{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:18:41Z","timestamp":1791227921542,"version":"4.1.0"},"reference-count":30,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Thyroid hormone (TH) augmentation, although commonly used for major depression, is sparingly used for bipolar disorder (BD) after the failure of mood-stabilizing agents. While the exact mechanisms of thyroid hormone action in BD remains unclear, central thyroid hormone deficit has been postulated as a mechanism for rapid cycling. This systematic review\u2014conducted in accordance with the PRISMA guidelines\u2014of eight studies synthesizes the evidence for TH augmentation in BD. A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials (RCT), open-label trials, and observational studies of levothyroxine (LT4) and triiodothyronine (T3) for BD. Open-label studies of high dose LT4 augmentation for bipolar depression and rapid cycling showed improvement in depression outcomes and reduction in recurrence, respectively. However, an RCT of high-dose LT4 did not show benefit in contrast to placebo. An RCT comparing LT4, T3, and placebo showed benefit only in rapid-cycling bipolar women. A meta-analysis could not be completed due to significant differences in study designs, interventions, and outcomes. Our systematic review shows mixed evidence and a lack of high-quality studies. The initial promise of supratherapeutic LT4 augmentation from open-label trials has not been consistently replicated in RCTs. Limited data are available for T3. The studies did not report significant thyrotoxicosis, and TH augmentation were well tolerated. Therefore, TH augmentation, especially with supratherapeutic doses, should be reserved for highly treatment-resistant bipolar depression and rapid-cycling BD.<\/jats:p>","DOI":"10.3390\/brainsci12111540","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:32:01Z","timestamp":1668393121000},"page":"1540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Thyroid Hormone Augmentation for Bipolar Disorder: A Systematic Review"],"prefix":"10.3390","volume":"12","author":[{"given":"Ashok","family":"Seshadri","sequence":"first","affiliation":[{"name":"Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA"},{"name":"Department of Psychiatry and Psychology, Mayo Clinic Health System, Austin, MN 55912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishnu","family":"Sundaresh","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Utah School of Medicine, Salt Lake City, UT 84108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry J.","family":"Prokop","sequence":"additional","affiliation":[{"name":"Mayo Medical Libraries, Mayo Clinic College of Medicine, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7062-8192","authenticated-orcid":false,"given":"Balwinder","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1001\/archpsyc.59.6.530","article-title":"The long-term natural history of the weekly symptomatic status of bipolar I disorder","volume":"59","author":"Judd","year":"2002","journal-title":"Arch. 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