Pharmacopsychiatry 2003; 36: 215-221
DOI: 10.1055/s-2003-45133
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Thyroid, Brain and Mood Modulation in Affective Disorder: Insights from Molecular Research and Functional Brain Imaging

M. Bauer1 , 2 , E. D. London2 , 3 , 4 , D. H. S. Silverman3 , N. Rasgon5 , J. Kirchheiner6 , P. C. Whybrow2
  • 1Department of Psychiatry and Psychotherapy, Charité - University Medicine Berlin, Campus Charité-Mitte (CCM), Berlin, Germany
  • 2Neuropsychiatric Institute & Hospital, and the Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA, USA
  • 3Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
  • 4Brain Research Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
  • 5Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Palo Alto, CA, USA
  • 6Institute of Clinical Pharmacology, Charité - University Medicine Berlin, Campus Charité-Mitte (CCM), Berlin, Germany
Further Information

Publication History

Publication Date:
15 December 2003 (online)

The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior.

Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [18F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.


  • 1 Altshuler L, Bauer M, Frye M, Gitlin M, Mintz J, Szuba M P, Leight K L, Whybrow P C. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.  Am J Psychiatr. 2001;  158 1617-1622
  • 2 Anderson G W, Mariash C N, Oppenheimer J H. Molecular actions of thyroid hormone. In: Braverman LE, Utiger RD, eds Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed Philadelphia; Lippincott Williams & Wilkins 2000: 174-195
  • 3 Aronson R, Offman H J, Joffe R T, Naylor D. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis.  Arch Gen Psychiatry. 1996;  53 842-848
  • 4 Bauer M, Adli M, Bschor T, Heinz A, Rasgon N, Frye M, Grunze H, Kupka R, Whybrow P C. Clinical applications of levothyroxine in refractory mood disorders.  Clin Appl Bipolar Disord. 2003;  2 49-56
  • 5 Bauer M, Baur H, Berghöfer A, Ströhle A, Hellweg R, Müller-Oerlinghausen B, Baumgartner A. Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders.  J Affect Disord. 2002;  68 285-294
  • 6 Bauer M, Berghöfer A, Bschor T, Baumgartner A, Kiesslinger U, Hellweg R, Adli M, Baethge C, Müller-Oerlinghausen B. Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders.  Neuropsychopharmacol. 2002;  27 620-628
  • 7 Bauer M, Fairbanks L, Berghöfer A, Hierholzer J, Bschor T, Rasgon N, Whybrow P C. No evidence of accelerated loss of bone density during maintenance treatment with supraphysiological doses of L-thyroxine in prophylaxis-resistant affective disorders. Submitted manuscript. 
  • 8 Bauer M, Heinz A, Whybrow P C. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain.  Mol Psychiatr. 2002;  7 140-156
  • 9 Bauer M, Hellweg R, Gräf K J, Baumgartner A. Treatment of refractory depression with high-dose thyroxine.  Neuropsychopharmacol. 1998;  18 444-455
  • 10 Bauer M, London E D, Rasgon N, Berman S M, Frye M A, Altshuler L, Mandelkern M A, Bramen J, Woods R, Mazziotta J C, Whybrow P C. Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in women with bipolar depression. Submitted manuscript. 
  • 11 Bauer M, Marseille D M, Geist C L, Van Herle K, Rasgon N, Martinez D, Miller K J, Haselrig T, Van Herle A J, Whybrow P C, Czernin J, Phelps M E, Silverman D HS. Effects of thyroid hormone replacement therapy on regional brain metabolism (abstract).  J Nucl Med. 2002;  43 (5, suppl) 254P
  • 12 Bauer M, Priebe S, Berghöfer A, Bschor T, Kiesslinger K, Whybrow P C. Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders.  J Affect Disord. 2001;  64 35-42
  • 13 Bauer M, Szuba M P, Whybrow P C. Psychiatric and behavioral manifestations of hyper- and hypothyroidism. In: Wolkowitz OM, Rothschild TJ (eds.) Psychoneuroendocrinology: The Scientific Basis of Clinical Practice. American Psychiatric Press, Inc Washington D.C; 2003: 419-444
  • 14 Bauer M, Whybrow P C. Thyroid hormone, brain, and behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, eds Hormones, Brain and Behavior. San Diego; Academic Press 2002: 238-264
