http://informahealthcare.com/erc ISSN: 0743-5800 (print), 1532-4206 (electronic) Endocr Res, Early Online: 1–6 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/07435800.2014.896924
Depressive symptoms in patients with subclinical hypothyroidism – the effect of treatment with levothyroxine: a double-blind randomized clinical trial* Laily Najafi, Mojtaba Malek, Ali Hadian, Ameneh Ebrahim Valojerdi, Mohammad E. Khamseh, and Rokhsareh Aghili
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Endocrine Research Center (Firouzgar), Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
Abstract
Keywords
Despite the increasing evidence for relationships between thyroid dysfunction and neuropsychiatric alterations, the effect of treatment of thyroid disease on various clinical psychiatric outcomes is controversial. The purpose of this study was to investigate the effect of levothyroxine treatment on depressive symptoms in subjects with subclinical hypothyroidism. A randomized double-blind placebo-controlled clinical trial was performed. Sixty subjects (51 females and 9 males) with subclinical hypothyroidism were enrolled. Beck Depression Inventory was completed for all participants at the beginning of the study and 12 weeks after enrollment. The intervention and control groups received levothyroxine and placebo, respectively, for 12 weeks. There were no statistical differences in the total depression score and its subscales between the two groups at the beginning of the study. The Beck Depression Inventory score decreased from 16.79 ± 13.25 to 12.37 ± 10.01 (p value ¼ 0.04) in the intervention group. The change in score was not significant for the control group (13.77 ± 11.71 to 11.86 ± 10.71; p value¼ 0.16). The affective subscale of Beck Depression Inventory did not change after 12 weeks of treatment with levothyroxine, while somatic subscale remarkably improved in the intervention group (p value ¼ 0.02). This study showed the efficacy of treatment of subclinical hypothyroidism in people with levothyroxine in relation to depressive symptoms.
Affective subscale, Beck Depression Inventory, depression, neuropsychiatric alterations, somatic subscale, thyroid dysfunction
Introduction Depression is a common and disabling disorder that affects 2–16% of adults (1). Although several behavioral and biologic factors may be involved in precipitating and perpetuating the symptoms of depression (2–9), the principal causes are not clear. Thyroid dysfunction may impair quality of life. Many investigators have recommended that either overt or subclinical hypothyroidism (SCH) is associated with an increase in the number and severity of depressive symptoms (10–12). Subclinical hypothyroidism is a term applied to individuals with a normal serum free thyroxine (T4) concentration and an increased serum thyrotropin (TSH). The prevalence of SCH is 4–10% in the adult population (13), and it has been associated with different negative clinical outcomes and an increased
*Place that study was performed: Endocrine Research Center (Firouzgar), Institute of Endocrinology & Metabolism, Iran University of Medical Sciences (IUMS). Correspondence: Dr. Mohammad E. Khamseh, MD, Director, Endocrine Research Center (Firouzgar), Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Firouzgar alley, Valadi St., Behafarin St., Karimkhan Ave., Vali-Asr Sq., 1593748711, Tehran, Iran. Tel: +98 21 88945172, 98 21 88945247. Fax: +98 21 88945173. E-mail: [email protected]
History Received 3 July 2013 Revised 30 November 2013 Accepted 17 February 2014 Published online 17 February 2015
risk of overt thyroid dysfunction (14). The most frequently cited symptoms are memory deficit, despondency, symptoms of depression, and anxiety (15). Clinical manifestations differ with age, duration, and severity of hormone shortage and are usually non-specific (16–18). In a literature review, we found one study showing an increased prevalence of previous depressive episodes in patients with SCH (19). Placidi et al. (20) reported a rate of 63% for psychiatric diagnosis in a sample of patients with thyroid dysfunction. In another study, anxiety and depression were more frequent in SCH compared with the control group (21). It is reported that treatment of thyroid dysfunction reduces psychiatric symptoms in general (22,23). In addition, policy makers suggest screening and treatment of SCH to prevent progression to overt thyroid dysfunction and to improve clinical outcomes, especially in elderly individuals (24–27). Despite the growing evidence for relationships between thyroid dysfunction and neuropsychiatric alterations, the effect of treatment on various clinical outcomes is controversial. Some studies reported an improvement of depressive symptoms after treatment with levothyroxine (28–30). However, the results of a randomized trial on treatment of SCH subjects and its effect on quality of life were inconclusive (31). The purpose of the current study was to investigate
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the effect of levothyroxine treatment on depressive symptoms in subjects with subclinical hypothyroidism.
