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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References
Post RM, Frye MA, Denicoff KD, Leverich GS, Kimbrell TA, Dunn RT . Beyond lithium in the treatment of bipolar illness. Neuropsychopharmacology 1998; 19: 206–219.
American Psychiatric Association. Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2nd ed. American Psychiatric Publishing, Inc: Washington, DC, 2002.
Stancer HC, Persad E . Treatment of intractable rapid-cycling manic-depressive disorder with levothyroxine. Arch Gen Psychiatry 1982; 39: 311–312.
Bauer MS, Whybrow PC . Rapid cycling bipolar affective disorders. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry 1990; 47: 435–440.
Afflelou S, Auriacombe M, Cazenave M, Chartres JP, Tignol J . Administration of high dose levothyroxine in treatment of rapid cycling bipolar disorders. Review of the literature and initial therapeutic application apropos of 6 cases [Article in French]. Encephale 1997; 23: 209–217.
Baumgartner A, Bauer M, Hellweg R . Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial. Neuropsychopharmacology 1994; 10: 183–189.
Bauer M, Priebe S, Berghöfer A, Bschor T, Kiesslinger K, Whybrow PC . Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders. J Affect Disord 2001; 64: 35–42.
Bauer M, Berghöfer A, Bschor T, Baumgartner A, Kiesslinger U, Hellweg R et al. Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. Neuropsychopharmacology 2002; 27: 620–628.
Bauer M, Adli M, Bschor T, Heinz A, Rasgon N, Frye M et al. Clinical applications of levothyroxine in refractory mood disorders. Clin Appl Bipolar Disord 2003; 2: 49–56.
Bauer M, Hellweg R, Gräf KJ, Baumgartner A . Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology 1998; 18: 444–455.
Rudas S, Schmitz M, Pichler P, Baumgartner A . Treatment of refractory chronic depression and dysthymia with high-dose thyroxine. Biol Psychiatry 1999; 2: 229–233.
Bernal J, Nunez J . Thyroid hormones and brain development. Eur J Endocrinol 1995; 133: 390–398.
Lechan RM, Toni R . Thyroid hormones in neural tissue. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds). Hormones, Brain and Behavior. Academic Press: San Diego, 2002, pp. 157–238.
Whybrow PC, Bauer M . Behavioral and psychiatric aspects of thyrotoxicosis. In: Braverman LE, Utiger RD (eds). Werner & Ingbar's The Thyroid. A Fundamental and Clinical Text, 9th ed. Lippincott Williams & Wilkins: Philadelphia, 2005, pp. 644–650.
Whybrow PC, Bauer M . Behavioral and psychiatric aspects of hypothyroidism. In: Braverman LE, Utiger RD (eds). Werner & Ingbar's The Thyroid. A Fundamental and Clinical Text, 9th ed. Lippincott Williams & Wilkins: Philadelphia, 2005, pp. 842–849.
Sokoloff L, Wechsler RL, Mangold R, Balls K, Kety SS . Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment. J Clin Invest 1953; 32: 202–208.
Sensenbach W, Madison L, Eisenberg S, Ochs L . The cerebral circulation and metabolism in hyperthyroidism and myxedema. J Clin Invest 1954; 33: 1434–1440.
O’Brien MD, Harris PH . Cerebral-cortex perfusion-rates in myxoedema. Lancet 1968; 1: 1170–1172.
Joffe RT, Sokolov STH . Thyroid hormones, the brain, and affective disorders. Crit Rev Neurobiol 1994; 8: 45–63.
Henley WN, Koehnle TJ . Thyroid hormones and the treatment of depression: An examination of basic hormonal actions in the mature mammalian brain. Synapse 1997; 27: 36–44.
Anderson GW, Mariash CN, Oppenheimer JH . Molecular actions of thyroid hormone. In: Braverman LE, Utiger RD (eds). Werner & Ingbar's The Thyroid. A Fundamental and Clinical Text, 8th ed. Lippincott Williams & Wilkins, Philadelphia, 2000, pp. 174–195.