  • 15 Bauer M, Whybrow P C. Thyroid hormone, neural tissue and mood modulation.  World J Biol Psychiatr. 2001;  2 57-67
  • 16 Bauer M S, Whybrow P C, Winokur A. Rapid cycling bipolar affective disorder. I. Association with grade I hypothyroidism.  Arch Gen Psychiatr. 1990;  47 427-432
  • 17 Bauer M S, Whybrow P C. Rapid cycling bipolar affective disorders. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study.  Arch Gen Psychiatr. 1990;  47 435-440
  • 18 Baumgartner A. Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research.  Int J Neuropsychopharmacol. 2000;  3 149-165
  • 19 Baumgartner A, Bauer M, Hellweg R. Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial.  Neuropsychopharmacol. 1994;  10 183-189
  • 20 Beierwaltes W H, Ruff G E. Thyroxin and triiodothyronine in excessive dosage to euthyroid humans.  Arch Intern Med. 1958;  101 569-576
  • 21 Braverman L E, Vagenakis A, Downs P, Foster A E, Sterling K, Ingbar S H. Effects of replacement doses of sodium-L-thyroxine on the peripheral metabolism of thyroxine and triiodothyronine in man.  J Clin Invest. 1973;  52 1010-1017
  • 22 Brody A L, Barsom M W, Bota R G, Saxena S. Prefrontal-subcortical and limbic circuit mediation of major depressive disorder.  Semin Clin Neuropsychiatr. 2001;  6 102-112
  • 23 Calza L, Aloe L, Giardino L. Thyroid hormone-induced plasticity in the adult rat brain.  Brain Res Bull. 1997;  44 549-557
  • 24 Clinical Society of L ondon. Report on myxedema. Trans Clin Soc Lond (suppl) 1888 21: 18
  • 25 Cohen JH 3 d, Ingbar S H, Braverman L E. Thyrotoxicosis due to ingestion of excess thyroid hormone.  Endocr Rev. 1989;  10 113-124
  • 26 Cole D P, Thase M E, Mallinger A G, Soares J C, Luther J F, Kupfer D J, Frank E. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function.  Am J Psychiatr. 2002;  159 116-121
  • 27 Constant E L, de Volder A G, Ivanoiu A, Bol A, Labar D, Seghers A, Cosnard G, Melin J, Daumerie C. Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study.  J Clin Endocrinol Metab. 2001;  86 3864-3870
  • 28 Drevets W C, Price J L, Simpson Jr J R, Todd R D, Reich T, Vannier M, Raichle M E. Subgenual prefrontal cortex abnormalities in mood disorders.  Nature. 1997;  386 824-827
  • 29 Drevets W C. Neuroimaging studies of mood disorders.  Biol Psychiatr. 2000;  48 813-29
  • 30 Flach F F, Celian C I, Rawson R W. Treatment of psychiatric disorders with triiodothyronine.  Am J Psychiatry. 1958;  114 841-842
  • 31 Frye M A, Denicoff K D, Bryan A L, Smith-Jackson E E, Ali S O, Luckenbaugh D, Leverich G S, Post R M. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients.  Am J Psychiatr. 1999;  156 1909-1914
  • 32 Gjessing R. Disturbances of somatic function in catatonia with a periodic course and their compensation.  J Ment Sci. 1938;  84 608-621
  • 33 Gyulai L, Bauer M, Espana-Garcia F, Hierholzer J, Baumgartner A, Whybrow P C. 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
  • 34 Gyulai L, Whybrow P C, Jaggi J, Bauer M S, Younkin S, Rubin L, Attie M. Bone mineral density and L-thyroxine treatment in rapidly cycling bipolar disorder.  Biol Psychiatr. 1997;  41 503-506
  • 35 Gyulai L, Bauer M, Bauer M S, García-España F, Cnaan A, Whybrow P C. Thyroid hypofunction in patients with rapid cycling bipolar disorder after lithium challenge.  Biol Psychiatry. 2003;  53 899-905
  • 36 Henley W N, Koehnle T J. Thyroid hormones and the treatment of depression: An examination of basic hormonal actions in the mature mammalian brain.  Synapse. 1997;  27 36-44
  • 37 Ketter T A, Kimbrell T A, George M S, Dunn R T, Speer A M, Benson B E, Willis M W, Danielson A, Frye M A, Herscovitch P, Post R M. Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.  Biol Psychiatr. 2001;  49 97-109
  • 38 Köhrle J. Thyroid hormone metabolism and action in the brain and pituitary.  Acta Med Austriaca. 2000;  27 1-7
  • 39 Lechan R M, Toni R. Thyroid hormones in neural tissue. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, eds Hormones, Brain and Behavior. San Diego; Academic Press 2002: 157-238
  • 40 Leonard J L, 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 Philadelphia; Lippincott Williams & Wilkins 2000: 136-171
