Behavioural Activation Therapy and Ketamine for Treatment-Resistant Depression

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: 1. Have greater reductions in depression symptoms than those who receive ketamine only 2. Have better response and remission rates than those who receive ketamine only 3. Experience better overall functioning, including mood, anxiety, quality of life, and physical activity than those who receive ketamine only 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. * All participants will undergo IV ketamine infusions administered twice weekly for three weeks. * Half of the participants in will also undergo BA therapy sessions twice weekly for three weeks. * Individuals with a sufficient treatment response after 3 weeks will proceed to undergo an additional 12 weeks of ketamine infusions (and those receiving BA therapy will continue to receive therapy for an additional 12 weeks).

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 (\