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Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression

Abstract

Supplementation of standard treatment with high-dose levothyroxine (L-T4) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T4 treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [18F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T4 (mean dose 320 μg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T4 treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T4 treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T4 improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T4 may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

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Acknowledgements

Supported by Deutsche Forschungsgemeinschaft Grant Ba 1504/3-1 (Dr Bauer), National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (Dr Bauer), the UCLA General Clinical Research Center (GCRC) Grant M01-RR00865, and a research grant from Forest Lab Inc., New York (Dr Bauer). For generous support, the authors also thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, Northstar Fund, and the National Center for Research Resources Grants RR12169, RR13642 and RR08655 (Drs Mazziotta and Woods).

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Preliminary reports were presented at the Annual Meeting of the American Psychiatric Association (May 5–7, 2001, New Orleans, LA, USA), the Fourth International Conference on Bipolar Disorder (June 14–16, 2001, Pittsburgh, PA, USA), the 7th World Congress of Biological Psychiatry (July 1–6, 2001, Berlin, Germany) and the 40th Annual Meeting of the American College of Neuropsychopharmacology (December 9–13, 2001, Waikoloa, HI, USA).

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Bauer, M., London, E., Rasgon, N. et al. Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression. Mol Psychiatry 10, 456–469 (2005). https://doi.org/10.1038/sj.mp.4001647

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