CBT Helps Sustain Esketamine

Aaron Beck developed the cognitive strategies behind this psychotherapy

Esketamine works fast. Therapy makes it last.

STUDY: Wilkinson ST et al, J Clin Psychiatry 2026;87(2):25m16285

STUDY TYPE: Randomized controlled trial

FUNDING: National Institute of Mental Health

Background

No one knows how to make esketamine and ketamine last, other than more of the medication. Cognitive behavioral therapy (CBT) showed promise in a small trial (n = 42), and that group from Yale returns here with larger confirmation.

The Study

• 93 adults with major depression and suicidal ideation, mostly inpatients, all severely ill.
• Randomized to 1) Esketamine with 16 weeks of CBT or 2) Esketamine with treatment as usual.
• Both groups received esketamine twice weekly for four weeks.
• After esketamine, the CBT group then continued with one to two therapy sessions weekly, using individual and computer-assisted sessions.

By week 18, the CBT group showed greater reductions in suicidal ideation on the Beck Scale for Suicidal Ideation (BSSI, mean difference −1.91) and depression severity on the Montgomery-Åsberg Depression Rating Scale (MADRS, mean difference −3.77). Clinician-rated suicide severity also favored CBT, but the Columbia Suicide Severity Rating Scale and actual suicide-related events did not differ between groups.

The graphic below shows how the benefits built over time, particularly for the Beck Suicidal (BSSI) and depression (MADRS) scales:

Limitations: Unblinded, difficult to compare an active treatment with treatment-as-usual.

Is this (es)Ketamine Assisted Psychotherapy?

The lead author, Sam Wilkinson, commented, “This is different than what most people conceptualize as KAP – ketamine-assisted psychotherapy, where patients engage in psychotherapy while under the acute influence of (es)ketamine.” 

Ketamine assisted therapy takes place right after the ketamine session, and incorporates therapeutic elements like mindfulness and music during while ketamine is infused. The idea is that ketamine induces transcendent states that can be capitalized on in therapy. Esketamine is less likely to induce those states, and this therapy used CBT not to build on the experience of the drug but in a more traditional mode of preventing depression.

What They Did in Therapy

• Psychoeducation
• Cognitive restructuring
• Behavioral activation
• Changing schemas
• Homework (activity logs, thought records)
• Attention to suicide and risk assessment
• Computerized sessions used the Good Days Ahead model

Practice Implications

1. Esketamine gets patients stable fast; CBT may help them stay there.
2. Learn other ways to integrate therapy and behavior change into esketamine/ketamine therapy in our print interview, and expanded Carlat Podcast interview with Kyle Greenway.