Original article| Volume 53, ISSUE 10, P899-905, May 15, 2003

Thyroid hypofunction in patients with rapid-cycling bipolar disorder after lithium challenge

  • Laszlo Gyulai
    Address reprint requests to Laszlo Gyulai, M.D., Bipolar Disorders Program, Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Suite 670, Philadelphia PA 19104, USA.
    Bipolar Disorders Program, Department of Psychiatry (LG), University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Michael Bauer
    Department of Psychiatry and Psychotherapy, Charité University Hospital, Humboldt University at Berlin (MB), Berlin, Germany

    Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Hospital (MB, PCW), University of California, Los Angeles, Los Angeles, California, USA
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  • Mark S Bauer
    Veteran’s Administration Medical Center (MSB), Providence, Rhode Island, USA
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  • Felipe García-España
    Department of Psychiatry (FG-E), Philadelphia, Pennsylvania, USA
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  • Avital Cnaan
    Department of Pediatrics, Division of Biostatistics and Epidemiology (AC), University of Pennsylvania, Philadelphia, Pennsylvania, USA
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  • Peter C Whybrow
    Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Hospital (MB, PCW), University of California, Los Angeles, Los Angeles, California, USA
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      There is debate whether patients with rapid-cycling bipolar disorder (BD) are predisposed to thyroid axis abnormalities and whether this may contribute to development of rapid mood shifts. Using lithium carbonate as a challenge to the hypothalamic-pituitary-thyroid (HPT) system, we determined whether patients with rapid-cycling BD are sensitive to the “antithyroid” properties of lithium.


      We studied the response to thyrotropin-releasing hormone (TRH) of HPT system hormones in 20 medication-free patients with rapid-cycling BD and compared these measurements with those of 20 healthy age- and gender-matched control subjects. The same measurements were repeated after both groups had received lithium carbonate for 4 weeks in sufficient doses to maintain blood levels between .7–1.2 mEq/L.


      At baseline, the results of thyroid function tests, including the TRH challenge test, did not differ between patients and control subjects. After treatment with lithium, serum concentrations of thyroxine significantly decreased, whereas basal thyrotropin (TSH) and ΔTSHmax significantly increased in both patients and control subjects; however, patients had significantly higher ΔTSHmax after TRH stimulation. More patients than control subjects developed laboratory evidence consistent with grade III hypothyroidism after lithium treatment.


      Rapid-cycling BD is associated with a latent hypofunction of the HPT system. This dysfunction becomes manifest with short-term lithium challenge.


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        • Albert P.S.
        Longitudinal data analysis (repeated measures) in clinical trials.
        Stat Med. 1999; 18: 1707-1732
        • Bartalena L.
        • Pellegrini L.
        • Meschi M.
        • Antonangeli L.
        • Bogazzi F.
        • Dell’Osso L.
        • et al.
        Evaluation of thyroid function in patients with rapid-cycling and non-rapid-cycling bipolar disorder.
        Psychiatry Res. 1990; 34: 13-17
      1. Bauer M, Berghöfer A, Bschor T, Baumgartner A, Kiesslinger U, Hellweg R, et al (2002): Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. Neuropsychopharmacology 27:620–628