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Methods Sixty patients with subclinical hypothyroidism referred to the Thyroid Clinic of the Institute of Endocrinology and Metabolism were recruited to a randomized double-blind, placebo-controlled clinical trial from September 2010 to August 2011. A simple blocked randomization method was used for the allocation of patients into two groups. Subjects who had a history of endocrine or autoimmune diseases other than subclinical hypothyroidism—for example, overt hypothyroidism, myxedema coma, proven psychiatric disorder, history of thyroid hormone, or corticosteroids replacement in the previous 2 months—were excluded from the study. Subjects who had diabetes mellitus, heart failure, chronic liver or pulmonary disorder, history of head trauma, seizure, known psychological or mental disorders and those who were pregnant were also excluded. The ethics committee of Tehran University of Medical Sciences approved the protocol and written informed consent was obtained from all participants. A detailed history and physical examination were performed for each patient by an expert physician. Demographic and clinical parameters including sex, age, occupation, level of education, as well as history of concurrent systemic diseases and use of medications were obtained via face-to-face patient interviewing. The anthropometric measures were undertaken by a trained nurse. Standing height was measured using a stadiometer (Seca Gmbh & Co., Hamburg, Germany) that was calibrated before each measurement and weight was measured using a calibrated digital scale (Seca Gmbh). Body mass index (BMI) was defined as weight (in kg) over height squared (in meters). Blood pressure was measured under standardized conditions (sitting position, after 5 min of resting; cessation of smoking, drinking tea or coffee or eating food for at least half an hour). Beck Depression Inventory (BDI-II) (Persian version) (32) was completed for all participants at the beginning of the study and 12 weeks after enrollment. The Inventory and thyroid hormone parameters of patients with subclinical hypothyroidism were compared to age- and sex-matched controls at enrollment and by the end of the study. The intervention group received 100 mg of levothyroxine (Iran Hormone Product) and the control group received placebo for 12 weeks. The participants were asked to bring the remaining tablets to the clinic to assess their compliance. Definition of subclinical hypothyroidism Subclinical hypothyroidism was defined as serum TSH level higher than 4.5 mIU/L in the presence of normal free T4 (0.8–2 ng/dl) and positive anti-TPO-Ab. Beck Depression Inventory The Beck Depression Inventory (BDI, BDI-II), created by Dr. Aaron T. Beck, is a 21-question multiple-choice selfreport inventory. It is one of the most widely used instruments for measuring the severity of depression. The BDI was originally developed to provide a quantitative assessment of
Endocr Res, Early Online: 1–6
the intensity of depression. Because it is designed to reflect the depth of depression, it can monitor changes over time and provide an objective measure for judging improvement and the effectiveness or otherwise of treatment methods (33). The BDI-II is a 1996 revision of the BDI (34), developed in response to the American Psychiatric Association’s publication of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), which changed many of the diagnostic criteria for Major Depressive Disorder. The cutoffs used differ from the original scores. The depth of depression is categorized as minimal depression (score ¼ 0–13), mild depression (score ¼ 14–19), moderate depression (score ¼ 20–28), and severe depression (score ¼ 29–63). Higher total scores indicate more severe depressive symptoms. The inventory defines two components for depression: the affective component (e.g. mood) and the physical or ‘‘somatic’’ component (e.g. loss of appetite). The BDI-II reflects this concept in two subscales. The purpose of the subscales is to help to determine the primary cause of a patient’s depression. The affective subscale contains eight items: pessimism, past failures, guilty feelings, punishment feelings, self-dislike, self-criticalness, suicidal thoughts or wishes, and worthlessness. The somatic subscale consists of 13 items: sadness, loss of pleasure, crying, agitation, loss of interest, indecisiveness, loss of energy, change in sleep patterns, irritability, change in appetite, concentration difficulties, tiredness and/or fatigue, and loss of interest in sex. The two subscales are moderately correlated at 0.57, suggesting that the physical and psychological aspects of depression are related rather than totally distinct (35,36). Laboratory measurements After an overnight fast (12 h), patients had venous blood samples taken for measurement of TSH, T4, and antiTPO-Ab. TSH was measured by the IRMA method using a standard kit (ImmunoTech kit) supplied by ImmunoTech Co. (Prague, Czech Republic). T4 and anti-TPO-Ab were measured by the RIA method using a standard kit (ImmunoTech kit) supplied by ImmunoTech Co. (Prague, Czech Republic). Statistical analysis All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 18.0, SPSS, Chicago, IL). Descriptive statistics methods (mean ± SD) were used for the baseline characteristics. We used nonparametric tests for comparison of quantitative variables (Mann–Whitney U test, McNemar test, and Wilcoxon test). Pearson’s correlation coefficient test was used for the assessment of correlation between quantitative variables. The p value 50.05 was taken as the cut-off level for the statistical significance. Results were presented with 95% confidence intervals (CIs).
Results In this study, 60 subclinical hypothyroid subjects were divided randomly into two groups, the intervention and the control group. The mean age of the participants was 34 ± 10
Depression and subclinical hypothyroidism
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DOI: 10.3109/07435800.2014.896924
years and 85% of them were female. The control group was composed of 25 females and 5 males (mean age: 36.07 years, range: 21–58 years) and the intervention group consisted of 26 females and 4 males (mean age: 32.37 years, range: 19–53 years). The mean for BMI was 24.9 ± 5.19. There were no statistical differences in the total depression score (intervention group: 17.07 ± 14.51 versus control group: 14.24 ± 11.35; p value ¼ 0.37) and the scores for the affective (intervention group: 4.45 ± 4.92 versus control group: 4.78 ± 5.17; p value ¼ 0.68) and somatic subscales (intervention group: 12.32 ± 10.71 versus control group: 9.11 ± 6.62; p value ¼ 0.15) at the beginning of the study. Baseline characteristics and thyroid hormone parameters of the participants are shown in Table 1. No correlation was detected between age and Beck Depression Inventory score. By the end of the study, serum TSH levels had normalized in all subjects in the intervention group. The changes in biochemical parameters from baseline are shown in Table 2. The most prevalent symptoms of subclinical hypothyroidism in two groups were weight gain, fatigue, muscle cramp, irregular menstruation, and limb numbness before treatment; however, no significant improvement was detected after treatment (Table 3). With regard to the symptoms, brittle nails Table 1. Baseline characteristics and thyroid hormone parameters of the participants. Variables Age (years) Female n (%) BMI (kg/m2) TSH (mIU/L) T4 (mg/dL)
Intervention group
Control group
p Value
32.47 ± 11.35 25 (83) 24.9 ± 4.83 8.29 ± 4.9 7.38 ± 1.37
36.07 ± 11.35 26 (86) 25.39 ± 3.82 8.12 ± 3.12 7.41 ± 1.48
0.4 0.9 0.7 0.9 0.92
Data are mean ± SD unless otherwise indicated.
