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

Last updated: March 26, 2025
Sponsor: University Health Network, Toronto
Overall Status: Active - Recruiting

Phase

2

Condition

Depression (Adult And Geriatric)

Depression (Major/severe)

Mood Disorders

Treatment

Midazolam Hydrochloride

Ketamine hydrochloride

i-CBT (Internet-based Cognitive Behavioural Therapy)

Clinical Study ID

NCT06480500
21-6000
  • Ages 21-65
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Provide written, voluntary informed consent prior to study enrollment. Substitutedecision makers will not be allowed to consent to study on a potential patient'sbehalf.

  2. Male or female between the age of 21 to 65, inclusive.

  3. Meets DSM-5 criteria for Major Depressive Disorder, currently experiencing a MajorDepressive Episode (MDE) without psychotic features. Diagnosis will be confirmedusing the Mini-International Neuropsychiatric Interview (MINI) conducted by adelegated physician or trained research study staff.

  4. Must present with a moderate to severe depressive episode, as determined by theMADRS score greater than 21.

  5. Must be at risk for suicide, operationalized as a response of 'yes' to items 1 or 2on the Suicidal Ideation subscale or 'yes to any item of the Suicidal Behavioursubscale on the C-SSRS.

  6. Current MDE has inadequate response to two or more adequate first-line treatmenttrials for MDD, as per the 2016 CANMAT Depression Guidelines.

  7. Access to reliable internet for the entire study period and an internet-based device (i.e., a smartphone, laptop, desktop or tablet).

  8. Must have the ability to speak and read English. This is due to the i-CBT modulesonly being offered in English presently.

Exclusion

Exclusion Criteria:

  1. Currently has symptoms of mania or hypomania or mixed state bipolar, as determinedby the Young Mania Rating Scale (YMRS) score greater than 12.

  2. 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. Othersecondary psychiatric comorbidities (e.g. anxiety disorders, trauma relateddisorders, etc.) will not be excluded.

  3. Lifetime history of a primary psychotic disorder (including, but not limited to,schizophrenia or schizoaffective disorder).

  4. Lifetime history of ketamine use disorder.

  5. History of neurological disorders (including, but not limited to, uncontrolledseizure 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 intracerebralhemorrhage).

  6. Presence a relative or absolute contraindication to ketamine or midazolam, includinga drug allergy, stroke history, uncontrolled hypertension, low or labile bloodpressure (as defined by a baseline systolic blood pressure > 140 mmHg and/ordiastolic blood pressure > 90 mmHg), recent myocardial infarction within past 12months, cardiac arrhythmia, severe coronary artery disease, heart failure ormoderate to severe hepatic impairment (defined as a Child-Pugh score of B or C) orsevere renal impairment (glomerular filtration rate (GFR) < 45 milliliters/min).

  7. Pregnant or breastfeeding women or women who intend to get pregnant. Patients whoare sexually active must agree to use a highly effective contraceptive method.

  8. Use of prohibited concomitant medications, which includes other forms of ketamineincluding racemic ketamine and esketamine, benzodiazepines, monoamine oxidaseinhibitors, stimulants or medical cannabis of any form. All other medications willbe permitted.

  9. Currently receiving CBT or CBT-related interventions (e.g., Dialectical BehaviouralTherapy).

  10. Changes in medication or non-CBT psychotherapy one month prior to study enrollment.

Study Design

Total Participants: 110
Treatment Group(s): 3
Primary Treatment: Midazolam Hydrochloride
Phase: 2
Study Start date:
January 02, 2024
Estimated Completion Date:
June 30, 2026

Connect with a study center

  • Toronto General Hospital

    Toronto, Ontario
    Canada

    Active - Recruiting

  • Ontario Shores Centre for Mental Health Sciences

    Whitby, Ontario
    Canada

    Active - Recruiting

Not the study for you?

Let us help you find the best match. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.