Köhrle J . Thyroid hormone metabolism and action in the brain and pituitary. Acta Med Austriaca 2000; 27: 1–7.
Bauer M, Whybrow PC . Thyroid hormone, brain, and behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds). Hormones, Brain and Behavior. Academic Press, San Diego, 2002, pp. 238–264.
Constant EL, de Volder AG, Ivanoiu A, Bol A, Labar D, Seghers A et al. Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. J Clin Endocrinol Metab 2001; 86: 3864–3870.
Bauer M, Marseille DM, Geist CL, Van Herle K, Rasgon N, Martinez D et al. Effects of thyroid hormone replacement therapy on regional brain metabolism (abstract). J Nucl Med 2002; 43(Suppl): 254P.
Silverman DHS, Geist CL, Van Herle K, Rasgon N, Martinez D, Miller KJ et al. Abnormal regional brain metabolism in patients with hypothyroidism secondary to Hashimoto's disease (abstract). J Nucl Med 2002; 43(Suppl): 254P.
Calza L, Aloe L, Giardino L . Thyroid hormone-induced plasticity in the adult rat brain. Brain Res Bull 1997; 44: 549–557.
Marangell LB, Ketter TA, George MS, Pazzaglia PJ, Callahan AM, Parekh P et al. Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. Am J Psychiatry 1997; 154: 224–230.
Drevets WC . Funcional neuroimaging studies of depression: the anatomy of melancholia. Annu Rev Med 1998; 49: 341–361.
Drevets WC . Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48: 813–829.
Brody AL, Barsom MW, Bota RG, Saxena S . Prefrontal-subcortical and limbic circuit mediation of major depressive disorder. Semin Clin Neuropsychiatry 2001; 6: 102–112.
Mayberg HS . Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimized treatment. Br Med Bull 2003; 65: 193–207.
Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW . Neuroimaging in bipolar disorder. Bipolar Disord 2000; 2: 148–164.
Drevets WC, Price JL, Simpson Jr JR, Todd RD, Reich T, Vannier M et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–827.
Baxter Jr LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250.
Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE et al. Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder. Biol Psychiatry 2001; 49: 97–109.
Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD . fMRI during affect discrimination in bipolar affective disorder. Bipolar Disord 2000; 2: 237–248.
Blumberg HP, Kaufman J, Martin A, Whiteman R, Zhang JH, Gore JC et al. Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry 2003; 60: 1201–1208.
Whybrow PC . Sex differences in thyroid axis function: relevance to affective disorder and its treatment. Depression 1995; 3: 33–42.
Altshuler L, Bauer M, Frye M, Gitlin M, Mintz J, Szuba MP et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry 2001; 158: 1617–1622.
First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), Clinician Version. American Psychiatric Press, Washington, DC, 1996.
Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.
Beck AT . Beck Depression Inventory. Harcourt Brace & Company, San Antonio, 1996.
Spearing MK, Post RM, Leverich GS, Brandt D, Nolen W . Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP. Psychiatr Res 1997; 73: 159–171.
Bauer M, Baur H, Berghöfer A, Ströhle A, Hellweg R, Müller-Oerlinghausen B et al. Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. J Affect Disord 2002; 68: 285–294.
Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T et al. The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res 1979; 44: 127–137.
Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE . Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol 1979; 6: 371–388.
Wellcome Department of Cognitive Neurology, London, UK. Statistical Parametric Mapping, Available at: http://www.fil.ion.ucl.ac.uk/spm/ Accessed 25th January 2000.
Friston KJ, Ashburner J, Poline JB, Frith CD, Heather JD, Frackowiak RSJ . Spatial registration and normalization of images. Hum Brain Mapp 1995; 2: 165–189.
Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith CD, Frackowiak RSJ . Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995; 2: 189–210.
Woods RP, Mazziotta JC, Cherry SR . MRI-PET registration with automated algorithm. J Comput Assist Tomogr 1993; 17: 536–546.
Talairach J, Tournoux P . Co-Planar Stereotaxic Atlas of the Human Brain. Thieme, New York, 1988.
Duvernoy HM . The Human Brain. Surface, Three-Dimensional Sectional Anatomy with MRI, and Blood Supply, 2nd ed. Springer, Wien, 1999.