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in the intervention group after treatment had a significant correlation with TSH level (p value ¼ 0.03). By the end of the study, the Beck Depression Inventory score decreased from 16.79 ± 13.25 to 12.37 ± 10.01 (p value ¼ 0.04) in the intervention group. The change was not significant for the control group (13.77 ± 11.71 to 11.86 ± 10.71; p value ¼ 0.16). Regarding the severity of depression, minimal depression was the most prevalent form (53.8%). No statistical difference was observed in relation to the severity of depression between the intervention and control groups at baseline and at the end of the study. Furthermore, no correlation was detected between the severity of depression and the TSH level. We conducted an analysis for the subscales of BDI in the intervention and control groups. This analysis showed that the affective subscale did not change after 12 weeks of treatment with levothyroxine. In contrast, the somatic subscale remarkably improved in the intervention group (p value ¼ 0.02). The scores of BDI and its subscales are illustrated in Table 4. The effect size in somatic subscale in the intervention group was 0.39 (moderate) and the control group was 0.26 (low).
Discussion We found a remarkable improvement in the BDI score and its somatic subscale in the intervention group after 12 weeks of treatment with levothyroxine. Thyroid hormones play an important role in the maturation and proper function of the central nervous system (37,38), growth, puberty, and metabolism (39). Thyroid dysfunction is a graded phenomenon (40). There is increasing evidence suggesting that mild (subclinical) thyroid disorders may be potential contributors to significant clinical conditions (40). Subclinical hypothyroidism may progress to overt hypothyroidism by 3–18% per year,
Table 2. Biochemical parameters before and after the treatment. Intervention group Variables TSH (mIU/L) T4 (mg/dL)
Baseline
a
8.29 ± 4.9 7.38 ± 1.37
Week 12
a
2.007 ± 1.34 8.607 ± 2.05
Control group a
p Value
Baseline
0.000 0.004
8.12 ± 3.12 7.41 ± 1.48
Week 12a
p Value
7.82 ± 5.17 8.13 ± 1.98
0.733 0.093
a
Data are shown as mean ± SD.
Table 3. The frequency of symptoms of subclinical hypothyroidism in the intervention and the control groups. Intervention group Symptoms Weight gain Dry skin Fatigue Muscle cramps Hoarseness Constipation Irregular menstruation Feel cold Dry hair Brittle nails Foot puffiness Limb numbness a
Data are shown as n (%).
a
Baseline (%) 17 13 25 19 5 7 11 12 7 11 4 14
(56.7) (43.3) (83.3) (63.3) (16.7) (23.3) (36.7) (40) (23) (37) (13) (46.7)
a
Week 12 (%) 10 9 23 15 3 4 9 15 9 17 5 13
(33.3 (30) (76.7) (50) (10) (13.3) (30) (50) (30) (57) (16) (44)
Control group p Value 0.11 0.34 0.4 0.34 0.6 0.5 0.7 0.39 1 0.07 0.62 1
a
Baseline (%) 16 14 25 17 4 10 24 11 11 12 1 8
(53 (46.7) (83.3) (56.7) (13.3) (33.3) (80) (37) (37) (40) (3.3) (27)
Week 12a (%) 9 11 24 15 4 7 24 8 7 7 1 11
(30) (36.7) (80) (50) (13.3) (23.3) (80) (27) (23) (23) (3.3) (37)
p Value 0.06 0.45 1 0.77 1 0.3 1 0.25 0.45 0.12 1 0.51
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Table 4. Scores of Beck Depression Inventory and its subscales at baseline and week 12. Intervention group Score b
BDI Affective subscale Somatic subscale
Baseline
a
16.79 ± 13.25 4.48 ± 5.08 12.32 ± 10.24
Week 12
a
12.37 ± 10.01 3.62 ± 5.27 9.12 ± 5.98
Control group a
p Value
Baseline
0.04 0.2 0.02
13.77 ± 11.71 4.78 ± 5.17 8.91 ± 6.95
Week 12a
p Value
11.86 ± 10.71 4.56 ± 4.68 7.08 ± 6.82
0.16 0.8 0.03
a
Data are shown as mean ± SD. Beck Depression Inventory.
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b
especially in the elderly (41,42). In comparison with overt hypothyroidism, which affects approximately 1% of the general population, SCH is a much more common disorder whose prevalence varies from 5% to 17% of the general population. The prevalence increases with age and gender, affecting 25% of women over 60 years of age (43). Patients with SCH may present non-specific symptoms such as dry skin, cold skin or feeling colder, constipation, slower thinking, and poor memory (44). A study of subclinical thyroid dysfunction indicated the evidence to be inconclusive for an association between subclinical thyroid disease and clinical symptoms (14). However, the relationship between thyroid dysfunction and depression is neither simple nor straightforward. There is now increasing evidence to suggest that SCH may be a predisposing factor for depression, cognitive impairment, dementia (43), and behavioral disturbance (15,43,45,46). Many studies have demonstrated an association between hypothyroidism and depressive symptoms (28–30,47–51). Although overt thyroid disorders negatively influence physical, behavioral, and cognitive functions (52), associations of SCH with these outcome measures are not clearly defined and studies demonstrate contradictory results (14,53–62). Subclinical hypothyroidism remarkably increases the risk of depression (63). Interestingly, depression is observed more frequently among individuals with SCH than those with overt hypothyroidism (63) or euthyroidism (64). Almeida et al. (64) reported a two-fold higher prevalence of depressive symptoms in SCH patients than healthy individuals (64). In another study, the prevalence of depressive symptoms in SCH population was reported to be 63.5%, and the most frequent symptoms were anxiety and somatization, cognitive impairment disturbances, psychomotor retardation, and sleep disorders (65). In contrast to the aforementioned studies, other authors have denied the existence of any association between SCH and depression (66–68). In a multicenter study of psychiatric morbidity in Brazil, the prevalence of anxiety disorder and depression were reported to be 18% and 3–10% in general population, respectively, but no correlation was found with thyroid function (69). Thus, there has been controversy regarding the clinical significance of SCH condition and its management. In the present study, we found a significant improvement in the intervention group after treatment with levothyroxine. However, a significant relationship was detected among serum T4, TSH levels, and Beck Depression Inventory score in the intervention group before and after the treatment.
