{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:54:06Z","timestamp":1791190446424,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Subthreshold bipolar disorder (SBD), also referred to as unspecified bipolar disorder, is frequently encountered in patients with treatment-resistant depression. It presents with depressive and subthreshold manic and mixed symptoms. Sustained remission with full functional recovery is the aim of treatment in mood disorders as residual symptoms may cause disability, while relapse may be associated with increased morbidity or mortality. To date, evidence for achieving sustained remission in SBD is absent, with no studies reporting sustained remission outcomes. The only available evidence to remission is at level 2 in a previous study by the author employing combined high-dose levothyroxine (HDT) and repetitive transcranial magnetic stimulation (rTMS). The management of SBD during pregnancy is particularly challenging due to the absence of evidence-based guidance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>We describe a retrospective case series of three women with longstanding treatment-resistant depressive presentations with a threat to life, later conceptualized within the bipolar spectrum. All patients had achieved sustained remission before pregnancy using a treatment approach combining HDT with rTMS (the Zamar Protocol), with or without low-dose quetiapine. Following shared decision making and counseling regarding the extremely limited evidence base, treatment was continued during pregnancy due to concerns about the riskof relapse and risk to life. All three patients maintained clinical stability during pregnancy, the postpartum period, and beyond. Across the three cases, five pregnancies occurred while patients remained on HDT-based treatment, with adjunctive rTMS used during selected periods. No maternal, obstetric, neonatal, or early developmental adverse outcomes were reported during the available follow-up. In one case, clinical deterioration followed a dose reduction and improved after re-escalation. The consistent biochemical pattern of elevated FT4 relative to FT3 (low FT3\/FT4 ratio) previously reported was observed across cases, which differed from typical thyrotoxic profiles. Variants in the deiodinase-related genes and the thyroid hormone transport pathways were identified, in keeping with previously published literature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This small retrospective case series suggests that continuation of HDT-based treatment, with or without adjunctive rTMS, may be a feasible option in carefully preselected patients with pre-pregnancy blood and genetic biomarkers and pre-pregnancy clinical response when presenting with severe life-threatening bipolar spectrum disorder presenting as treatment-resistant depression. These findings established safety and efficacy at a low level of evidence (level 4 CEBM) and highlight the need for more robust prospective research. Careful discussion with the patient and spouse exploring the risk\u2013benefit ratio and any evidence-based available acceptable alternatives, particularly when there exists a risk to life, is necessary.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1872443","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:21:57Z","timestamp":1791188517000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Treatment of subthreshold bipolar disorder in pregnancy: a report on the effectiveness of the Zamar Protocol\u00ae in three treatment-resistant depression cases"],"prefix":"10.3389","volume":"17","author":[{"given":"Antonios C.","family":"Zamar","sequence":"first","affiliation":[{"name":"The London Psychiatry Centre","place":["London, United 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Cyprus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelos","family":"Halaris","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Neurosciences, Stritch School of Medicine, Loyola University of Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George P.","family":"Chrousos","sequence":"additional","affiliation":[{"name":"University Research Institute of Maternal and Child Health and Precision Medicine, Medical School, National and Kapodistrian University of Athens, and Hellenic Pasteur Institute","place":["Athens, Greece"]},{"name":"UNESCO Chair on Adolescent Health Care","place":["Athens, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1139\/jpn.0301","article-title":"Treating mood 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