Esketamine plus a thinking-skills therapy in treatment-resistant depression: 6-month study

The question

In people whose depression has not responded to previous treatments, how do symptoms and repetitive negative thinking change over six months with nasal esketamine, with a depression-specific metacognitive training programme, or with both together?

What they did

This was a multicentre observational study in routine clinical care, not a randomized trial. Of 65 patients screened, 12 were excluded for an absolute contraindication and 53 were enrolled into three groups: esketamine alone (15), metacognitive training alone (12), and both combined (26). Metacognitive training is a structured group programme that targets unhelpful thinking habits. Depression severity was measured with the MADRS scale and rumination (getting stuck in repetitive negative thoughts) with the RRS scale over six months.

What they found

Seven people did not complete the six-month assessment (six from the esketamine-alone group, one from the combined group), leaving 46 completers. All three groups changed over time, and the statistical models showed the groups differed in how they changed for both depression scores (F(2,42) = 24.97, p<.001) and rumination scores (F(2,42) = 5.59, p=.007). Among completers, response on the depression scale at six months was 3/9 (33.3%) with esketamine alone, 4/12 (33.3%) with training alone, and 23/25 (92.0%) with the combination. Counting everyone enrolled and treating dropouts as non-responders, the figures were 3/15 (20.0%), 4/12 (33.3%) and 23/26 (88.5%).

The fine print

People were not randomly assigned to groups, and everyone knew which treatment they were getting, so expectations and clinician choices could shape the results. The sample was small and unevenly split, dropout was concentrated in the esketamine-only group, baseline rumination was higher in the combined group, and past exposure to non-drug treatments differed markedly between groups — the authors themselves flag this as a likely confounder. Follow-up stopped at six months, and this summary is based on the abstract alone.

What it means

In everyday clinical practice, combining esketamine with a structured thinking-skills programme was associated with better six-month depression and rumination scores than either approach alone, but the study’s design means this is a hypothesis to test in a randomized trial, not proof that the combination works better.

Evidence grade: Low. Non-randomized, open-label observational study in routine care with a modest sample, uneven group sizes and acknowledged baseline imbalances.

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