588. Lithium and Quetiapine Augmentation Therapy in treatment-resistant depression with atypical features

Abstract

Abstract Background Treatment-resistant depression (TRD) affects up to half of patients with major depressive disorder and is associated with poorer health outcomes. Lithium and quetiapine are established augmentation strategies in cases of TRD, but there is limited evidence to inform treatment choice in different depressive subtypes. Atypical depression, characterised by mood reactivity and reversed neurovegetative symptoms, represents a clinically distinct presentation that may impact treatment outcomes in TRD. Aims & Objectives This secondary analysis of the Lithium versus Quetiapine in Treatment-Resistant Depression (LQD) trial examined whether atypical depressive features moderated treatment outcomes with lithium or quetiapine augmentation in TRD, and whether the presence of atypical features was associated with significant differences in sociodemographic, psychopathological and biochemical variables. Method The LQD trial was a pragmatic, multicentre, randomised, open-label study with blinded outcome assessment. Adults with TRD (n = 212) were randomised to lithium or quetiapine augmentation and followed for 52 weeks using several psychometric scales. Atypical depression was operationalised using DSM-5-TR criteria based on the relevant Inventory of Depressive Symptomatology–Clinician Rated (IDS–C) items. Depression severity was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR). Longitudinal changes in depression severity were analysed using mixed-effects linear regression models with fixed effects for time, treatment arm, atypicality and the interaction between treatment and atypicality. Random effects accounted for patient-level variability and for the three stratification factors (baseline depression severity, treatment resistance severity, geographical region). Differences in sociodemographic, psychopathological and biochemical variables between atypical and non-atypical patients and attrition rates were assessed using binomial logistic regression models. Results Atypical features were present in 21.7% of participants and were evenly distributed across treatment arms. Both lithium and quetiapine were associated with significant reductions in depressive symptoms over time. Quetiapine produced lower MADRS scores than lithium across follow-up (mean difference −2.15 points, p = 0.03), an effect that remained significant after adjusting for atypicality. Atypical features did not significantly moderate treatment response. Notably, patients with atypical features showed overall clinical improvement with quetiapine despite reversed neurovegetative symptoms. Quetiapine was associated with higher retention, particularly among atypical patients, with a 64% lower odds of dropout compared with lithium (p = 0.02). Discussion & Conclusions This secondary analysis of the LQD trial shows that, in this sample of patients with TRD, the superiority of quetiapine augmentation over lithium in TRD extends to patients with atypical depressive features. Although atypicality did not moderate symptom response, improved retention rates suggest better acceptability of quetiapine in this subgroup. Both treatments remain effective options, allowing for personalised augmentation strategies based on patient characteristics and side-effect profile. Further research is needed to clarify whether quetiapine’s benefits reflect direct antidepressant effects or indirect effects related to improvements in sleep, appetite, and anxiety.