Adding psychotherapy to esketamine sessions for treatment-resistant depression: a small open trial

The question

Does adding structured psychotherapy to repeated esketamine sessions improve depression outcomes more than esketamine alone in people whose depression has not responded to standard treatments?

What they did

Forty-six outpatients with treatment-resistant depression received eight weekly injections of esketamine under the skin, at 0.5 to 1.0 mg per kilogram of body weight. They were assigned in sequence, not randomly, to esketamine alone (23 people) or esketamine plus ketamine-assisted psychotherapy (23 people). Depression was measured with a clinician-rated scale (MADRS) and a self-report questionnaire (BDI-II) during treatment and at follow-ups for up to six months afterwards. Everyone knew which group they were in.

What they found

Both groups improved significantly. MADRS scores were lower in the psychotherapy group at the seventh and eighth sessions (p = 0.015 and p = 0.041). At the end of treatment, response and remission rates were 52.2% and 34.8% in the esketamine-only group, versus 78.3% and 78.3% in the psychotherapy group; only the difference in remission reached statistical significance (p = 0.007). Self-reported scores suggested the psychotherapy group felt better earlier. Over the six-month follow-up, there were no significant differences between the groups.

The fine print

This was an exploratory, non-randomized, open-label trial: people were assigned in sequence rather than by chance, and both patients and staff knew who got psychotherapy, which can inflate reported benefit. With 23 people per group, the estimates are imprecise, and the identical 78.3% response and remission figures in one group reflect how few people that represents. Any early advantage faded by six months. This summary is based on the abstract only, which does not report side effects.

What it means

Pairing structured psychotherapy with esketamine sessions may speed up improvement and raise short-term remission rates in treatment-resistant depression, but the difference did not last to six months and the study design cannot prove the psychotherapy caused the benefit.

Evidence grade: Low. Open-label trial with no randomization and no placebo group, only 46 people in total, so group differences could reflect expectation or allocation effects.

This summary is based on the study’s published abstract.