using the Clinician-Administered Dissociative States Scale (CADSS), 23-item

  30 minutes Post-Infusion

Study Arms (2)

i-CBT and IV ketamine

EXPERIMENTAL

Participants will receive internet-based cognitive therapy (i-CBT) for 13 weeks. During the first 4 weeks of i-CBT, participants will also be administered 6 infusions of ketamine intravenously. The first two infusions will be dosed at 0.5 mg/kg over a period of 40 mins. For infusions 3 and 4, patients will be flexibly-dosed between 0.5 mg/kg to 0.75 mg/kg, depending on clinical response to first two infusions. For infusions 5 and 6, patients will be flexibly-dosed between 0.5-0.85 mg/kg, depending on the clinical response to the first 4 infusions.

Drug: Ketamine hydrochloride; Behavioral: i-CBT (Internet-based Cognitive Behavioural Therapy)

i-CBT and IV midazolam

ACTIVE COMPARATOR

Participants will receive internet-based cognitive therapy (i-CBT) for 13 weeks. During the first 4 weeks of i-CBT, participants will also be administered 6 infusions of midazolam intravenously. The first two infusions will be dosed at 0.02 mg/kg over a period of 40 mins. For infusions 3 and 4, patients will be flexibly-dosed between 0.02 mg/kg to 0.03 mg/kg, depending on clinical response to first two infusions. For infusions 5 and 6, patients will be flexibly-dosed between 0.02 mg/kg to 0.035 mg/kg, depending on the clinical response to the first 4 infusions.

Behavioral: i-CBT (Internet-based Cognitive Behavioural Therapy); Drug: Midazolam Hydrochloride

Interventions

Midazolam Hydrochloride DRUG

55 patients will receive midazolam hydrochloride, over six infusions, flexibly dosed between 0.02 mg/kg to 0.035 mg/kg.

i-CBT and IV midazolam

Ketamine hydrochloride DRUG

55 patients will receive ketamine hydrochloride, over six infusions, flexibly dosed between 0.5 mg/kg to 0.85 mg/kg.

i-CBT and IV ketamine

i-CBT (Internet-based Cognitive Behavioural Therapy) BEHAVIORAL

Each week for 13 weeks, participants will watch an online module that last approximately 45-50 mins each, with homework at the end of each module. Homework is submitted and reviewed by a therapist, who will provide personalized feedback before progression to the next module.

i-CBT and IV ketamine; i-CBT and IV midazolam

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patient's behalf.
• Male or female between the age of 21 to 65, inclusive.
• Meets DSM-5 criteria for Major Depressive Disorder, currently experiencing a Major Depressive Episode (MDE) without psychotic features. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study staff.
• Must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
• Must be at risk for suicide, operationalized as a response of 'yes' to items 1 or 2 on the Suicidal Ideation subscale or 'yes to any item of the Suicidal Behaviour subscale on the C-SSRS.
• Current MDE has inadequate response to two or more adequate first-line treatment trials for MDD, as per the 2016 CANMAT Depression Guidelines.
• Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet).
• Must have the ability to speak and read English. This is due to the i-CBT modules only being offered in English presently.

You may not qualify if:

• Currently has symptoms of mania or hypomania or mixed state bipolar, as determined by the Young Mania Rating Scale (YMRS) score greater than 12.
• Current symptoms of psychosis or a substance use disorder within the past 3 months. Past history of psychotic features during a mood episode will not be excluded. Other secondary psychiatric comorbidities (e.g. anxiety disorders, trauma related disorders, etc.) will not be excluded.
• Lifetime history of a primary psychotic disorder (including, but not limited to, schizophrenia or schizoaffective disorder).
• Lifetime history of ketamine use disorder.
• History of neurological disorders (including, but not limited to, uncontrolled seizure disorder, history of stroke within past 12 months, major head injuries, aneurysmal vascular disease \[including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels\], arteriovenous malformation, or intracerebral hemorrhage).
• Presence a relative or absolute contraindication to ketamine or midazolam, including a drug allergy, stroke history, uncontrolled hypertension, low or labile blood pressure (as defined by a baseline systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg), recent myocardial infarction within past 12 months, cardiac arrhythmia, severe coronary artery disease, heart failure or moderate to severe hepatic impairment (defined as a Child-Pugh score of B or C) or severe renal impairment (glomerular filtration rate (GFR) \< 45 milliliters/min).
• Pregnant or breastfeeding women or women who intend to get pregnant. Patients who are sexually active must agree to use a highly effective contraceptive method.
• Use of prohibited concomitant medications, which includes other forms of ketamine including racemic ketamine and esketamine, benzodiazepines, monoamine oxidase inhibitors, stimulants or medical cannabis of any form. All other medications will be permitted.
• Currently receiving CBT or CBT-related interventions (e.g., Dialectical Behavioural Therapy).
• Changes in medication or non-CBT psychotherapy one month prior to study enrollment.

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Ontario Shores Centre for Mental Health Sciences: collaborator

Study Sites (1)

Toronto General Hospital

Toronto, Ontario, Canada

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Suicide; Depressive Disorder, Treatment-Resistant

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Self-Injurious Behavior; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

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

Study Officials

• Rodrigo Mansur

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Simryn Selby, MSc

CONTACT

416-603-5800; simryn.selby@uhn.ca

Orly Lipsitz

CONTACT

orly.lipsitz@uhn.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2022
• First Posted: June 28, 2024
• Study Start: January 2, 2024
• Primary Completion: March 1, 2026
• Study Completion (Estimated): June 1, 2026
• Last Updated: December 5, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)