Surks et al. (52) reported that data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. But several studies have obtained outcomes in agreement with our study, that is, psychological symptoms and quality of life have improved in overt and SCH groups as a result of the treatment (28–30,46). The results of several interventional studies have reported the beneficial effects of thyroid hormones to thyroxine (T4) (70–73). In the late 1960s, Prange and colleagues (74) indicated that supplementation with 25 mg of triiodothyronine (T3) increased the efficacy and the speed of patients’ response to antidepressant treatment. Depressive symptomatology improved with thyroxine. TSH levels were positively related to depressive symptomatology (75). In contrast to our results, certain studies have shown that levothyroxine replacement therapy alone was not effective in inducing complete remission of depressive symptoms (65) or slight improvement was reported (76). Our study has some impressive strength. It was a randomized, double-blind placebo-controlled clinical trial. Beck Depression Inventory and thyroid hormone parameters of the patients with subclinical hypothyroidism were compared to the age and sex-matched controls at the beginning and end of the study. All the recruited subjects completed the trial. Moreover, TSH levels in all subjects in the intervention group were normalized (TSH 54.5 mU/L) by the end of the study and no TSH suppression was observed in the levothyroxine group. There are, however, some limitations to this study. The study might not have sufficient ability to detect the differences between the groups in certain subscales of Beck Depression Inventory due to small sample size and short duration of treatment. We were also unable to analyze the effect of race/ethnicity or social economic status. In addition, the BDI suffers from the same defects as other self-report inventories, in that scores may be easily exaggerated or minimized by the person completing them.
Conclusions This study determined the efficacy of treatment of SCH patients with levothyroxine with regard to depressive symptoms. The findings highlight the importance of psychiatric evaluation in management of patients with SCH and that SCH might be considered as a possible risk factor for depression.
Acknowledgements The authors wish to thank the staff who greatly helped us to complete the project, especially Ms. Leila Mahmoodi.
DOI: 10.3109/07435800.2014.896924
In addition, we appreciate all people who contributed to this study.
Ethical approval This project was accepted by ethical committee of Tehran University of Medical Sciences; ethical code: 13/2/1390 and written informed consent was obtained from all participants.
Declaration of interest
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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This study was funded and supported by Tehran University of Medical Sciences (TUMS); Grant No. 90-01-122-12951.
Author contributions (1) Study conception/design: Khamseh, Malek, Najafi, Hadian, Ebrahim Valojerdi. (2) Data collection/analysis: Hadian, Najafi, Ebrahim Valojerdi. (3) Drafting of manuscript: Khamseh, Malek, Hadian, Najafi, Ebrahim Valojerdi. (4) Critical revisions for important intellectual content and administrative/technical/material support: Khamseh, Malek, Hadian. (5) Supervision: Khamseh, Malek, Hadian, Najafi. (6) Statistical expertise: Najafi, Ebrahim Valojerdi.
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40. Hoogendoorn EH, Heijer MD, Dijk AJ, et al. Sub-clinical hyperthyroidism: to treat or not to treat? Postgrad Med J 2004; 80:394–8. 41. Pale JV, Franklyn JA, Cross KW, et al. Prevalence and follow up of abnormal thyrotophin (TSH) concentration in the elderly in the United Kingdom. Clin Endocrinol 1991;34:77–83. 42. Kabadi UM. Subclinical hypothyroidism. Natural course of syndrome during a prolonged follow-up study. Arch Intern Med 1993;153:957–61. 43. Davis JD, Stern RA, Flashman LA. Cognitive and neuropsychiatric aspects of subclinical hypothyroidism: significance in the elderly. Curr Psychiatry Rep 2003;5:384–90. 44. Villar HCCE, Saconato H, Valente O, et al. Thyroid hormone replacement for subclinical hypothyroidism. Coch Data Syst Rev 2007;3:CD003419. 45. Vaisman M. Clı´nica me´dica, doenc¸as da tireo´ide. Sa˜o Paulo, SP: Atheneu; 2003. 46. Gulseren S, Gulseren L, Hekimsoy Z, et al. Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction. Arch Med Res 2006;37:133–9. 47. Kramer CK, von Mu¨hlen D, Kritz-Silverstein D, et al. The association of thyroid stimulating hormone levels with cognitive function and depressed mood: the Rancho Bernardo study. J Nutr Health Aging 2009;13:317–21. 48. Saravanan P, Chau WR, Roberts N. Psychological well being in patients on adequate doses of L-thyroxine: results of a large controlled community-based questionnaire study. Clin Endocrinol 2003;57:577–85. 49. Larisch R, Kley K, Nikolaus S, et al. Depression and anxiety in different thyroid function states. Horm Metab Res 2004;36:650–3. 50. Samuels MH, Schuff KG, Carlson NE, et al. Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis. J Clin Endocrinol Metab 2008;93:1730–6. 51. Lasser RA, Baldessarini RJ. Thyroid hormones in depressive disorders: a reappraisal of clinical utility. Harv Rev Psychiatry 1997;4:291–305. 52. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. J Am Med Assoc 2004;291:228–38. 53. Simonsick EM, Newman AB, Ferrucci L, et al. Subclinical hypothyroidism and functional mobility in older adults. Arch Intern Med 2009;169:2011–17. 54. Schlote B, Nowotny B, Schaaf L, et al. Subclinical hyperthyroidism: physical and mental state of patients. European Arch Psychiatry Clin Neurosci 1992;241:357–64. 55. Razvi S, Weaver JU, Vanderpump MP, et al. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab 2010;95:1734–40. 56. Reuters VS, Teixeira PF, Vigario PS, et al. Functional capacity and muscular abnormalities in subclinical hypothyroidism. Am J Med Sci 2009;338:259–63. 57. Portella RB, Silva JL, Wagman MB, et al. Exercise performance in young and middle-aged female patients with subclinical hyperthyroidism. Thyroid 2006;16:731–5. 58. Brennan MD, Powell C, Kaufman KR, et al. The impact of overt and subclinical hyperthyroidism on skeletal muscle. Thyroid 2006; 16:375–80. 59. Ceresini G, Lauretani F, Maggio M, et al. Thyroid function abnormalities and cognitive impairment in elderly people: results of the Invecchiare in Chianti study. J Am Geriatr Soc 2009;57:89–93.