        • Bauer M.S.
        • Calabrese J.
        • Dunner D.L.
        • Post R.
        • Whybrow P.C.
        • Gyulai L.
        • et al.
        Multisite data reanalysis of the validity of rapid cycling as a course modifier for bipolar disorder in DSM-IV.
        Am J Psychiatry. 1994; 151: 506-515
        • Bauer M.S.
        • Whybrow P.C.
        Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine.
        Arch Gen Psychiatry. 1990; 47: 435-440
        • Bauer M.S.
        • Whybrow P.C.
        • Winokur A.
        Rapid cycling bipolar affective disorder. I. Association with grade I hypothyroidism.
        Arch Gen Psychiatry. 1990; 47: 427-432
        • Baumgartner A.
        • Pinna G.
        • Hiedra L.
        • Gaio U.
        • Hessenius C.
        • Campos-Barros A.
        • et al.
        Effects of lithium and carbamazepine on thyroid hormone metabolism in rat brain.
        Neuropsychopharmacol. 1997; 16: 25-41
        • Child C.
        • Nolan G.
        • Jubiz W.
        Changes in serum thyroxine, triiodothyronine, and thyrotropin induced by lithium in normal subjects and in rats.
        Clin Pharmacol Ther. 1977; 20: 715-719
        • Cho J.T.
        • Bone S.
        • Dunner D.L.
        • Colt E.
        • Fieve R.R.
        The effect of lithium treatment on thyroid function in patients with primary affective disorder.
        Am J Psychiatry. 1979; 136: 115-116
        • Coryell W.
        • Endicott J.
        • Keller M.
        Rapidly cycling affective disorder. Demographics, diagnosis, family history, and course.
        Arch Gen Psychiatry. 1992; 49: 126-131
        • Cowdry R.W.
        • Wehr T.A.
        • Zis A.P.
        • Goodwin F.K.
        Thyroid abnormalities associated with rapid-cycling bipolar illness.
        Arch Gen Psychiatry. 1983; 40: 414-420
        • Crantz F.R.
        • Silva J.E.
        • Larsen P.R.
        Analysis of the sources and quantity of 3,5,3′-iodothyronine specifically bound to nuclear receptors in rat cerebral cortex and cerebellum.
        Endocrinology. 1982; 110: 367-375
        • Dunner D.
        • Fieve R.
        Clinical factors in lithium carbonate prophylaxis failure.
        Arch Gen Psychiatry. 1974; 30: 229-233
        • Gary K.A.
        • Winokur A.
        • Douglas S.D.
        • Kapoor S.
        • Zaugg L.
        • Dinges D.F.
        Total sleep deprivation and the thyroid axis.
        Aviat Space Environ Med. 1996; 67: 513-519
        • Grof E.
        • Grof P.
        • Brown G.M.
        • Downie S.
        Lithium effects on neuroendocrine function.
        Prog Neuropsychopharmacol Biol Psychiatry. 1984; 8: 541-546
        • Hahn C.G.
        • Pawlyk A.C.
        • Whybrow P.C.
        • Gyulai L.
        • Tejani-Butt S.M.
        Lithium administration affects gene expression of thyroid hormone receptors in rat brain.
        Life Sci. 1999; 64: 1793-1802
        • Hahn C.G.
        • Pawlyk A.C.
        • Whybrow P.C.
        • Tejani-Butt S.M.
        Differential expression of thyroid hormone receptor isoforms by thyroid hormone and lithium in rat GH3 and B103 cells.
        Biol Psychiatry. 1999; 45: 1004-1012
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Joffe R.T.
        • Kutcher S.
        • MacDonald C.
        Thyroid function and bipolar affective disorder.
        Psychiatry Res. 1988; 25: 117-121
        • Kupka R.W.
        • Nolen W.A.
        • Post R.M.
        • McElroy S.L.
        • Altshuler L.L.
        • Denicoff K.D.
        • et al.
        High rate of autoimmune thyroiditis in bipolar disorder.
        Biol Psychiatry. 2002; 51: 305-311
        • Kusalic M.
        Grade II and grade III hypothyroidism in rapid-cycling bipolar patients.
        Neuropsychobiology. 1992; 25: 177-181
        • Kushner J.P.
        • Wartofsky L.
        Lithium-thyroid interactions-An overview.
        in: Johnson F.N. Lithium Therapy Monographs. Vol. 2: Lithium and the Endocrine System. Karger, Basel1988: 74-98
        • Lauridsen U.B.
        • Kirkegaard C.
        • Nerup J.
        Lithium and the pituitary-thyroid axis in normal subjects.
        J Clin Endocrinol Metab. 1974; 39: 383-385
        • Lazarus J.H.
        The effects of lithium therapy on thyroid and thyrotropin-releasing hormone.
        Thyroid. 1998; 8: 909-913
        • Lazarus J.H.
        • Bennie E.H.
        Effect of lithium on thyroid function in man.
        Acta Endocrinol. 1972; 70: 266-272
        • Lombardi G.
        • Panza N.
        • Biondi B.
        • Di Lorenzo L.
        • Lupoli G.
        • Muscettola G.
        • et al.
