Development of Ketamine-Assisted Cognitive Behavioral Therapy to Reduce Depression and Suicidal Ideation

Research Aims and Hypotheses: This project will develop and test Ketamine-Assisted Cognitive Behavioral Therapy (CBT-K) to reduce depression and suicidal thoughts among individuals receiving intravenous or intranasal ketamine for depression. Ketamine-based treatments (KBT) can reduce suicidal ideation within hours but benefits often fade within days or weeks. Cognitive Behavioral Therapy (CBT) helps people change unhelpful thinking patterns and engage in meaningful activities. Ketamine can briefly open a window in which the brain is more flexible and able to learn. By combining both treatments, CBT-K is designed to enhance and prolong the benefits of ketamine.

Aim 1: To work with patients, clinicians, and therapists to develop and refine a CBT-K manual that is practical, safe, and acceptable.

Aim 2: To test whether CBT-K is feasible (can be delivered successfully) and acceptable (viewed positively by participants) in a small pilot study of 20 adults receiving KBT for depression. We hypothesize that at least 80% of participants will attend most sessions and rate the program highly on satisfaction and usefulness.

Aim 3: Explore whether CBT-K reduces depression and suicidal thinking and improves coping, self-compassion, and daily functioning.

Sample: Twenty adults with major depression and suicidal thoughts starting intravenous or intranasal ketamine at the Massachusetts General Hospital (MGH) Ketamine Clinic will be enrolled. Participants will represent diverse backgrounds to ensure the therapy is relevant, inclusive, and generalizable to clinical populations.

Measures: Assessments will occur before, during, and after CBT-K. Depression will be measured using the Quick Inventory of Depressive Symptoms (QIDS-C). Suicidal ideation and behavior will be assessed with the Columbia Suicide Severity Rating Scale (C-SSRS) and the Concise Health Risk Tracking Scale (CHRT-SR). Additional questionnaires will evaluate emotion regulation, rumination, distress tolerance, self-compassion, anxiety, and daily functioning. Feasibility and acceptability will be measured using validated questionnaires, therapist fidelity ratings, and participant exit interviews.

Procedures: The study follows the NIH Stage Model for behavioral intervention development. Phase I will include focus groups and interviews with patients, therapists, and ketamine providers to refine the CBT-K manual. Phase II will pilot the revised manual in 20 participants receiving ketamine. Each participant will complete 1-2 preparation sessions before starting ketamine, focused on goal setting, mindset, and mindfulness, followed by 12-14 integration sessions within 24-48 hours after dosing. CBT-K sessions will help participants process experiences, reframe negative thoughts, and plan behavior changes during periods of enhanced neuroplasticity.

Potential Impact: CBT-K addresses a major unmet need by combining ketamine’s rapid antidepressant and anti-suicidal effects with psychotherapy to produce lasting cognitive and emotional benefits. This approach may reduce depression and suicidal thinking while improving quality of life. CBT-K can be delivered within standard care, making it scalable and accessible.

Next Steps: Findings from this pilot will refine the CBT-K manual and provide effect size estimates for a larger randomized trial. Future studies will test CBT-K against standard care and explore mechanisms of change. Ultimately, this research seeks to create an effective, accessible treatment to reduce suicide risk and support recovery in individuals with treatment-resistant depression.