Clinical trial NCT06480500: i-CBT and IV Ketamine for Suicidality in Treatment-Resistant Depression: A Randomized, Midazolam-Controlled Clinical Trial
Official title: Integrated Internet-Based Cognitive Behavioural Therapy (i-CBT) and Intravenous Ketamine for Suicidality in Treatment-Resistant Depression: A Randomized, Midazolam-Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Major Depressive Disorder
Suicide
Treatment Resistant Depression
Keywords: MDD
Ketamine
Internet-Based Cognitive Behavioural Therapy
Suicide
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Ontario Shores Centre for Mental Health Sciences
First posted: 2024-06-28
Enrollment: 110
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. 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.
2. Male or female between the age of 21 to 65, inclusive.
3. 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.
4. Must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
5. 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.
6. Current MDE has inadequate response to two or more adequate first-line treatment trials 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 modules only being offered in English presently.

Exclusion Criteria:

1. Currently has symptoms of mania or hypomania or mixed state bipolar, as determined by 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. Other secondary psychiatric comorbidities (e.g. anxiety disorders, trauma related disorders, 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, 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).
6. 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).
7. 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.
8. 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.
9. Currently receiving CBT or CBT-related interventions (e.g., Dialectical Behavioural Therapy).
10. Changes in medication or non-CBT psychotherapy one month prior to study enrollment.

Primary outcomes:
measure: Suicidality severity using the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: 30 Days, up to 91 Days.
Secondary outcomes:
measure: Objective Depressive Symptom Severity using the Montgomery-Asberg Depression Rating Scale (MADRS)
timeFrame: Day 30, Day 91
measure: Subjective Depressive Symptom Severity using the McIntyre and Rosenblat Rapid Response Scale (MARRRS)
timeFrame: Day 30, Day 91
measure: Subjective Depressive Symptom Severity using Quick Inventory for Depressive Symptomatology, Self-Report, 16-item (QIDS-SR-16)
timeFrame: Day 30, Day 91
measure: Symptom Severity and Treatment response using the Clinical Global Impressions Scale (CGI)
timeFrame: Day 30, Day 91
measure: Dissociative Symptom Severity using the Clinician-Administered Dissociative States Scale (CADSS), 23-item
timeFrame: 30 minutes Post-Infusion
measure: Treatment-Emergent Psychiatric Symptoms using the Brief Psychiatric Rating Scale (BPRS)
timeFrame: 30 minutes Post infusion, Day 30, Day 91
measure: Treatment-Emergent Manic Symptoms using the Young Mania Rating Scale (YMRS)
timeFrame: 30 minutes Post infusion, Day 30, Day 91
measure: Mystical Type Experiences using the Mystical Experiences Questionnaire (MEQ)
timeFrame: 30 minutes Post Infusion, Day 30, Day 91
measure: Subjective Wellbeing using the World Health Organization-5 Well-Being Index (WHO-5)
timeFrame: Day 30, Day 91
measure: Impairments in Work and Activities using the World Productivity and Impairment Questionnaire (WPAI)
timeFrame: Day 30, Day 91
measure: Subjective Cognitive Impairment using the Perceived Deficits Questionnaire - Depression - 5-Item (PDQ-5-D)
timeFrame: Day 30, Day 91
measure: Cognitive Function using the Digit Symbol Substitution Test (DSST)
timeFrame: Day 30, Day 91
measure: Cognitive Processing Speed using the Trail Making Test A (TMT-A)
timeFrame: Day 30, Day 91
measure: Executing Functioning using the Trail Making Test B (TMT-B)
timeFrame: Day 30, Day 91
measure: Anxiety using the Generalized Anxiety Disorder-7 (GAD-7)
timeFrame: Day 30, Day 91
measure: Hedonic/Pleasure Capacity using the Snaith-Hamilton Pleasure Scale (SHAPS)
timeFrame: Day 30, Day 91
measure: Reaction Time using the Choice Reaction Time Identification Task (CRT)
timeFrame: Day 30, Day 91
measure: Psychomotor signs of depression using the Core Assessment of Psychomotor Change (CORE)
timeFrame: Day 30, Day 91
measure: Verbal Fluency using the FAS test
timeFrame: Day 30, Day 91
measure: Verbal Memory using the California Verbal Learning Test Second Edition (CVLT-II)
timeFrame: Day 30, Day 91
measure: Loneliness using the UCLA Loneliness Scale (UCLA)
timeFrame: Day 30, Day 91
measure: Subjective Perception of pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath using the Edmonton Symptom Assessment System Revised (ESAS-r)
timeFrame: Day 30, Day 91
measure: Symptoms of PTSD using the PTSD Checklist for DSM-5 (PCL-5)
timeFrame: Day 30, Day 91
measure: Borderline Personality Disorder Symptoms using the Borderline Symptom List (BSL-23)
timeFrame: Day 30, Day 91
measure: Sleep Quality using the The Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Day 30, Day 91
measure: Automatic negative self-schema using the Depression Implicit Association Test (Depression IAT)
timeFrame: Day 30, Day 91
measure: Depression Rumination using the The 10-item ruminative response scale (RRS-10)
timeFrame: Day 30, Day 91
measure: i-CBT engagement using number of logins per day into i-CBT platform
timeFrame: Weekly up to Day 91.
measure: i-CBT engagement using amount of time logged into the i-CBT platform.
timeFrame: Weekly up to Day 91.
measure: i-CBT engagement using time spent on each i-CBT module
timeFrame: Weekly up to Day 91.
measure: i-CBT engagement
timeFrame: Weekly up to Day 91.
measure: Addiction Potential Using the Drug Liking and Craving Questionnaire (DLCQ)
timeFrame: 30 minutes Post Infusion, at Day 30, weekly after Day 30 up to Day 91.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Whitby
country: Canada
facility: Ontario Shores Centre for Mental Health Sciences
state: Ontario
Study officials:
affiliation: University Health Network, Toronto
name: Rodrigo Mansur
role: PRINCIPAL_INVESTIGATOR
References: