Beyond first-line antidepressants: lithium, quetiapine, or esketamine? Integrating meta-analyses and preliminary head-to-head evidence.
David Eckert, Siegfried Kasper
The World Journal of Biological Psychiatry January 22, 2026 DOI: 10.1080/15622975.2026.2617195 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Peer reviewed |
|---|---|
| Sample size | 4 |
| Population | Adults with treatment-resistant depression |
| Interventions | Lithium Quetiapine Esketamine |
| Topics | Esketamine Ketamine |
| Keywords | Treatment-resistant depression trd Lithium Pharmacological augmentation Quetiapine |
| Key findings | All three agents (lithium, quetiapine, esketamine) are effective for treatment-resistant depression, with a descriptive superiority of esketamine over quetiapine and of quetiapine over lithium. |
Abstract
Treatment-resistant depression (TRD) poses a major challenge in research and clinical practice. Various guidelines recommend different pharmacological approaches. While lithium and second-generation antipsychotics have traditionally been the drugs of choice in cases of medication resistance, recent years have seen increasing evidence for the efficacy of esketamine as a fast-acting agent against depression. Although there is a large body of meta-analytical evidence, direct comparisons between the agents are scarce. A systematic review of databases was conducted for randomised and naturalistic head-to-head studies comparing augmentation with lithium, quetiapine, or (es)ketamine in adults with TRD was included. Findings from relevant meta-analyses were integrated qualitatively. We found four studies, comprising three trials comparing lithium and quetiapine and one comparing esketamine and quetiapine. In summary, (1) all three agents are effective, (2) there may be a descriptive superiority of esketamine over quetiapine and of quetiapine over lithium. The results generally argue for a re-evaluation of existing treatment algorithms in guidelines. However, since all three are fundamentally different molecules with different pharmacokinetic and pharmacodynamic properties and differ in (1) side effects and contraindications as well as (2) profile focus, embedding them in a comprehensive clinical context is important.
Comparable studies
Other systematic reviews and meta-analyses on esketamine, most cited first.
Citations in the library
Cites 27
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Better Biomarkers, Faster Drugs, Stronger Models: Progress Towards Precision Psychiatry. Missouri medicine 2023
- Management of Treatment-Resistant Depression: Challenges and Strategies Neuropsychiatric Disease and Treatment 2020
and 22 more in the library