Combined Ketamine and Cognitive-Behavioral Therapy: Leveraging Metaplasticity to Enhance Treatment Outcomes
FOCUS The Journal of Lifelong Learning in Psychiatry July 1, 2026 Morgan S. Hardy, S. William Li, Samuel T. Wilkinson
Ketamine, a rapid-acting antidepressant for treatment-resistant depression, works by blocking NMDA glutamate receptors and inducing a temporary state of enhanced neuroplasticity and metaplasticity—the brain's increased capacity for future plastic changes. This creates a posttreatment window of heightened cognitive flexibility, making patients more responsive to other interventions. Combining ketamine with cognitive-behavioral therapy (CBT) may leverage these neurobiological changes to produce a more durable antidepressant effect and reduce relapse. This differs from ketamine-assisted psychotherapy, which emphasizes the drug's consciousness-altering experience. Early studies show promise, but evidence is limited and optimal timing and structure remain undefined. The review summarizes the theoretical rationale and emerging evidence for integrating ketamine or esketamine with cognitive therapies, evaluates recent clinical trials, and proposes a framework for interventional psychiatrists.