        Effects of lithium treatment on hypothalamic-pituitary-thyroid axis.
        J Endocrinol Invest. 1993; 16: 259-263
        • Loranger A.W.
        Personality Disorders Examination (PDE). D.V. Communications, Yonkers, New York1988
        • Maj M.
        • Magliano L.
        • Pirozzi R.
        • Marasco C.
        • Guarneri M.
        Validity of rapid cycling as a course specifier for bipolar disorder.
        Am J Psychiatry. 1994; 151: 1015-1019
        • McKeon P.
        • Manley P.
        • Swanwick G.
        Manic-depressive illness—I. Clinical characteristics in bipolar subtypes.
        Irish J Psychol Med. 1992; 9: 6-9
        • McLarty D.G.
        • O’Boyle J.H.
        • Spencer C.A.
        • Ratcliffe J.G.
        Effect of lithium on hypothalamic-pituitary-thyroid function in patients with affective disorders.
        Br Med J. 1975; 3: 623-626
        • Mori M.
        • Tajima K.
        • Oda Y.
        • Matsui I.
        • Mashita K.
        • Tarui S.
        Inhibitory effect of lithium on the release of thyroid hormones from thyrotropin-stimulated mouse thyroids in a perifusion system.
        Endocrinology. 1989; 124: 1365-1369
        • Myers D.H.
        • Carter R.A.
        • Burns B.H.
        • Armond A.
        • Hussain S.B.
        • Chengapa V.K.
        A prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies.
        Psychological Med. 1985; 15: 55-61
        • Oomen H.A.P.C.
        • Schipperijn A.J.M.
        • Drexhage H.A.
        The prevalence of affective disorder and in particular of a rapid cycling of bipolar disorder in patients with abnormal thyroid function tests.
        Clin Endocrinol. 1996; 45: 215-223
        • Perrild H.
        • Hegedues L.
        • Arnung K.
        Sex related goitrogenic effect of lithium carbonate in healthy young subjects.
        Acta Endocrinol. 1984; 106: 203-208
        • Post R.M.
        • Kramlinger K.G.
        • Joffe R.T.
        • Roy-Byrne P.R.
        • Rosoff A.
        • Frye M.A.
        • Huggins T.
        Rapid cycling bipolar affective disorder.
        Psychiatry Res. 1997; 72: 1-7
        • Sack D.A.
        • James S.P.
        • Rosenthal N.E.
        • Wehr T.A.
        Deficient nocturnal surge of TSH secretion during sleep and sleep deprivation in rapid-cycling bipolar illness.
        Psychiatry Res. 1988; 23: 179-191
        • Smigan L.
        • Wahlin A.
        • Jacobsson L.
        • von Knorring L.
        Lithium therapy and thyroid function tests.
        Neuropsychobiology. 1984; 11: 39-43
        • Spitzer R.L.
        • Williams J.B.W.
        • Gibbon M.
        • First M.B.
        Structural Clinical Interview for DSM-III-R—Patient Edition. New York State Psychiatric Institute, New York1989
        • St Germain D.
        Regulatory effect of lithium on thyroxine metabolism in murine neural and anterior pituitary tissue.
        Endocrinology. 1987; 120: 1430-1438
        • Takahashi S.
        • Kondo H.
        • Yoshimura M.
        • Ochi Y.
        Thyroid function levels and thyrotropin responses to TRH administration in manic patients receiving lithium carbonate.
        Folia Psychiatr Neurol Jpn. 1975; 29: 231-237
        • Villeneuve A.
        • Gautier J.
        • Jus A.
        • Perron D.
        The effect of lithium on thyroid in man.
        Int J Clin Pharmacol. 1974; 9: 75-80
        • Wehr T.A.
        • Sack D.A.
        • Rosenthal N.E.
        • Cowdry R.W.
        Rapid cycling affective disorder.
        Am J Psychiatry. 1988; 145: 179-184
        • Wenzel K.W.
        • Meinhold H.
        • Raffenberg M.
        • Adlkofer F.
        • Schleusner H.
        Classification of hypothyroidism in evaluating patients after radioiodine therapy by serum cholesterol, T3-uptake, total T4, fT4-index, total T3, basal TSH and TRH test.
        Eur J Clin Invest. 1974; 4: 141-148
        • Whybrow P.C.
        The therapeutic use of triiodothyronine and high-dose thyroxine in psychiatric disorder.
        Acta Med Austriaca. 1994; 21: 47-52
        • Winokur A.
        • Caroff S.N.
        • Amsterdam J.D.
        • Maislin G.
        Administration of thyrotropin-releasing hormone at weekly intervals results in a diminished thyrotropin response.
        Biol Psychiatry. 1984; 19: 695-702
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        • Meyer D.A.
        A rating scale for mania.
        Br J Psychiatry. 1978; 133: 429-435
        • Zeger S.L.
        • Liang K.Y.
        • Albert P.S.
        Models for longitudinal data.
        Biometrics. 1988; 44: 1049-1060