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60. Begin ME, Langlois MF, Lorrain D, et al. Thyroid function and cognition during aging. Curr Gerontol Geriatr Res 2008;2008: 474868. 61. Park YJ, Lee EJ, Lee YJ, et al. Subclinical hypothyroidism (SCH) is not associated with metabolic derangement, cognitive impairment, depression or poor quality of life (QoL) in elderly subjects. Arch Gerontol Geriatr 2010;50:e68–73. 62. Parle J, Roberts L, Wilson S, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study. J Clin Endocrinol Metab 2010;95:3623–32. 63. Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr 2007;44:21–8. 64. Almeida C, Brasil MA, Costa AJ, et al. Subclinical hypothyroidism: psychiatric disorders and symptoms. Rev Bras Psiquiatr 2007;29: 157–9. 65. Demartini B, Masu A, Scarone S, et al. Prevalence of depression in patients affected by subclinical hypothyroidism. Panminerva Med 2010;52:277–82. 66. Engum A, Bjoro T, Mykletun A, et al. An association between depression, anxiety and thyroid function–a clinical fact or an artefact? Acta Psychiatr Scand 2002;106:27–34. 67. de Jongh RT, Lips P, van Schoor NM, et al. Endogenous subclinical thyroid disorders, physical and cognitive function, depression, and mortality in older individuals. Eur J Endocrinol 2011;165: 545–54. 68. Jorde R, Waterloo K, Storhaug H, et al. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 2006;91:145–53. 69. Almeida-Filho N, Mari Jde J, Coutinho E, et al. Brazilian multicentric study of psychiatric morbidity. Methodological features and prevalence estimates. Br J Psychiatry 1997;171: 524–9. 70. Baumgartner A. Thyroxine and the treatment of affective disorders: an overview of the results of basic and clinical research. Int J Neuropsychopharmacol 2000;3:149–65. 71. Aronson R, Offman HJ, Joffe RT, et al. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry 1996;53:842–8. 72. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006; 163:1519–30. 73. Cooper-Kazaz R, Apter JT, Cohen R, et al. Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry 2007; 64:679–88. 74. Prange Jr AJ, Wilson IC, Rabon AM, et al. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 1969;126:457–69. 75. Cleare AJ, McGregor A, Chambers SM, et al. Thyroxine replacement increases central 5-hydroxytryptamine activity and reduces depressive symptoms in hypothyroidism. Neuroendocrinology 1996;64:65–9. 76. van Harten AC, Leue C, Verhey FR. Should depressive symptoms in patients with subclinical hypothyroidism be treated with thyroid hormone? Tijdschr Psychiatr 2008;50:539–43.
Depressive symptoms in patients with subclinical hypothyroidism – the effect of treatment with levothyroxine: a double-blind randomized clinical trial* Laily Najafi, Mojtaba Malek, Ali Hadian, Ameneh Ebrahim Valojerdi, Mohammad E. Khamseh, and Rokhsareh Aghili
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Endocrine Research Center (Firouzgar), Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
Abstract
Keywords
Despite the increasing evidence for relationships between thyroid dysfunction and neuropsychiatric alterations, the effect of treatment of thyroid disease on various clinical psychiatric outcomes is controversial. The purpose of this study was to investigate the effect of levothyroxine treatment on depressive symptoms in subjects with subclinical hypothyroidism. A randomized double-blind placebo-controlled clinical trial was performed. Sixty subjects (51 females and 9 males) with subclinical hypothyroidism were enrolled. Beck Depression Inventory was completed for all participants at the beginning of the study and 12 weeks after enrollment. The intervention and control groups received levothyroxine and placebo, respectively, for 12 weeks. There were no statistical differences in the total depression score and its subscales between the two groups at the beginning of the study. The Beck Depression Inventory score decreased from 16.79 ± 13.25 to 12.37 ± 10.01 (p value ¼ 0.04) in the intervention group. The change in score was not significant for the control group (13.77 ± 11.71 to 11.86 ± 10.71; p value¼ 0.16). The affective subscale of Beck Depression Inventory did not change after 12 weeks of treatment with levothyroxine, while somatic subscale remarkably improved in the intervention group (p value ¼ 0.02). This study showed the efficacy of treatment of subclinical hypothyroidism in people with levothyroxine in relation to depressive symptoms.
