Nonpharmacological Augmentation of Ketamine, Neuroplasticity, and Behavioral Therapy

Morgan Hardy, MD, and William Li, MD, presented a review of evidence on the combinatorial use of cognitive behavioral therapy with ketamine to extend the durability of antidepressant response.

Hardy and Li identified the central limitation of ketamine as the brevity of its therapeutic effect—typically waning after approximately 7 days despite rapid onset. They described the metaplastic window induced by ketamine within 12 to 72 hours of infusion as a neurobiological opportunity: preclinical and clinical studies, including their own group's work at Yale and the ENDURE trial targeting patients with major depression and active suicidal ideation, have demonstrated that behavioral therapies delivered within this window produce greater and more durable antidepressant effects than ketamine alone.^1,2 As Li summarized, "if we can capture that metaplastic neuroplastic window to rewire the brain, it's going to be more efficacious for patients or it's going to last longer."

Hardy and Li identified scalability as the primary barrier to clinical implementation, noting that cognitive behavioral therapy is costly and highly variable in delivery. They described a forthcoming feasibility study at Yale pairing esketamine or transcranial magnetic stimulation with Rejoyn—currently the only FDA-cleared prescription digital therapeutic for major depressive disorder—to explore whether a commercially available digital tool could extend antidepressant response and address the scalability challenge inherent in delivering behavioral therapy at scale.

Hardy emphasized that ketamine and esketamine's phased, nondaily dosing schedule may reduce long-term adverse effects compared to chronically administered agents such as antipsychotics, and expressed hope that combining pharmacological and nonpharmacological modalities could ultimately reduce patients' dependence on ongoing pharmacotherapy.

Dr Hardy is a psychiatrist at Yale School of Medicine specializing in interventional psychiatry.

Dr Li is a third-year psychiatry resident in the research track at Yale.

References

1. Kitay BM, Murphy E, Macaluso M, et al. Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: the CBT-ENDURE randomized clinical trial study protocol. Psychiatry Res. 2023;330:115585.

2. Agnorelli C, Spriggs M, Godfrey K, et al. Neuroplasticity and psychedelics: a comprehensive examination of classic and nonclassic compounds in pre and clinical models. Neur Biobehav Rev. 2025.