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

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Abstract

BACKGROUND: Pharmacological 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. OBJECTIVE: To 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. FINDINGS: Fifty-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. CONCLUSION: The 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.

Abstract as published, via PubMed.