Affective subscale, Beck Depression Inventory, depression, neuropsychiatric alterations, somatic subscale, thyroid dysfunction
Introduction Depression is a common and disabling disorder that affects 2–16% of adults (1). Although several behavioral and biologic factors may be involved in precipitating and perpetuating the symptoms of depression (2–9), the principal causes are not clear. Thyroid dysfunction may impair quality of life. Many investigators have recommended that either overt or subclinical hypothyroidism (SCH) is associated with an increase in the number and severity of depressive symptoms (10–12). Subclinical hypothyroidism is a term applied to individuals with a normal serum free thyroxine (T4) concentration and an increased serum thyrotropin (TSH). The prevalence of SCH is 4–10% in the adult population (13), and it has been associated with different negative clinical outcomes and an increased
*Place that study was performed: Endocrine Research Center (Firouzgar), Institute of Endocrinology & Metabolism, Iran University of Medical Sciences (IUMS). Correspondence: Dr. Mohammad E. Khamseh, MD, Director, Endocrine Research Center (Firouzgar), Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Firouzgar alley, Valadi St., Behafarin St., Karimkhan Ave., Vali-Asr Sq., 1593748711, Tehran, Iran. Tel: +98 21 88945172, 98 21 88945247. Fax: +98 21 88945173. E-mail: [email protected]
History Received 3 July 2013 Revised 30 November 2013 Accepted 17 February 2014 Published online 17 February 2015
risk of overt thyroid dysfunction (14). The most frequently cited symptoms are memory deficit, despondency, symptoms of depression, and anxiety (15). Clinical manifestations differ with age, duration, and severity of hormone shortage and are usually non-specific (16–18). In a literature review, we found one study showing an increased prevalence of previous depressive episodes in patients with SCH (19). Placidi et al. (20) reported a rate of 63% for psychiatric diagnosis in a sample of patients with thyroid dysfunction. In another study, anxiety and depression were more frequent in SCH compared with the control group (21). It is reported that treatment of thyroid dysfunction reduces psychiatric symptoms in general (22,23). In addition, policy makers suggest screening and treatment of SCH to prevent progression to overt thyroid dysfunction and to improve clinical outcomes, especially in elderly individuals (24–27). Despite the growing evidence for relationships between thyroid dysfunction and neuropsychiatric alterations, the effect of treatment on various clinical outcomes is controversial. Some studies reported an improvement of depressive symptoms after treatment with levothyroxine (28–30). However, the results of a randomized trial on treatment of SCH subjects and its effect on quality of life were inconclusive (31). The purpose of the current study was to investigate
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the effect of levothyroxine treatment on depressive symptoms in subjects with subclinical hypothyroidism.
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Methods Sixty patients with subclinical hypothyroidism referred to the Thyroid Clinic of the Institute of Endocrinology and Metabolism were recruited to a randomized double-blind, placebo-controlled clinical trial from September 2010 to August 2011. A simple blocked randomization method was used for the allocation of patients into two groups. Subjects who had a history of endocrine or autoimmune diseases other than subclinical hypothyroidism—for example, overt hypothyroidism, myxedema coma, proven psychiatric disorder, history of thyroid hormone, or corticosteroids replacement in the previous 2 months—were excluded from the study. Subjects who had diabetes mellitus, heart failure, chronic liver or pulmonary disorder, history of head trauma, seizure, known psychological or mental disorders and those who were pregnant were also excluded. The ethics committee of Tehran University of Medical Sciences approved the protocol and written informed consent was obtained from all participants. A detailed history and physical examination were performed for each patient by an expert physician. Demographic and clinical parameters including sex, age, occupation, level of education, as well as history of concurrent systemic diseases and use of medications were obtained via face-to-face patient interviewing. The anthropometric measures were undertaken by a trained nurse. Standing height was measured using a stadiometer (Seca Gmbh & Co., Hamburg, Germany) that was calibrated before each measurement and weight was measured using a calibrated digital scale (Seca Gmbh). Body mass index (BMI) was defined as weight (in kg) over height squared (in meters). Blood pressure was measured under standardized conditions (sitting position, after 5 min of resting; cessation of smoking, drinking tea or coffee or eating food for at least half an hour). Beck Depression Inventory (BDI-II) (Persian version) (32) was completed for all participants at the beginning of the study and 12 weeks after enrollment. The Inventory and thyroid hormone parameters of patients with subclinical hypothyroidism were compared to age- and sex-matched controls at enrollment and by the end of the study. The intervention group received 100 mg of levothyroxine (Iran Hormone Product) and the control group received placebo for 12 weeks. The participants were asked to bring the remaining tablets to the clinic to assess their compliance. Definition of subclinical hypothyroidism Subclinical hypothyroidism was defined as serum TSH level higher than 4.5 mIU/L in the presence of normal free T4 (0.8–2 ng/dl) and positive anti-TPO-Ab. Beck Depression Inventory The Beck Depression Inventory (BDI, BDI-II), created by Dr. Aaron T. Beck, is a 21-question multiple-choice selfreport inventory. It is one of the most widely used instruments for measuring the severity of depression. The BDI was originally developed to provide a quantitative assessment of