Dolan RJ, Bench CJ, Brown RG, Scott LC, Friston KJ, Frackowiak RS . Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment. J Neurol Neurosurg Psychiatr 1992; 55: 768–773.
Bauer M, Whybrow PC . Thyroid hormone, neural tissue and mood modulation. World J Biol Psychiatry 2001; 2: 57–67.
Bauer MS, Whybrow PC, Winokur A . Rapid cycling bipolar affective disorder. I. Association with grade I hypothyroidism. Arch Gen Psychiatry 1990; 47: 427–432.
Frye MA, Denicoff KD, Bryan AL, Smith-Jackson EE, Ali SO, Luckenbaugh D et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry 1999; 156: 1909–1914.
Cole DP, Thase ME, Mallinger AG, Soares JC, Luther JF, Kupfer DJ et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry 2002; 159: 116–121.
Toft AD . Thyroxine therapy. N Engl J Med 1994; 331: 174–180.
Gyulai L, Whybrow PC, Jaggi J, Bauer MS, Younkin S, Rubin L et al. Bone mineral density and L-thyroxine treatment in rapidly cycling bipolar disorder. Biol Psychiatry 1997; 41: 503–506.
Gyulai L, Bauer M, Espana-Garcia F, Hierholzer J, Baumgartner A, Whybrow PC . Bone mineral density in pre- and post-menopausal women with affective disorder treated with long-term L-thyroxine augmentation. J Affect Disord 2001; 66: 185–191.
Bauer M, Fairbanks L, Berghöfer A, Hierholzer J, Bschor T, Baethge C et al. Bone mineral density during maintenance treatment with supraphysiological doses of levothyroxine in affective disorders: a longitudinal study. J Affect Disord 2004; 83: 183–190.
Refetoff S . Resistance to thyroid hormone. In: Braverman LE, Utiger RD (eds). Werner & Ingbar's The Thyroid. A Fundamental and Clinical Text, 8th ed. Lippincott Williams & Wilkins: Philadelphia, 2000, pp. 1028–1043.
Leonard JL, Koehrle J . Intracellular pathways of iodothyronine metabolism. In: Braverman LE, Utiger RD (eds). Werner & Ingbar's The Thyroid. A Fundamental and Clinical Text, 8th ed. Lippincott Williams & Wilkins: Philadelphia, 2000 pp. 136–171.
Schwartz HL, Oppenheimer JH . Nuclear triiodothyronine receptor sites in brain: probable identity with hepatic receptors and regional distribution. Endocrinology 1978; 103: 267–273.
Ruel J, Faure R, Dussault JH . Regional distribution of nuclear T3 receptors in rat brain and evidence for preferential localization in neurons. J Endocrinol Invest 1985; 8: 343–348.
Bauer M, Heinz A, Whybrow PC . Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol Psychiatry 2002; 7: 140–156.
Whybrow PC, Prange Jr AJ . A hypothesis of thyroid–catecholamine–receptor interaction. Arch Gen Psychiatry 1981; 38: 106–113.
Kieseppa T, van Erp TG, Haukka J, Partonen T, Cannon TD, Poutanen VP et al. Reduced left hemispheric white matter volume in twins with bipolar I disorder. Biol Psychiatry 2003; 54: 896–905.
Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X et al. MRI-based measurements of temporal lobe and ventricular structures in patients with bipolar I and bipolar II disorders. J Affect Disord 2000; 60: 25–32.
Brambilla P, Harenski K, Nicoletti M, Sassi RB, Mallinger AG, Frank E et al. MRI investigation of temporal lobe structures in bipolar patients. J Psychiatr Res 2003; 37: 287–295.
Stapleton JM, Morgan MJ, Liu X, Yung BC, Phillips RL, Wong DF et al. Cerebral glucose utilization is reduced in second test session. J Cereb Blood Flow Metab 1997; 17: 704–712.
Oldfield RC . The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971; 9: 97–113.
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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DOI: https://doi.org/10.1038/sj.mp.4001647
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