Ketamine With Dialectical Behavioural Therapy (DBT) for Suicidality in Individuals With Treatment-Resistant Depression and Borderline Personality Disorder (KET-DBT) (KET-DBT)

Combining Ketamine With Dialectical Behavioural Therapy (DBT) for Suicidality in Individuals With Treatment-Resistant Depression and Borderline Personality Disorder: A Phase II Randomized, Midazolam-Controlled Clinical Trial (KET-DBT)

The goal of this clinical trial is to learn if intravenous (IV) ketamine with Dialectical Behavioural Therapy (DBT) reduces suicidal ideation in individuals with suicidality who have been diagnosed with Borderline Personality Disorder and either Major Depressive Disorder or Bipolar Disorder. The main question it aims to answer is:

Does IV ketamine and DBT produce more rapid and robust improvements in suicidal ideation (SI) severity between baseline and Day 35 compared to IV midazolam and DBT, as measured by changes in the Modified Scale for Suicidal Ideation (MSSI) scores ?

Researchers will compare six IV ketamine infusions and DBT to an active placebo (a look-alike substance that mimics some of ketamine's effects and not others) and DBT to see if IV ketamine with DBT is more effective at reducing SI severity.

Participants will:

• Complete six infusions of either IV ketamine or IV midazolam
• Take part in 6 months of DBT (includes both weekly one-on-one sessions, and group sessions, starting week 5 of the trial)
• Visit the hospital for scheduled in-person visits
• Join a call or videocall for scheduled remote visits
• Complete a variety of different mood, cognitive and behavioral assessments

Study Overview

• Status: Not yet recruiting
• Conditions: Suicidal Ideation; Major Depressive Disorder (MDD); Bipolar Disorder (BD); Bipolar Disorder I or II; Borderline Personality Disorder (BPD); Treatment-resistant Bipolar Depression; Treatment-Resistant Major Depressive Disorder
• Intervention / Treatment: Drug: Ketamine Hydrochloride; Behavioral: Dialectical Behavioral Therapy (DBT); Drug: Midazolam Hydrochloride

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Orly Lipsitz; Phone Number: 437-882-9458; Email: ket.dbt@uhn.ca
• Study Contact Backup: Name: Deep Grewal; Email: actu@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults between the age of 18 to 70, inclusive;
2. Meets criteria for BPD, as determined by clinical assessment by a psychiatrist or psychologist and confirmed by the International Personality Disorder Examination (IPDE);
3. Meets DSM-5 criteria for MDD or BD (I or II), currently experiencing a MDE without psychotic features, as diagnosed by a study psychiatrist or psychologist. Diagnosis will be confirmed using the Mini- International Neuropsychiatric Interview (MINI);
4. Current MDE must be moderate to severe, as determined by the MADRS score >20 with an inadequate response to two or more guideline-concordant treatment trials as defined by the Antidepressant Treatment History Form-Short Form (ATHF- SF);
5. No changes in pharmacotherapy for MDD/BD in the last month or changes in psychotherapy in the past month;
6. Baseline SI as shown by two consecutive MSSI scores > 10 two weeks apart.

Exclusion Criteria:

1. Past or current history of a psychotic disorder as determined by clinical assessment and MINI;
2. Current or recent (within the past 3 months) manic or hypomanic episode as determined by clinical assessment via YMRS (score > 12) and the MINI;
3. Meeting criteria for Moderate to Severe Alcohol or substance use disorders currently or within the past 3 months;
4. Lifetime history of ketamine use disorder or illicit ketamine use.
5. Acute suicide risk requiring involuntary inpatient treatment under the Mental Health Act (MHA).
6. Presence of a relative or absolute contraindication to ketamine or midazolam, including a drug allergy, lifetime history of stroke, uncontrolled hypertension (Systolic BP > 160 or Diastolic BP > 100), low or labile blood pressure (Systolic BP < 100 or Diastolic BP < 60), recent (within the past 6 months) myocardial infarction, severe coronary artery disease (ascertained through participant's medical history), or moderate to severe renal (GFR scores ≤ 44) or hepatic impairment (A Child-Pugh score of ≥ 7);
7. Currently pregnant or breastfeeding or planning on getting pregnant within the first two months of the trial or planning on getting someone else pregnant within the first two months of trial. Participants who are sexually active must agree to use a highly effective contraceptive method (please see exhaustive list in Section 3.6.1);
8. Current use of prohibited concomitant medications, including other forms of ketamine or esketamine, high dose daily benzodiazepines (greater than 4 mg lorazepam equivalent daily) or monoamine oxidase inhibitors;
9. Currently engaged (or completed within the past year) in DBT treatment. NOTE: Individuals who have received only DBT skills training in the past year will be considered eligible to participate;
10. Those engaged in other forms of psychotherapy must be willing to discontinue for the duration of the 6-month DBT intervention (standard for DBT). There should be no changes in psychotherapy 30 days prior to baseline (i.e., Screening Visit 2).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine and Dialectical Behavioural Therapy; All participants in the trial will receive DBT. DBT will begin prior to ketamine infusions and will continue for 6 months of the trial. There will be individual DBT and also group DBT that will begin in Week 5 of the trial. Participants in this arm will receive six infusions of ketamine over a month. The first two infusions will be dosed at 0.5mg/kg over a period of 40 minutes. 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, participants will be flexibly dosed between 0.5 mg/kg to 0.85 mg/kg.	Drug: Ketamine Hydrochloride; Participants in this arm will receive six ketamine hydrochloride infusions over a month, with doses ranging between 0.5 mg/kg to 0.85 mg/kg; Behavioral: Dialectical Behavioral Therapy (DBT); All participants in this trial will receive DBT over six months. Eligible participants will begin with weekly individual sessions, followed by the addition of weekly group sessions beginning in week 5 of the trial.
Placebo Comparator: Midazolam and Dialectical Behavioural Therapy; All participants in the trial will receive DBT. DBT will begin prior to midazolam infusions and will continue for 6 months of the trial. There will be individual DBT and also group DBT that will begin in Week 5 of the trial. Participants in this arm will receive six infusions of midazolam over a month. The first two infusions will be dosed at 0.02 mg/kg over a period of 40 minutes. 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, participants will be flexibly dosed between 0.2 mg/kg to 0.035 mg/kg.	Behavioral: Dialectical Behavioral Therapy (DBT); All participants in this trial will receive DBT over six months. Eligible participants will begin with weekly individual sessions, followed by the addition of weekly group sessions beginning in week 5 of the trial.; Drug: Midazolam Hydrochloride; Participants in this arm will receive six midazolam hydrochloride infusions over a month, with doses ranging between 0.02 mg/kg to 0.035 mg/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in suicidal ideation severity using the Modified Scale for Suicidal Ideation (MSSI)	The MSSI is a clinician administered scale used to assess presence or absence of suicidal ideation as well as intensity of suicidal ideation in the previous 48 hours. It consists of 18 items, with each item scored from 0 to 3. Total scores are summed and severity can be categorized as low (0-3), mild (9-20), or severe (>21).	From Baseline to Day 35 (Primary Endpoint)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in suicidal ideation severity over a longer period of time using the Modified Scale for Suicidal Ideation (MSSI)	Evaluating changes in MSSI scores between baseline and Month 6 and between baseline and Month 9. The MSSI is a clinician administered scale used to assess presence or absence of suicidal ideation as well as intensity of suicidal ideation in the previous 48 hours. It consists of 18 items, with each item scored from 0 to 3. Total scores are summed and severity can be categorized as low (0-3), mild (9-20), or severe (>21).	From Baseline to Month 6 and Month 9
