A Phase 2/3 interventional study of Ketamine (0.5 mg/kg) and Behavioural Activation Therapy in Treatment Resistant Depression and Major Depressive Disorder (MDD), sponsored by The Royal's Institute of Mental Health Research. Recruiting at 1 site in Canada. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-11-09.
Sponsored by The Royal's Institute of Mental Health Research · Phase 2/3, Interventional, and Treatment
The goal of this clinical trial is to see if combining ketamine with behavioral activation (BA) therapy to treat moderate to severe treatment-resistant depression improves depressive symptoms and general functioning more than ketamine alone.
We aim to find out whether participants who receive both treatments:
Participants will be randomized to one of two groups: Arm 1) concurrent ketamine and BA therapy started from treatment initiation, or Arm 2) ketamine treatment alone.
This phase III study is a single-site, prospective, parallel-arm, randomized proof-of-concept clinical trial designed to estimate the preliminary effects of augmenting repeated IV ketamine treatment with concurrent BA therapy, in individuals experiencing moderate to severe treatment resistant depressive episode.
The overall goal of this work is to maximize and sustain the beneficial effects of ketamine through combined treatment with BA therapy. The central hypothesis is that patients treated concurrently with ketamine and BA will demonstrate preliminary evidence of benefit, reflected by greater improvement in depressive symptoms and participant-reported functional outcomes compared to those treated with ketamine alone.
Participants will be randomized to one of two groups: Arm 1) concurrent ketamine and BA therapy started from treatment initiation, or Arm 2) ketamine treatment alone. Both arms will undergo IV ketamine infusions administered twice weekly for three weeks (Induction Phase). Participants in Arm 1 will also undergo BA therapy sessions twice weekly for three weeks during the Induction Phase. Responders to Induction Phase treatment (defined as ≥50% reduction in MADRS total scores from Baseline to end of Induction Phase) will proceed to undergo an additional 12 weeks of ketamine infusions in the Maintenance and Discharge Preparation Phases (weekly for 8 weeks, then every other week for 4 weeks, respectively). Nonresponders to the Induction Phase (\<50% reduction in MADRS total scores) will cease receiving ketamine infusions. Those in Arm 2 (ketamine alone) will complete their study participation at this point. Those in Arm 1 (BA+ketamine) will proceed to undergo an additional 12 weeks of BA therapy in the Maintenance and Discharge Preparation Phases (weekly for 8 weeks, then every other week for 4 weeks).
448 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 147 are open to participants now.
This study's planned enrollment of 60 is close to the median of 59 across 372 interventional studies indexed under Depressive Disorder, Treatment-Resistant.
Browse Depressive Disorder, Treatment-Resistant studies →The Royal's Institute of Mental Health Research is the lead sponsor of 7 studies on the registry; 6 are open to participants now.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants receive IV ketamine infusions and concurrent BA therapy, both administered twice weekly for three weeks (Induction Phase). Responders to Induction Phase treatment will proceed to undergo an additional 12 weeks of ketamine infusions and BA therapy in the Maintenance and Discharge Preparation Phases (weekly for 8 weeks, then every other week for 4 weeks, respectively). Nonresponders to the Induction Phase will cease receiving ketamine infusions and will undergo an additional 12 weeks of BA therapy in the Maintenance and Discharge Preparation Phases (weekly for 8 weeks, then every other week for 4 weeks).
Drug: Ketamine (0.5 mg/kg) · Behavioral: Behavioural Activation Therapy
Participants will undergo IV ketamine infusions administered twice weekly for three weeks (Induction Phase). Responders to Induction Phase treatment will proceed to undergo an additional 12 weeks of ketamine infusions in the Maintenance and Discharge Preparation Phases (weekly for 8 weeks, then every other week for 4 weeks, respectively). Nonresponders to the Induction Phase will complete their study participation at this point.
Drug: Ketamine (0.5 mg/kg)
Drug page: Ketamine
IV ketamine will be administered under medical supervision at a fixed dose of 0.5 mg/kg infused over 40 minutes. Treatments will be administered twice weekly for three weeks during the Induction Phase (6 treatments). Participants' response to ketamine will be assessed after the Induction Phase. Those who do not meet response criteria (\<50% reduction in MADRS score) will be deemed Nonresponders and will conclude receiving ketamine at that time. Those who meet the response criteria (≥50% reduction in MADRS score) will be deemed Responders and will proceed to the Maintenance Phase. During the Maintenance Phase, ketamine treatments will be administered once weekly for 8 weeks (8 treatments), followed by once biweekly for four weeks during the Discharge Preparation Phase (2 treatments). Responders will receive a total of 16 ketamine infusions over 15 weeks.
BA therapy is a structured, primarily talk therapy that focuses on helping people with depression increase engagement in positive, meaningful activities and reduce avoidance behaviors that reinforce low mood. The BA therapy protocol will be based on the approach described by Martell et al. (2022). Therapy sessions will be delivered virtually or in person according to participant preference. Participants in Arm 1 will receive a total of 16 BA sessions at a frequency of twice weekly for 3 weeks during the Induction Phase (6 sessions), once weekly for 8 weeks during the Maintenance Phase (8 sessions), and once biweekly for 4 weeks during the Discharge Preparation Phase (2 sessions). BA therapy sessions can occur on the same day as ketamine infusions, but not during or after the infusion.
Change in MADRS from Baseline
Estimated between-group difference in change in MADRS total score from baseline (Pre-Treatment/Week 0) to the end of the Induction Phase (Post-Induction/Week 3). Additional efficacy assessment time point will include end of study (Post-Treatment/Week 15).
Time frame: Week 0 to end of Week 3 and end of Week 15
Clinically Meaningful Antidepressant Outcomes
Estimated between-group differences in clinically meaningful antidepressant outcomes, including response rate (≥50% decrease in MADRS score) and remission rate (MADRS score ≤10), assessed from baseline (Pre-Treatment/Week 0) to end of Induction Phase (Post-Induction/Week 3), with additional assessment time point at the end of study (Post-Treatment/Week 15).
Time frame: Week 0 to end of Week 3 and end of Week 15
Change in Perceived Functioning from Baseline
Estimated between-group differences in changes in participant-reported functional outcomes, including self-reported depression, anxiety, quality of life, anhedonia, physical activity, and functional disability, assessed from baseline (Pre-Treatment/Week 0) to end of Induction Phase (Post-Induction/Week 3), with additional assessment time point at the end of study (Post-Treatment/Week 15).
Time frame: Week 0 to end of Week 3 and end of Week 15
Plan to share: Yes — IPD collected and stored within the Cardio-Neuro-Mind Data Platform (CNMDP) to which data sharing consent has been provided by the individual participant.
No publications or documents are linked to this record.
Started Oct 2026 (actual). Primary completion is estimated for Sep 2029, 35 months after the start.
Start moved once since we started tracking on Sep 25, 2026: Sep 2026 → Oct 2026, on Nov 9, 2026.
Earlier changes are on the record history on ClinicalTrials.gov ↗
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Depressive Disorder, Treatment-Resistant →
The Royal's Institute of Mental Health Research