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the intensity of depression. Because it is designed to reflect the depth of depression, it can monitor changes over time and provide an objective measure for judging improvement and the effectiveness or otherwise of treatment methods (33). The BDI-II is a 1996 revision of the BDI (34), developed in response to the American Psychiatric Association’s publication of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), which changed many of the diagnostic criteria for Major Depressive Disorder. The cutoffs used differ from the original scores. The depth of depression is categorized as minimal depression (score ¼ 0–13), mild depression (score ¼ 14–19), moderate depression (score ¼ 20–28), and severe depression (score ¼ 29–63). Higher total scores indicate more severe depressive symptoms. The inventory defines two components for depression: the affective component (e.g. mood) and the physical or ‘‘somatic’’ component (e.g. loss of appetite). The BDI-II reflects this concept in two subscales. The purpose of the subscales is to help to determine the primary cause of a patient’s depression. The affective subscale contains eight items: pessimism, past failures, guilty feelings, punishment feelings, self-dislike, self-criticalness, suicidal thoughts or wishes, and worthlessness. The somatic subscale consists of 13 items: sadness, loss of pleasure, crying, agitation, loss of interest, indecisiveness, loss of energy, change in sleep patterns, irritability, change in appetite, concentration difficulties, tiredness and/or fatigue, and loss of interest in sex. The two subscales are moderately correlated at 0.57, suggesting that the physical and psychological aspects of depression are related rather than totally distinct (35,36). Laboratory measurements After an overnight fast (12 h), patients had venous blood samples taken for measurement of TSH, T4, and antiTPO-Ab. TSH was measured by the IRMA method using a standard kit (ImmunoTech kit) supplied by ImmunoTech Co. (Prague, Czech Republic). T4 and anti-TPO-Ab were measured by the RIA method using a standard kit (ImmunoTech kit) supplied by ImmunoTech Co. (Prague, Czech Republic). Statistical analysis All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS version 18.0, SPSS, Chicago, IL). Descriptive statistics methods (mean ± SD) were used for the baseline characteristics. We used nonparametric tests for comparison of quantitative variables (Mann–Whitney U test, McNemar test, and Wilcoxon test). Pearson’s correlation coefficient test was used for the assessment of correlation between quantitative variables. The p value 50.05 was taken as the cut-off level for the statistical significance. Results were presented with 95% confidence intervals (CIs).
Results In this study, 60 subclinical hypothyroid subjects were divided randomly into two groups, the intervention and the control group. The mean age of the participants was 34 ± 10
Depression and subclinical hypothyroidism
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DOI: 10.3109/07435800.2014.896924
years and 85% of them were female. The control group was composed of 25 females and 5 males (mean age: 36.07 years, range: 21–58 years) and the intervention group consisted of 26 females and 4 males (mean age: 32.37 years, range: 19–53 years). The mean for BMI was 24.9 ± 5.19. There were no statistical differences in the total depression score (intervention group: 17.07 ± 14.51 versus control group: 14.24 ± 11.35; p value ¼ 0.37) and the scores for the affective (intervention group: 4.45 ± 4.92 versus control group: 4.78 ± 5.17; p value ¼ 0.68) and somatic subscales (intervention group: 12.32 ± 10.71 versus control group: 9.11 ± 6.62; p value ¼ 0.15) at the beginning of the study. Baseline characteristics and thyroid hormone parameters of the participants are shown in Table 1. No correlation was detected between age and Beck Depression Inventory score. By the end of the study, serum TSH levels had normalized in all subjects in the intervention group. The changes in biochemical parameters from baseline are shown in Table 2. The most prevalent symptoms of subclinical hypothyroidism in two groups were weight gain, fatigue, muscle cramp, irregular menstruation, and limb numbness before treatment; however, no significant improvement was detected after treatment (Table 3). With regard to the symptoms, brittle nails Table 1. Baseline characteristics and thyroid hormone parameters of the participants. Variables Age (years) Female n (%) BMI (kg/m2) TSH (mIU/L) T4 (mg/dL)
Intervention group
Control group
p Value
32.47 ± 11.35 25 (83) 24.9 ± 4.83 8.29 ± 4.9 7.38 ± 1.37
36.07 ± 11.35 26 (86) 25.39 ± 3.82 8.12 ± 3.12 7.41 ± 1.48
0.4 0.9 0.7 0.9 0.92
Data are mean ± SD unless otherwise indicated.
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in the intervention group after treatment had a significant correlation with TSH level (p value ¼ 0.03). By the end of the study, the Beck Depression Inventory score decreased from 16.79 ± 13.25 to 12.37 ± 10.01 (p value ¼ 0.04) in the intervention group. The change was not significant for the control group (13.77 ± 11.71 to 11.86 ± 10.71; p value ¼ 0.16). Regarding the severity of depression, minimal depression was the most prevalent form (53.8%). No statistical difference was observed in relation to the severity of depression between the intervention and control groups at baseline and at the end of the study. Furthermore, no correlation was detected between the severity of depression and the TSH level. We conducted an analysis for the subscales of BDI in the intervention and control groups. This analysis showed that the affective subscale did not change after 12 weeks of treatment with levothyroxine. In contrast, the somatic subscale remarkably improved in the intervention group (p value ¼ 0.02). The scores of BDI and its subscales are illustrated in Table 4. The effect size in somatic subscale in the intervention group was 0.39 (moderate) and the control group was 0.26 (low).
