Walker Percy, Hitchhikers, near Vicksburg, Mississippi (1936)
For the first time, we have durable data on augmentation
STUDY: Strawbridge R et al, British Journal of Psychiatry 2026
STUDY TYPE: Guest editorial / expert review
FUNDING: National Institute for Health and Care Research (NIHR), UK
Background
Treatment-resistant depression is a long-term disorder. Until now, treatment has rested on short-term trials.
The Studies
Strawbridge’s editorial focuses on three well-powered long-term trials that I have reviewed separately in this blog:
- LQD (n=212, 52 weeks): quetiapine versus lithium augmentation. Quetiapine outperformed lithium on most outcomes.
- PAX-D (n=151, 48 weeks): pramipexole versus placebo. Pramipexole showed a large effect size, though with tolerability concerns.
- ESCAPE-TRD (n=676, 32 weeks): esketamine nasal spray versus quetiapine. Esketamine showed higher remission rates and favorable cost-effectiveness despite higher drug costs.
Efficacy
All three agents produced durable benefit beyond six months. Quetiapine beat lithium in symptom reduction. Pramipexole showed a large effect size against placebo in patients who failed an average of 3.5 trials. Esketamine outperformed quetiapine in remission and relapse prevention, though blinding was imperfect and manufacturer funding raises questions about effect size inflation.
Risks
- Lithium: Thyroid, renal function, toxicity from narrow therapeutic window
- Pramipexole: Nausea (short-term), hedonic dysregulation (1-3%), orthostasis, edema
- Quetiapine: Metabolic syndrome, tardive dyskinesia, orthostasis, fatigue
- Esketamine: Addiction/dependence, acute hypertension, neurotoxicity in higher doses, mental status change, requirement for in-office monitoring
Practice Implications
- All of these therapies are close in efficacy, and can be matched to fit the right patient.
- Lithium has stronger neuroprotective effects and — in bipolar disorder — reduces all-cause mortality. In unipolar, it prevents hospitalization and suicide. It is more effective in recurrent depression, where it prevented episodes in a meta-analysis of 21 randomized trials, including a trial where it sustained recovery after ECT.
- However, quetiapine and esketamine have a bigger effect than lithium in these trials.
- Meanwhile, TMS is registering larger effects than pharmacologic augmentation.
- Explore more options in Difficult to Treat Depression.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
