Reappraising lithium, triiodothyronine and second-generation antipsychotic augmentation treatment for major depression: a systematic review and meta-analysis with bias-adjustment analyses.

backgroundPharmacological augmentation is commonly used for patients with major depressive disorder (MDD) who respond inadequately to antidepressant treatment. However, the robustness of evidence supporting lithium, second-generation antipsychotics (SGAs), and triiodothyronine (T3) augmentation for MDD remains uncertain.

objectiveTo reappraise the efficacy and robustness of evidence for pharmacological augmentation strategies for MDD, focusing on lithium, SGAs, and T3. STUDY SELECTION AND ANALYSIS: We systematically searched five electronic databases and included placebo-controlled RCTs in adults with MDD who received augmentation with lithium, SGAs, or T3. The primary outcome was response rate (defined as ≥50% depressive symptom reduction). Random-effects meta-analysis and trial sequential analysis (TSA) were conducted. We also performed publication-bias-adjustment analyses, including PET-PEESE and selection models. Subgroup analyses were conducted for individual SGAs.: To reappraise the efficacy and robustness of evidence for pharmacological augmentation strategies for MDD, focusing on lithium, SGAs, and T3.

findingsFifty-six RCTs were included (n=13616). SGA augmentation was associated with a higher response than placebo (k=45; reported as OR with 95% CI: 1.53; 1.42-1.65; I²=0%), and the evidence was supported by TSA. Conversely, while lithium showed benefit in conventional meta-analysis (k=17; OR 2.06; 1.30-3.27; I²=11.5%), this effect was not supported by TSA (accrued information size reached 8% of the required information size; 1.99, TSA-adjusted 95% CI 0.02-189.11) and became statistically non-significant in the PET-PEESE-adjusted and selection models. Additionally, T3 augmentation was not associated with significantly higher response than controls (k = 6; 1.19; 0.53-2.70). Among individual SGAs, only aripiprazole, quetiapine, brexpiprazole, and cariprazine demonstrated TSA-supported efficacy, whereas evidence for other SGAs was limited or inconclusive.

conclusionThe certainty and robustness of evidence for lithium and T3 augmentation remained limited. Evidence for T3 was sparse and did not show a significant advantage over control, while interpretation of the lithium findings is further constrained by the fact that most trials were conducted before treatment-resistant depression was more operationally defined in contemporary research. SGAs with TSA-supported benefits (aripiprazole, quetiapine, brexpiprazole and cariprazine) may be prioritised, pending individual patient considerations. STUDY REGISTRATION: https://osf.io/27gp9.