Influence of Levothyroxine in Augmentation Therapy for Bipolar Depression on Central Serotonergic Function

Abstract

Introduction: Adjunctive treatment with supraphysiological doses of levothyroxine (L-T₄) in bipolar depression shows promise, but the neurobiological mechanisms underlying clinical improvement are unknown. It has been postulated from animal studies that exogenous thyroid hormones may exert their modulatory effects in patients with affective disorders via an increase in serotonergic neurotransmission. Therefore, we investigated the loudness dependence of auditory evoked potentials (LDAEP) as a measure of central serotonergic activity and response to L-T4.

Methods: This 6-week, double-blind, randomized, placebo-controlled study assessed the efficacy of L-T₄ adjunctive to continuing treatment with mood stabilizer and/or antidepressant medication in 20 patients with bipolar depression. LDAEP was assessed before and after treatment with L-T₄.

Results: Scores of the Hamilton Depression Rating Scale and Montgomery Asberg Depression Rating Scale decreased significantly during the study. There was no difference in pre- and post-treatment LDAEP between the groups, and no correlation between LDAEP and psychometric measures in the course of the study.

Discussion: The hypothesis of a relationship between response of augmentation therapy with levothyroxine in bipolar depression and serotonergic activity could not be confirmed.

Key words

bipolar depression - serotonin - loudness dependence of auditory evoked potentials - augmentation - levothyroxine

^* Authors contributed equally.

• References

• 1 Bauer M, Ritter P, Grunze H et al. Treatment options for acute depression in bipolar disorder. Bipolar Disord 2012; 14: 37-50
• 2 Bauer M, Whybrow PC. Thyroid hormone, neural tissue and mood modulation. World J Biol Psychiatr 2001; 2: 57-67
• 3 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. San Diego: Academic Press; 2002: 239-264
• 4 Bauer M, Hellweg R, Gräf KJ et al. Treatment of refractory depression with high-dose thyroxine. Neuropsychopharmacology 1998; 18: 444-455
• 5 Bauer M, London ED, Rasgon N et al. Supraphysiological doses of levothyroxine regional cerebral alter metabolism and improve mood in bipolar depression. Mol Psychiatry 2005; 10: 456-469
• 6 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
• 7 Whybrow PC, Prange Jr AJ. A hypothesis of thyroid-catecholamine-receptor interaction. Arch Gen Psychiatry 1981; 38: 106-113
• 8 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
• 9 Hegerl U, Juckel G. Intensity dependence of auditory evoked potentials as an indicator of central serotonergic neurotransmission: a new hypothesis. Biol Psychiatry 1993; 33: 173-187
• 10 Juckel G, Molnar M, Hegerl U et al. Auditory-evoked potentials as indicator of brain serotonergic activity – first evidence in behaving cats. Biol Psychiatry 1997; 41: 1181-1195
• 11 Juckel G, Hegerl U, Molnar M et al. Auditory evoked potentials reflect serotonergic neuronal activity – a study in behaving cats administered drugs acting on 5-HT1A autoreceptors in the dorsal raphe nucleus. Neuropsychopharmacology 1999; 21: 710-716
• 12 Juckel G, Gallinat J, Riedel M et al. Serotonergic dysfunction in schizophrenia assessed by the loudness dependence measure of primary auditory cortex evoked activity. Schizophr Res 2003; 64: 115-124
• 13 Juckel G, Mavrogiorgou P, Bredemeier S et al. Loudness dependence of primary auditory-cortex-evoked activity as predictor of therapeutic outcome to prophylactic lithium treatment in affective disorders – a retrospective study. Pharmacopsychiatry 2004; 37: 46-51
• 14 Pogarell O, Tatsch K, Juckel G et al. Serotonin and dopamine transporter availabilities correlate with the loudness dependence of auditory evoked potentials in patients with obsessive-compulsive disorder. Neuropsychopharmacology 2004; 29: 1910-1917
• 15 Stamm T, Lewitzka L, Sauer C et al. Supraphysiologic doses of levothyroxine as adjunctive therapy in bipolar depression: a randomized, double-blind, placebo-controlled study. J Clin Psychiat 2013; [epub ahead of print]
• 16 Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56-62
• 17 Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134: 382-389
• 18 Young RC, Biggs JT, Ziegler VE et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978; 133: 429-435
• 19 Uhl I, Gorynia I, Gallinat J et al. Is the loudness dependence of auditory evoked potentials modulated by the selective serotonin reuptake inhibitor citalopram in healthy subjects?. Hum Psychopharmacol 2006; 21: 463-471
• 20 Cuellar AK, Johnson SL, Winters R. Distinction between bipolar and unipolar depression. Clin Psychol Rev 2005; 25: 307-339
• 21 Park YM, Lee SH, Kim S et al. The loudness dependence of the auditory evoked potential (LDAEP) in schizophrenia, bipolar disorder, major depressive disorder, anxiety disorder, and healthy controls. Prog Neuropsychopharmacol Biol Psychiatry 2010; 17: 313-316
• 22 Ostermann J, Uhl I, Köhler E et al. The loudness dependence of auditory evoked potentials and effects of psychopharmacotherapy and psychopathology in a sample of psychiatric inpatients. Hum Psychopharmacology 2012; 27: 595-604
• 23 Linka T, Sartory G, Gastpar M et al. Clinical symptoms of major depression are associated with the intensity dependence of auditory event-related potential components. Psychiatry Res 2009; 30: 139-143
• 24 Juckel G, Pogarell O, Augustin H et al. Differential prediction of first clinical response to serotonergic and noradrenergic antidepressants using the loudness dependence of auditory evoked potentials in patients with major depressive disorder. J Clin Psychiatry 2007; 68: 1206-1212
• 25 Park YM, Kim DW, Kim S et al. The loudness dependence of the auditory evoked potential (LDAEP) as a predictor of the response to escitalopram in patients with generalized anxiety disorder. Psychopharmacology (Berl) 2011; 213: 625-632
• 26 Oliva J, Leung S, Croft RJ et al. The loudness dependence auditory evoked potential is insensitive to acute changes in serotonergic and noradrenergic neurotransmission. Hum Psychopharmacol 2010; 25: 423-427
• 27 Simmons JG, Nathan PJ, Berger G et al. Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants. Psychopharmacology (Berl) 2011; 217: 101-110