Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial

This randomized study (n=28) with patients who responded to ketamine treatment for depression (TRD) received either cognitive-behavioural therapy (CBT) or conventional treatment. There was a significant (moderate effect) on a score of depression (QIDS) that favoured the CBT group at the end of the study (14 weeks).


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.”

Authors: Samuel T. Wilkinson, Taeho G. Rhee, Jutta Joormann, Ryan Webler, Mayra Ortiz Lopez, Brandon Kitay, Madonna Fasula, Christina Elder, Lisa Fenton & Gerard Sanacora


Institutes associated with this publication

Yale University
The Yale Psychedelic Science Group was established in 2016.

Compound Details

The psychedelics given at which dose and how many times

Ketamine 50 mg | 6x

Linked Clinical Trial

Cognitive Therapy to Sustain the Antidepressant Effects of Intravenous Ketamine in Treatment-resistant Depression
The goals of this study are: 1) to investigate the efficacy of combining ketamine with intensive cognitive behavioral therapy (CBT) to sustain the antidepressant effects of ketamine; and 2) to determine ketamine's delayed effects on learning and memory, and to explore the relationship between any ketamine-induced changes in learning and memory and duration of antidepressant efficacy, with and without CBT augmentation.