  • 41 Marangell L B, Ketter T A, George M S, Pazzaglia P J, Callahan A M, Parekh P, Andreason P J, Horwitz B, Herscovitch P, Post R M. Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders.  Am J Psychiatr. 1997;  154 224-230
  • 42 Minoshima S, Giordani B, Berent S, Frey K A, Foster N L, Kuhl D E. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease.  Ann Neurol. 1997;  42 85-94
  • 43 Prange AJ J r, Wilson I C, Rabon A M, Lipton M A. Enhancement of imipramine antidepressant activity by thyroid hormone.  Am J Psychiatry. 1969;  126 457-469
  • 44 Refetoff S. Resistance to thyroid hormone. In: Braverman LE, Utiger RD, eds Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed Philadelphia; Lippincott Williams & Wilkins 2000: 1028-1043
  • 45 Reichlin S, Utiger R D. Regulation of the pituitary-thyroid axis in man: relationship of TSH concentration to concentration of free and total thyroxine in plasma.  J Clin Endocrinol Metab. 1967;  27 251-255
  • 46 Robbins J. Transthyretin from discovery to now.  Clin Chem Lab Med. 2002;  40 1183-1190
  • 47 Rudas S, Schmitz M, Pichler P, Baumgartner A. Treatment of refractory chronic depression and dysthymia with high-dose thyroxine.  Biol Psychiatr. 1999;  2 229-233
  • 48 Ruel J, Faure R, Dussault J H. Regional distribution of nuclear T3 receptors in rat brain and evidence for preferential localization in neurons.  J Endocrinol Invest. 1985;  8 343-348
  • 49 Schwartz H L, Oppenheimer J H. Nuclear triiodothyronine receptor sites in brain: probable identity with hepatic receptors and regional distribution.  Endocrinol. 1978;  103 267-273
  • 50 Sensenbach W, Madison L, Eisenberg S, Ochs L. The cerebral circulation and metabolism in hyperthyroidism and myxedema.  J Clin Invest. 1954;  33 1434-1440
  • 51 Silverman D HS, Geist C L, Van Herle K, Rasgon N, Martinez D, Miller K J, Haselrig T, Van Herle A J, Whybrow P C, Czernin J, Phelps M E, Bauer M. Abnormal regional brain metabolism in patients with hypothyroidism secondary to Hashimoto’s disease (abstract).  J Nucl Med. 2002;  43 (5, suppl) 254P
  • 52 Sokoloff L, Wechsler R L, Mangold R, Balls K, Kety S S. Cerebral blood flow and oxygen consumption in hyperthyroidism before and after treatment.  J Clin Invest. 1953;  32 202-208
  • 53 Stancer H C, Persad E. Treatment of intractable rapid-cycling manic-depressive disorder with levothyroxine.  Arch Gen Psychiatr. 1982;  39 311-312
  • 54 Sullivan G M, Hatterer J A, Herbert J, Chen X, Roose S P, Attia E, Mann J J, Marangell L B, Goetz R R, Gorman J M. Low levels of transthyretin in the CSF of depressed patients.  Am J Psychiatry. 1999;  156 710-715
  • 55 Toft A D. Thyroxine therapy.  N Engl J Med. 1994;  331 174-180
  • 56 Whybrow P C, Bauer M. Behavioral and psychiatric aspects of hypothyroidism. In: Braverman LE, Utiger RD, eds Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed Philadelphia; Lippincott Williams & Wilkins 2000: 837-842
  • 57 Whybrow P C, Bauer M. Behavioral and psychiatric aspects of thyrotoxicosis. In: Braverman LE, Utiger RD, eds Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed Philadelphia; Lippincott Williams & Wilkins 2000: 673-678
  • 58 Whybrow P C, Prange AJ J r. A hypothesis of thyroid-catecholamine-receptor interaction.  Arch Gen Psychiatr. 1981;  38 106-113
  • 59 Whybrow P C, Prange AJ J r, Treadway C R. Mental changes accompanying thyroid gland dysfunction.  Arch Gen Psychiatry. 1969;  20 48-63
  • 60 Whybrow P C. The therapeutic use of triiodothyronine and high-dose thyroxine in psychiatric disorder.  Acta med Austriaca. 1994;  21 47-52
  • 61 Whybrow P C. Sex differences in thyroid axis function: Relevance to affective disorder and its treatment.  Depression. 1995;  3 33-42
  • 62 Wilson I C, Prange AJ J r, Lara P P. L-Triiodothyronine alone and with imipramine in the treatment of depressed women. In: Prange AJ Jr (ed.) The Thyroid Axis, Drugs, and Behavior. Raven Press New York; 1974: 49-62

Michael Bauer, M.D., Ph. D.

Department of Psychiatry and Psychotherapy

Charité - University Medicine Berlin

Campus Charité-Mitte (CCM)

Schumannstr. 20/21

10117 Berlin


Phone: +49-30-450 51 70 70

Fax: +49-30-450-51 79 62