Lithium and quetiapine augmentation therapy in treatment-resistant depression with atypical features

Why clinicians should know about it

• Picked for Psychiatry and Mental Health (paper of the day, 28 September 2026): Lithium vs quetiapine augmentation in treatment‑resistant depression

Abstract

Up to 50% of patients with depression do not adequately respond to standard antidepressant therapy, resulting in treatment-resistant depression (TRD), for which lithium and quetiapine are common augmentation strategies. Atypical depression, characterised by mood reactivity and reversed neurovegetative symptoms, is a clinically distinct subtype that may influence treatment response. This secondary analysis of the Lithium versus Quetiapine in Treatment-Resistant Depression (LQD) trial, a randomised controlled trial comparing lithium and quetiapine augmentation in TRD, examined whether atypical features moderated treatment outcomes. A total of 212 patients were enrolled, of whom 15.1% (n = 32) presented atypical features. Both treatments significantly improved depressive symptoms over the 52-week follow-up, with QIDS-SR scores decreasing by an average of 0.09 points per week (p < 0.001), leading to an improvement from approximately moderate to mild depressive illness over the 52-week follow-up. No significant differences emerged between lithium and quetiapine after adjustment for atypicality, and atypical features did not significantly moderate treatment response in either the completer or modified intention-to-treat analyses. Nevertheless, increased sleep and appetite did not preclude overall improvement in depressive symptoms with either treatment, despite concerns that their side-effect profiles might adversely affect patients with reversed neurovegetative symptoms. Overall, these findings support the effectiveness of both lithium and quetiapine augmentation in TRD regardless of atypical depressive features. Given the small atypical subgroup and the modest predictive performance of some models, these findings should be considered exploratory. Further studies with larger samples and prospective assessment of depressive subtypes are needed to confirm these results.

Abstract as published, via PubMed.