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).