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

Abstract

<b><i>Introduction:</i></b> Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. <b><i>Objective:</i></b> We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 <i>d</i> = 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 (<i>F</i> = 4.58; <i>p</i> = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen <i>d</i> = 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 (<i>N</i> = 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 (<i>t</i>[8] = 2.33; <i>p</i> < 0.05) whereas nonresponders did not (<i>t</i>[10] <1; <i>p</i> ns). <b><i>Conclusions:</i></b> 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.

Ketamine Assisted Psychotherapy: A Systematic Narrative Review of the Literature

“…In their subsequent 2021 randomized controlled trial, Wilkinson et al 35 administered 6 IV ketamine (0.5mg/kg over 40 min) sessions over the course of 3 weeks to 42 severely depressed patients. Of the 42 subjects, 28 (66.7%) achieved a response to ketamine as defined as a >50% improvement in depression severity by the end of the last ketamine session.…”

“… 44 While there were no reported differences in reductions of depression and anxiety scores between the single and multi-dose groups in the above studies, multiple administrations of ketamine seemed to prolong therapeutic effects and resulted in initial non-responders experiencing apparent ketamine-related benefits. 34 , 46 As ketamine non-responders are identifiable, 23 , 34 , 35 , 46 the frequency of ketamine administration during KAP treatments can be further investigated to maximize overall responsiveness.…”

“…As mentioned above, some individuals appear not to respond to ketamine administration and have been called “non-responders”. 23 , 28 , 34 , 35 , 46 It may be possible that those who do not achieve an immediate response to standard doses of ketamine may require either additional ketamine sessions, or perhaps require a higher dose, titrated to effect. 34 , 44 , 46 More investigation is necessary to understand whether individuals are genuinely “non-responders” to ketamine, or if the dosage of ketamine can be tailored to the individual to elicit a response.…”

Ketamine treatment for depression: a review

“…To date, ketamine’s utility in enhancing psychotherapy has mainly been explored in smaller studies. One open-label study of 16 patients with TRD found that psychotherapy extended ketamine’s rapid antidepressant effects, though most responders relapsed after ceasing CBT [ 67 ]. A recent follow-up study randomized 28 patients who had achieved response after six ketamine infusions to receive either CBT or treatment as usual [ 67 ].…”

“…One open-label study of 16 patients with TRD found that psychotherapy extended ketamine’s rapid antidepressant effects, though most responders relapsed after ceasing CBT [ 67 ]. A recent follow-up study randomized 28 patients who had achieved response after six ketamine infusions to receive either CBT or treatment as usual [ 67 ]. After 14 weeks of therapy, the investigators found a moderate, though not statistically significant, improvement in MADRS scores and a significant effect as measured by the Quick Inventory of Depressive Symptomatology, Self-Report 16-Item (QIDS-SR-16) in the CBT group.…”