Endoxifen augmentation in treatment-resistant rapid cycling bipolar disorder: A case series in elderly females

Rapid cycling affective disorder (RCAD) is a severe, often treatment-refractory subtype of bipolar disorder, predominantly affecting females, and marked by frequent, destabilizing mood shifts. While sodium valproate is widely employed as a first-line mood stabilizer, its effectiveness diminishes in chronic presentations, even when combined with agents such as aripiprazole, quetiapine, or lithium. Emerging research highlights the role of estrogen receptor modulation in enhancing mood stabilization, especially in women with resistant affective symptoms. This case series details three female patients with persistent RCAD who demonstrated only partial benefit from sodium valproate alongside atypical antipsychotics or lithium. Each was subsequently administered adjunctive endoxifen, an active metabolite of tamoxifen and a potent selective estrogen receptor modulator. Over a 10–12-month follow-up, patients were evaluated using standardized mood rating scales such as the Young Mania Rating Scale and Hamilton Depression Rating Scale, and were followed up for almost a year to track any relapses. All three exhibited marked clinical improvement following endoxifen augmentation, including prolonged remission and decreased severity and frequency of mood episodes. The combination therapy was well tolerated, with no notable side effects observed despite 10 months of endoxifen treatment. These preliminary observations point toward a possible synergistic interaction between sodium valproate and endoxifen in managing RCAD in females. Endoxifen may offer a novel augmentation option in resistant cases. Further controlled studies are necessary to confirm these results and explore the underlying neuroendocrine pathways.