Behavioural Activation Therapy and Ketamine for Treatment-Resistant Depression

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).

• Ketamine (0.5 mg/kg) (Drug): 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.
• Behavioural Activation Therapy (Behavioral): 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.

Primary outcomes

• Change in MADRS from Baseline [Week 0 to end of Week 3 and end of Week 15]: 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).

Secondary outcomes

• Clinically Meaningful Antidepressant Outcomes [Week 0 to end of Week 3 and end of Week 15]: 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).
• Change in Perceived Functioning from Baseline [Week 0 to end of Week 3 and end of Week 15]: 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).

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. English speaking
2. Age 18-65 at Screening
3. Meeting criteria for major depressive disorder (MDD), in a major depressive episode without psychotic symptoms according to the Diagnostic and Statistical Manual for Mental Disorders (DSM-5)
4. Have not responded adequately to at least two separate courses of treatment with different antidepressants, each of adequate dose and duration, in the current depressive episode
5. Currently in a moderate to severe depressive episode, with a minimum MADRS score of ≥22 at Screening
6. Be under the care of a designated health care provider (e.g., family physician or psychiatrist) to follow their care after the completion of the study
7. Willing to maintain stable doses of concomitant psychotropic medications throughout the study
8. Willing to abstain from taking prohibited medications on the days of treatment (i.e., for 12 hours prior to treatment) as per study physician instruction (e.g., benzodiazepines, cannabis)
9. Able to secure a ride/chaperone home from all ketamine infusions.

Exclusion Criteria:

1. Body mass index (BMI) ≥35
2. Depression secondary to a stroke, cancer, or other clinically significant medical illness, per study physician judgement
3. Not medically cleared to receive ketamine treatment due to presence of clinically relevant disease, per study physician judgement (e.g., uncontrolled hypertension, renal or hepatic impairment, significant coronary artery disease, vascular disease, diabetes mellitus, seizure disorder, intracerebral hemorrhage, history of cerebrovascular accident \[CVA\])
4. Pregnant, breastfeeding or of childbearing potential and unwilling to use an approved method of contraception during the study, as assessed during the Screening Visit medical clearance
5. History of a primary psychotic disorder (e.g., schizophrenia), or current or recent (<2 years) acute episode of psychosis
6. Current and/or recent history (<12 months) of substance use disorder/dependence (except for alcohol, cannabis, caffeine or nicotine) as defined by DSM-5 criteria
7. Current and/or recent history (<6 months) of cannabis use disorder as defined by DSM-5 criteria, or unable to abstain from using cannabis 12 hours before and 12 hours after each ketamine infusion
8. Current and/or recent history (<6 months) of alcohol use disorder as defined by DSM-5 criteria, or unable to abstain from using alcohol 12 hours before and 12 hours after each ketamine infusion
9. Concurrent use of ketamine or psychedelics in any form
10. A previous history or known diagnosis of major neurocognitive disorder
11. Known or suspected history of intolerance, allergy or hypersensitivity to ketamine
12. Any other condition or circumstance that, in the opinion of the QI/study physicians, would adversely affect the participant's ability to complete the study procedures or its measures
13. Concurrent psychotherapy treatment outside the clinical trial. A participant may opt to pause or terminate their current ongoing psychotherapy to participate in the study, at their own discretion.
14. Concurrent active electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS) therapy.

• Jeanne Talbot, MD, PhD, Principal investigator, The University of Ottawa Institute of Mental Health Research (IMHR) at The Royal
• Jennifer Phillips, PhD, Principal investigator, The University of Ottawa Institute of Mental Health Research (IMHR) at The Royal