Morning Sun, Edward Hopper, 1952 (the model is the artist’s wife)
Experts weigh in on three top augmentation options
STUDY: Eckert D et al, Int J Psychiatry Clin Pract 2026.
STUDY TYPE: Narrative review
FUNDING: Independent
Background
When two antidepressants fail, guidelines recommend augmentation, but don’t say which. This narrative review from Switzerland and Vienna looked for differences among three with the strongest evidence: Lithium, quetiapine (Seroquel), and esketamine (Spravato).
These three have different mechanisms, but share neuroprotective, neuroplastic, and glutamatergic pathways.
Different Benefits
- Suspect bipolarity? Lithium is the gold standard; quetiapine is a reasonable alternative (serum level 0.6-0.8)
- Psychotic features? Quetiapine’s antipsychotic properties make it the obvious pick (usually need 400-800 mg there)
- Suicidality? Both lithium (long-term prevention) and esketamine (rapid, acute reduction) have supporting data. The urgency of the situation might separate them.
- Anxiety, agitation, and insomnia point to quetiapine
Dr. Aiken’s notes:
- For overall efficacy, esketamine surpassed quetiapine, and quetiapine surpassed lithium, in large randomized trials, but the results were minimal and the responses likely vary by the characteristics above
- Lithium has the best evidence for prevention after ECT. It also has support in psychotic depression, though not randomized.
Different Risks
- Renal risks argue against lithium, while liver risks dissuade quetiapine and esketamine (the authors express concern about their hepatic metabolism, but both are also linked to liver injury)
- Metabolic risks argue against quetiapine (and tardive dyskinesia)
- Poorly controlled hypertension is a caution with esketamine
- Lithium and quetiapine require lab monitoring, while esketamine is expensive and requires in-office administration with blood pressure monitoring
Dr. Aiken’s notes:
- Lithium lowers the risk of suicidal overdose, but with its narrow therapeutic window it has a risk of accidental toxicity
- Esketamine’s potential long-term risks are not well-established, and may include tolerance, withdrawal, misuse, an bladder problems. However, earlier concerns about cognitive problems or neurotoxicity have not panned out.
Learn more
- Learn more about how to personalize the choice in Difficult to Treat Depression.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
