Systematic review · 2026
Comparing lithium, quetiapine and esketamine as add-ons for hard-to-treat depression
- Original title
- Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence.
- Authors
- Eckert D, Kasper S
- Journal
- The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 2026
- Molecules
- Esketamine, Ketamine
- Conditions
- Treatment-resistant depression
- Evidence grade
- Low
- Source
- Read the original paper
The question
When standard antidepressants do not work, which add-on drug performs best: lithium, quetiapine, or esketamine?
What they did
The authors searched research databases for randomised and real-world studies that directly compared these three add-on treatments in adults with treatment-resistant depression, meaning depression that has not responded to standard antidepressants. They also reviewed existing meta-analyses (studies that pool results from many trials) and described those findings alongside the direct comparisons. The number of patients involved was not reported in the abstract.
What they found
Only four direct comparison studies were found: three compared lithium with quetiapine, and one compared esketamine with quetiapine. All three add-on drugs appeared effective. The authors describe a possible edge for esketamine over quetiapine, and for quetiapine over lithium, but they present this as a descriptive impression rather than a statistically tested result.
The fine print
Only four head-to-head studies existed, and just one of them involved esketamine, so the comparison rests on very thin direct evidence. The findings were described qualitatively rather than pooled into a single statistical estimate, and the abstract does not report how many patients were included, how long they were followed, or any effect sizes. Side effects and contraindications differ substantially between these drugs, which the authors note matters for real-world use. This summary is based on the abstract only.
What it means
Lithium, quetiapine and esketamine all appear to help when antidepressants alone have not worked, but there is too little direct comparison research to say confidently which is best for whom.
Evidence grade: Low. A systematic review that found only four head-to-head studies and combined the wider meta-analytic evidence qualitatively rather than pooling it statistically.
This summary is based on the study’s published abstract.