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Publications

Journal Article Systematic Review Meta-Analysis Epublish

PubMed: 42532626 DOI: 10.1136/bmjment-2026-302656

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

BMJ Ment Health 29(1)

Authors: Tien-Wei Hsu, Chih-Wei Hsu, Trevor Thompson, Andre F Carvalho, Brendon Stubbs, Ping-Tao Tseng, Fu-Chi Yang, Chia-Ling Yu, Yu-Kang Tu, Chih-Sung Liang

Affiliations

  • Department of Psychiatry, E-Da Dachang Hospital, Kaohsiung, Taiwan.
  • Departmnt of Psychiatry, E-Da Hospital, Kaohsiung, Taiwan.
  • School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
  • Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
  • Centre for Chronic Illness and Ageing, University of Greenwich, London, UK.
  • IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, Deakin University, Melbourne, Victoria, Australia.
  • Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
  • Comprehensive Centre for Clinical Neurosciences and Mental Health (C3NMH), Medical University of Vienna, Vienna, Austria.
  • Clinical Division of Social Psychiatry, Department of Psychiatry & Psychotherapy, Medical University of Vienna, Vienna, Austria.
  • Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
  • Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.
  • Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
  • Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan.
  • Department of Neurology, Tri-Service General Hospital, Taipei City, Taiwan.
  • Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  • Institute of Epidemiology & Preventive Medicine, National Taiwan University, Taipei City, Taiwan.
  • Department of Dentistry, National Taiwan University Hospital, Taipei City, Taiwan.
  • Department of Psychiatry, Tri-Service General Hospital Beitou Branch, Taipei, Taiwan. Department of Psychiatry, School of Medicine, College of Medicine, National Defense Medical University, Taipei, Taiwan.

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.

MeSH

Depression, Aripiprazole, Bias, Triiodothyronine, Antipsychotic Agents, Therapeutics, Mental Health