Changes in suicidal behavior (SB) and self-harm (SH) using the Suicide Attempt Self-Injury Interview (SASII)	The SASII is a semi-structured interview that will measure suicidal behavior and self-harm. The SASII is used to collect details of the topography, intent, medical severity, social context, precipitating and concurrent events, and outcomes of non-suicidal self-injury and suicidal behavior during a target time period (in this trial, the target time period will be 'past 3 months').	From Baseline to Months 3, 6, and 9
Changes in suicidal behavior (SB) and self-harm (SH) using the Lifetime Suicide Attempt Self-Injury Interview (L-SASII)	The L-SASII will be administered at baseline to obtain a count of lifetime history of suicide attempts and non-suicidal self-injury.	From Baseline to Months 3, 6, and 9
Changes in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS)	The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity.	From Baseline to Day 35 (Primary Endpoint), Month 6 and Month 9
Changes in personality psychopathology evaluated using the Borderline Symptom List-23 (BSL-23)	Changes in borderline personality disorder symptom severity and general personality psychopathology will be evaluated using the BSL-23, self-report assessment. This scale assesses a list of 23 problems on a scale of 0-4.	From Baseline to Day 35 (Primary Endpoint), Month 6 and Month 9
Changes in personality psychopathology using Level of Personality Functioning Scale (LPFS)	Changes in borderline personality disorder symptom severity and general personality psychopathology will be assessed using the LPFS, an 80-item self-report assessment. Items are rated on a scale from 1 to 4, with 1 indicating "totally false, not true at all" and 4 indicating "very true".	From Baseline to Day 35 (Primary Endpoint), Month 6 and Month 9
Changes in personality psychopathology using the Symptom-Checklist-90-Revised (SCL-90-R)	Changes in borderline personality disorder symptom severity and general personality psychopathology will be assessed using the SCL-90-R, a 90-item self-report assessment.	From Baseline to Day 35 (Primary Endpoint), Month 6 and Month 9
Changes in anxiety as measured by the Generalized Anxiety Disorder-7 (GAD-7)	The GAD-7 is a brief self-report measure of generalized anxiety. It consists of 7 items rated from 0 ('not at all sure') to 3 ('nearly every day').	From Baseline to Day 35 (Primary Endpoint), Month 6 and Month 9
Safety and tolerability evaluated by Adverse Events	Safety and tolerability will be evaluated by acute and sub-acute treatment-emergent adverse events using standardized adverse effects monitoring.	Across 9 Months
Safety and tolerability measured by using the Clinician Administered Dissociative Symptom Scale (CADSS)	Safety and tolerability will be evaluated using CADSS. It is a clinician administered instrument for the measurement of present-state dissociative symptoms. It is a 27-item scale with 19 subject-rated items and 8-items scored by an observer.	Across 9 months
Safety and tolerability evaluated by the Brief Psychiatric Rating Scale - Positive Symptom Subscale (BPRS-PS)	The BPRS is a clinician-administered scale that measures positive symptoms, general psychopathology, and affective symptoms to measure psychopathology severity. The positive symptoms subscale will be administered, which measures symptoms commonly seen in psychosis, including unusual thought content, conceptual disorganization, hallucinatory behaviour, and grandiosity.	Across 9 months

Collaborators and Investigators

• Sponsor: Joshua Rosenblat
• Investigators: Principal Investigator: Joshua D. Rosenblat, MD, MSc, Toronto Western Hospital, Psychiatry

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: April 13, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Borderline Personality Disorder; ketamine; Major Depressive Disorder (MDD); Suicidality; Treatment-Resistant Depression; Bipolar Disorder (BD); Dialectical Behavioural Therapy (DBT)
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Mental Disorders; Behavioral Symptoms; Self-Injurious Behavior; Mood Disorders; Suicide; Personality Disorders; Depressive Disorder; Behavior; Suicidal Ideation; Bipolar Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Borderline Personality Disorder; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Benzazepines; Benzodiazepines; Midazolam; Ketamine
• Other Study ID Numbers: 25-5431

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No