Efficacy and safety of supraphysiologic doses of levothyroxine for patients with bipolar depression in adults: A systematic review

Background: In bipolar disorder (BD), depression is the most difficult-to-treat dimension and available evidence suggests that add-on supraphysiological doses of levothyroxine may be an effective augmenting agent. Aim: This systematic review has been conducted to evaluate the efficacy and safety of supraphysiologic doses of levothyroxine in bipolar depression in adults. Methods: After a comprehensive literature search on MEDLINE/PubMed, Scopus, Cochrane databases and International Clinical Trial Registry Platform (ICTRP), reviewers extracted data from eight relevant articles. PRISMA guidelines were followed in the selection, analysis and reporting of findings. Quality assessment was done using the risk of bias assessment and a random effects model was used to estimate effect size. Meta-analysis could not be done due to the lack of randomized, placebo-controlled trials and adequate data. A systematic review was done on eight studies and analysis on the pre–post change in Hamilton depression rating scale score (HDRS) was done for six studies. Results: The random model analysis of pooled effects showed a standardized mean difference of HDRS score by 2.62 (95% CI: 2.21–3.04; p Conclusion: Add-on supraphysiological dose of levothyroxine has a potential role in attenuating depressive symptoms in bipolar depression, especially in therapy-resistant BD. PROSPERO Registration Number: CRD42020218456.