Quetiapine beat lithium in the longest trial yet, especially in patients with high anxiety
STUDY: Cleare AJ et al, Lancet Psychiatry 2025;12:276–288, PMID: 40023713 and Rifkin-Zybutz R et al, Psychopharmacology 2026.
STUDY TYPE: Randomized, open-label, pragmatic trial, with a secondary analysis of anxiety levels
EVIDENCE GRADE: Moderate (6/10)
FUNDING: National Institute for Health and Care Research (UK)
Background
Lithium and quetiapine are both first-line augmentation options for treatment-resistant depression — but we’ve had little to guide the choice between them. Prior head-to-head trials ran no longer than 8 weeks. This is the first to follow patients for a full year.
The Study
212 adults with treatment-resistant major depression (inadequate response to two or more antidepressants) were randomized to augmentation with quetiapine (target 150–300 mg/day, mean 195 mg/day) or lithium (target 0.6–1.2 mmol/L, mean 0.85 mmol/L) for 52 weeks. The trial was pragmatic — participants were randomized to the decision to prescribe, with initiation and continuation left to clinical judgment, mirroring real practice. There were two primary outcome: Symptom burden over 12 months using the Depression scale (QIDS-SR) and time to medication discontinuation.
Quetiapine improved symptoms more, both in the short- and long-term (p = 0.03). At week 52, quetiapine patients also had lower clinician-rated depression scores (MADRS) and better functioning. Tolerability was similar for both, and time to discontinuation trended in favor of quetiapine (median 365 vs. 212 days) but didn’t reach significance. Quetiapine also generated more quality-adjusted life-years.
A Second Look at Anxiety
In a separate paper, the authors reanalyzed the data, stratified by baseline anxiety, finding that:
- Queitapine’s superiority only held up for patients with high anxiety
- However, both medications had similar benefits on anxiety
Those two conclusions seem paradoxical, but the authors speculated that anxiety may be a marker for more severe illness and that quetiapine had stronger effects there. Still, there are reasons to prefer quetiapine in anxious patients. It is the only antipsychotic with robust data in generalized anxiety disorder, and one of two medications with benefits in anxious bipolar (the other is valproate).
Limitations
The study had no placebo, was not blinded, and had a high high drop out rate. The anxiety analysis was a secondary look at the data so is statistically unreliable.
Practice Implications
- In long-term trials, lithium usually performs better than antipsychotics in depression.
- Quetiapine may be an exception. Among the antipsychotics, it has unique benefits for sleep quality and anxiety.
- Quetiapine’s metabolite (norquetiapine) is similar to SNRI antidepressants, which may explain some of those benefits.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Which of these is better tolerated in your practice?
