Ketamine and esketamine for hard-to-treat depression in youth: a review of the evidence

The question

Do ketamine and esketamine help children and adolescents whose depression has not responded to standard treatments?

What they did

Researchers searched the MEDLINE database on July 5th, 2024 using the keyword ‘esketamine’, following the PRISMA method for systematic reviews. The two reviews (one for ketamine, one for esketamine) were registered in advance with PROSPERO. Of 5,131 articles first identified, 29 were included for analysis and discussion.

What they found

Only one double-blind randomized controlled trial was found for ketamine and one for esketamine. The ketamine trial used a single dose with a crossover design, measured effects at 24 hours, and reported that the benefit lasted at least two weeks, but found no effect on suicidal thinking. The esketamine trial reported that mood and suicidality improved after three infusions; the improvement in depressive symptoms lasted to the end of the study, but the improvement in suicidality did not. Ketamine reduced negativity bias and depressive thinking style, and esketamine did not harm thinking skills and improved processing speed. The authors noted that all published reports were positive, yet the data were too scarce to be convincing.

The fine print

There were only two double-blind randomized trials in the whole field, and the review did not pool participant numbers, so the total number of young people studied is not given in the abstract. A literature where every published report is positive can reflect publication bias. The authors also flag unknown effects on the developing brain. This summary is based on the abstract only.

What it means

There is not yet convincing evidence that ketamine or esketamine work for treatment-resistant depression in children and adolescents; the few studies available point in a positive direction but are too small and too few to draw conclusions.

Evidence grade: Low. A systematic review that found only two double-blind randomized trials, with the rest of the 29 included papers being smaller or uncontrolled reports.

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