Brain as a Target for Triiodothyronine

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1 Brain as a Target for Triiodothyronine Robertas Bunevičius MD, PhD Institute of Psychophysiology and Rehabilitation Lithuanian University of Health Sciences Cambridge, 2012

2 Institute of Psychophysiology and Rehabilitation of the Lithuanian University of Health Sciences Palanga, Lithuania

5 Relative risk of coronary heart disease in patients with clinical depression and traditional risk factors. Rozanski et al., 2005

6 Freedom from cardiac mortality after MI related to severity of depression. Lesperance et al. 2002

7 Jiang et al., 2007

10 Staniute et al., 2012

11 Staniute et al., 2012

12 Contribution of depression to development and promotion of CAD Lett et al., 2004

13 Glial Cell Neuron CSF Tanycyte TR DNA Nucleus mrna Protein T3 T4 MCT8? T4 D2 T3? MCT8 T3 D3 T2? ChP OATP1c1 MCT8 T4 T3 OATP1c1 T4? T3 Endothelium Circulation Thyroid hormone delivery and metabolism in the brain. BBB Bunevicius & Prange, Neuropsychiatric disorders, Springer, 2010

T3 Endothelium Circulation Thyroid hormone delivery and metabolism in

14 HPT Axis Function in Depression Blunted TSH response to TRH stimulation in depression (Prange et al., 1972; Bunevičius et al., 1994) Diminished nocturnal surge of TSH (Bartalena et al., 1990) High T4 and low TSH concentrations (Forman- Hoffman & Philibert, 2006) Low T3 concentration (Wang & Shin, 1989; Premachandra et al.,2006)

, 1994) Diminished nocturnal surge of TSH (Bartalena et al.

15 The relationship of deiodinase 1 genotype and thyroid function to lifetime history of major depression (Philibert et al., 2011) 1,555 subjects from three longitudinal ethnically diverse wellcharacterized studies for lifetime MD and thyroid function no association of current FT4 levels with lifetime MD in either ethnic group two variants in DIO1 (including rs ), were associated with altered FT4 levels in both White and African American subjects DIO1 rs genotype was associated with lifetime MD in white female subjects, in particular those from high-risk cohorts

of current FT4 levels with lifetime MD in either ethnic group two variants in DIO1 (including rs11206244), were associated with altered FT4

16 Bunevicius et al., Clin Cardiology, 2006

17 Associations of fatigue and exercise capacity with thyroid hormone and cortisol concentrations in 83 patients with CAD, β (p). Free T 3 Free T 4 TSH Cortisol AM Cortisol MFI -20 General fatigue Univariate Multivariate* (.015) (.029) MFI -20 Physical fatigue Univariate Multivariate* (.007) (.030) MFI -20 Univariate (.082) (.023) Mental fatigue Multivariate* -.200(.027) Dutch Exertion Fatigue Scale Univariate Multivariate* (.006) (.009) Exercise capacity (Watts) Univariate Multivariate* (.085) *Multivariate models, adjusted for age, gender, BMI, NYHA class, symptoms of depression and symptoms of anxiety Bunevicius et al., Psychosom Med, submitted

007) -.224 (.030) MFI -20 Univariate -.192 (.082) -.250 (.023) Mental fatigue Multivariate* -.200(.027) Dutch Exertion Fatigue Scale Univariate Multivariate* -.300 (.006) -.

18 Significant associations of health-related quality of life with thyroid hormone and cortisol concentrations in 122 patients with CAD, β (p). SF-36 Free T 3 ln Free T 4 Cortisol AM Cortisol PM ln Physical functioning Univariate.223 (.022).286 (.003) Multivariate*.233 (.014) Role limitations due to Univariate.315 (.001) emotional problems (ln) Multivariate*.358 (<.001) Social functioning Univariate.211 (.030).247 (.011) Mental health Energy/vitality Pain General health perception Multivariate* Univariate Multivariate* Univariate Multivariate* Univariate Multivariate* Univariate Multivariate*.215 (.028).214 (.021).169 (.039).204 (.037).228 (.019).187 (.031).199 (.041).250 (.010).264 (.009) (.005) (.027) (.017) *Multivariate models, adjusted for age, gender, BMI, NYHA class, symptoms of depression and symptoms of anxiety Cortisol (.015) (.022) Bunevicius et al., Psychoneuroendocrinology, submitted

001) emotional problems (ln) Multivariate*.358 (<.001) Social functioning Univariate.211 (.030).247 (.

19 Scores on well-being questionnaires by OATP1c1 genotype in hypothyroidism treated with T4 Wendy M. van der Deure et al. 2008

20 DIO2 polymorphism and well-being in hypothyroidism treated with T4

21 Bunevicius et al., NEJM, 1999

22 Preference of T4 vs. T4+T3 Bunevicius et al Walsh et al Sawka et al Clyde et al Siegmund et al.2004 Saravanan et al Escobar-Morreale et al Appelhof et al Nygaard et al T4+T3 T4 =T4+T3 Not assessed Not assessed Not assessed T4+T3 T4+T3 T4+T3 T4+T3

23 N=552 Visit 1 at baseline Visit 2 at 3 months Visit 3 at 12 months Significant effect of the interaction between the DIO2 genotype and treatment at follow-up (visits 2 and 3) on GHQ scores, TSQ scores and satisfaction. For GHQ and TSQ scores, higher scores indicate worse wellbeing. For satisfaction higher scores indicate more satisfied. Squares and continuous line T4/T3 treatment group, Triangles and dashed line T4 only group.

24 Lithium vs. T3 augmentation in Star*D study Nierenberg et al., 2006

25 Sertraline and liothyronine in major depression Cooper-Kazaz et al. 2007

27 Acceleration of Escitalopram effects with T3 in depressed women HAM-D 17 VAS - depression T3 Placebo Triiodothyronine Placebo days days Bunevicius et al., unpublished

28 Conclusions Low T3 syndrome is related to both cardiac function and mental function. Low T3 syndrome may be a physiological mechanism connecting CAD with depression, fatigue and HRQoL in vulnerable patients. Compensation of low T3 syndrome may lead to improvement in both cardiac and psychological function. Polymorphism of Thyroid axis related proteins may play a role in T3 effects

29 Thank you for attention and T3!

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