Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial
In a proof-of-concept randomised sequential trial in treatment‑resistant depression, responders to six ketamine infusions were randomised to 14 weeks of CBT versus treatment‑as‑usual and CBT showed a significant group-by-time advantage on self-report depressive symptoms (QIDS; moderate-to-large Cohen d ≈ 0.71), while the primary clinician-rated outcome (MADRS) showed a non-significant moderate effect (d = 0.65). A subset analysis also found improved accuracy on an emotional N‑back task among ketamine responders.
Authors
- Gerard Sanacora
- Scott Wilkinson
Published
Abstract
Introduction
Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure.
Objective
We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD).
Methods
Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model.
Results
Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI –0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI –0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] <1; p ns).
Conclusions
This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.
Research Summary of 'Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial'
Introduction
Wilkinson and colleagues frame the study against the backdrop of ketamine's emergence as a rapid-acting antidepressant and the practical and safety concerns surrounding long-term ketamine/esketamine maintenance. The introduction notes that maintenance regimens can be time-consuming, costly, and disruptive, and that although one-year safety data exist for esketamine, concerns about abuse liability and other adverse outcomes remain. The authors highlight evidence that ketamine enhances synaptic neuroplasticity and may rapidly improve cognitive flexibility, suggesting a time-limited window in which psychotherapeutic interventions could be more effective. Building on this rationale, the investigators tested whether cognitive behavioural therapy (CBT) delivered after a course of intravenous ketamine could sustain antidepressant benefit in treatment-resistant depression (TRD). Using a sequential treatment model, they conducted a proof-of-concept randomised trial to evaluate feasibility and efficacy, hypothesising that CBT would improve longer-term outcomes following ketamine by leveraging ketamine-induced increases in neuroplasticity and cognitive control.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Wilkinson, S. T., Rhee, T. G., Joormann, J., Webler, R., Ortiz Lopez, M., Kitay, B., Fasula, M., Elder, C., Fenton, L., & Sanacora, G. (2021). Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. Psychotherapy and Psychosomatics, 90(5), 318-327. https://doi.org/10.1159/000517074
References (5)
Papers cited by this study that are also in Blossom
Murrough, J. W., Perez, A. M., Pillemer, S. et al. · Biological Psychiatry (2012)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Girgenti, M. J., Ghosal, S., Lopresto, D. et al. · Neurobiology of Disease (2017)
Wilkinson, S. T., Katz, R. B., Toprak, M. et al. · Journal of Clinical Psychiatry (2018)
Zarate, C. A., Brutsche, N. E., Ibrahim, L. et al. · Biological Psychiatry (2012)
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Earleywine, M., Falabella, G. S., Oliva, A. B. et al. · Journal of Psychoactive Drugs (2024)
Aepfelbacher, J., Panny, B., Price, R. · Biological Psychiatry (2024)
Zavaliangos-Petropulu, A., Mcclintock, S. M., Khalil, J. et al. · Journal of Affective Disorders (2023)
Chmielewska, Z., Jakuszkowiak-Wojten, K., Wiglusz, M. S. et al. · Brain Sciences (2023)
Price, R. B., Spotts, C., Panny, B. et al. · American Journal of Psychiatry (2022)
Cavarra, M., Falzone, A., Ramaekers, J. G. et al. · Frontiers in Psychology (2022)
Grabski, M., McAndrew, A., Lawn, W. et al. · American Journal of Psychiatry (2022)
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