A major randomized controlled trial published in The Lancet Psychiatry (April 2025) compared the long-term clinical and economic outcomes of quetiapine versus lithium as augmentation strategies in treatment-resistant depression (TRD). The LQD study enrolled 212 adults across six NHS sites in the UK, all of whom had failed at least two prior antidepressant trials and met DSM-5 criteria for major depressive disorder. Participants were randomized to receive augmentation with either lithium or quetiapine, with follow-up extending to 12 months. The two coprimary outcomes were longitudinal depressive symptom burden, assessed weekly via the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), and time to all-cause treatment discontinuation.

Results demonstrated that quetiapine led to a significantly lower cumulative burden of depressive symptoms over 12 months compared with lithium (area under the curve –68.36; 95% CI –129.95 to –6.76; p = 0.0296), though there was no statistically significant difference in time to discontinuation. Quetiapine also showed advantages in clinician-rated depression severity (MADRS) and functional outcomes (WSAS) at week 52. From a health economic perspective, quetiapine was more cost-effective across both NHS/personal social services and societal perspectives, with lower overall costs and higher quality-adjusted life years (QALYs). Serious adverse events occurred in 7% of quetiapine-treated patients and 11% in the lithium group, with overdose being the most common in both arms. One lithium-related case of acute renal failure was noted.

These findings suggest quetiapine may be a more effective and cost-efficient first-line augmentation option for TRD in routine clinical practice. However, the authors caution that lithium remains a valuable treatment, especially in cases where long-term anti-suicidal benefits are prioritized. Future research should focus on predictors of treatment response and tolerability to guide more personalized augmentation strategies.

Reference:
Cleare AJ et al. Lancet Psychiatry. 2025;12(4):276–288. Abstract.