Discussion We found a remarkable improvement in the BDI score and its somatic subscale in the intervention group after 12 weeks of treatment with levothyroxine. Thyroid hormones play an important role in the maturation and proper function of the central nervous system (37,38), growth, puberty, and metabolism (39). Thyroid dysfunction is a graded phenomenon (40). There is increasing evidence suggesting that mild (subclinical) thyroid disorders may be potential contributors to significant clinical conditions (40). Subclinical hypothyroidism may progress to overt hypothyroidism by 3–18% per year,
Table 2. Biochemical parameters before and after the treatment. Intervention group Variables TSH (mIU/L) T4 (mg/dL)
Baseline
a
8.29 ± 4.9 7.38 ± 1.37
Week 12
a
2.007 ± 1.34 8.607 ± 2.05
Control group a
p Value
Baseline
0.000 0.004
8.12 ± 3.12 7.41 ± 1.48
Week 12a
p Value
7.82 ± 5.17 8.13 ± 1.98
0.733 0.093
a
Data are shown as mean ± SD.
Table 3. The frequency of symptoms of subclinical hypothyroidism in the intervention and the control groups. Intervention group Symptoms Weight gain Dry skin Fatigue Muscle cramps Hoarseness Constipation Irregular menstruation Feel cold Dry hair Brittle nails Foot puffiness Limb numbness a
Data are shown as n (%).
a
Baseline (%) 17 13 25 19 5 7 11 12 7 11 4 14
(56.7) (43.3) (83.3) (63.3) (16.7) (23.3) (36.7) (40) (23) (37) (13) (46.7)
a
Week 12 (%) 10 9 23 15 3 4 9 15 9 17 5 13
(33.3 (30) (76.7) (50) (10) (13.3) (30) (50) (30) (57) (16) (44)
Control group p Value 0.11 0.34 0.4 0.34 0.6 0.5 0.7 0.39 1 0.07 0.62 1
a
Baseline (%) 16 14 25 17 4 10 24 11 11 12 1 8
(53 (46.7) (83.3) (56.7) (13.3) (33.3) (80) (37) (37) (40) (3.3) (27)
Week 12a (%) 9 11 24 15 4 7 24 8 7 7 1 11
(30) (36.7) (80) (50) (13.3) (23.3) (80) (27) (23) (23) (3.3) (37)
p Value 0.06 0.45 1 0.77 1 0.3 1 0.25 0.45 0.12 1 0.51
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Table 4. Scores of Beck Depression Inventory and its subscales at baseline and week 12. Intervention group Score b
BDI Affective subscale Somatic subscale
Baseline
a
16.79 ± 13.25 4.48 ± 5.08 12.32 ± 10.24
Week 12
a
12.37 ± 10.01 3.62 ± 5.27 9.12 ± 5.98
Control group a
p Value
Baseline
0.04 0.2 0.02
13.77 ± 11.71 4.78 ± 5.17 8.91 ± 6.95
Week 12a
p Value
11.86 ± 10.71 4.56 ± 4.68 7.08 ± 6.82
0.16 0.8 0.03
a
Data are shown as mean ± SD. Beck Depression Inventory.
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b
especially in the elderly (41,42). In comparison with overt hypothyroidism, which affects approximately 1% of the general population, SCH is a much more common disorder whose prevalence varies from 5% to 17% of the general population. The prevalence increases with age and gender, affecting 25% of women over 60 years of age (43). Patients with SCH may present non-specific symptoms such as dry skin, cold skin or feeling colder, constipation, slower thinking, and poor memory (44). A study of subclinical thyroid dysfunction indicated the evidence to be inconclusive for an association between subclinical thyroid disease and clinical symptoms (14). However, the relationship between thyroid dysfunction and depression is neither simple nor straightforward. There is now increasing evidence to suggest that SCH may be a predisposing factor for depression, cognitive impairment, dementia (43), and behavioral disturbance (15,43,45,46). Many studies have demonstrated an association between hypothyroidism and depressive symptoms (28–30,47–51). Although overt thyroid disorders negatively influence physical, behavioral, and cognitive functions (52), associations of SCH with these outcome measures are not clearly defined and studies demonstrate contradictory results (14,53–62). Subclinical hypothyroidism remarkably increases the risk of depression (63). Interestingly, depression is observed more frequently among individuals with SCH than those with overt hypothyroidism (63) or euthyroidism (64). Almeida et al. (64) reported a two-fold higher prevalence of depressive symptoms in SCH patients than healthy individuals (64). In another study, the prevalence of depressive symptoms in SCH population was reported to be 63.5%, and the most frequent symptoms were anxiety and somatization, cognitive impairment disturbances, psychomotor retardation, and sleep disorders (65). In contrast to the aforementioned studies, other authors have denied the existence of any association between SCH and depression (66–68). In a multicenter study of psychiatric morbidity in Brazil, the prevalence of anxiety disorder and depression were reported to be 18% and 3–10% in general population, respectively, but no correlation was found with thyroid function (69). Thus, there has been controversy regarding the clinical significance of SCH condition and its management. In the present study, we found a significant improvement in the intervention group after treatment with levothyroxine. However, a significant relationship was detected among serum T4, TSH levels, and Beck Depression Inventory score in the intervention group before and after the treatment.
Surks et al. (52) reported that data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. But several studies have obtained outcomes in agreement with our study, that is, psychological symptoms and quality of life have improved in overt and SCH groups as a result of the treatment (28–30,46). The results of several interventional studies have reported the beneficial effects of thyroid hormones to thyroxine (T4) (70–73). In the late 1960s, Prange and colleagues (74) indicated that supplementation with 25 mg of triiodothyronine (T3) increased the efficacy and the speed of patients’ response to antidepressant treatment. Depressive symptomatology improved with thyroxine. TSH levels were positively related to depressive symptomatology (75). In contrast to our results, certain studies have shown that levothyroxine replacement therapy alone was not effective in inducing complete remission of depressive symptoms (65) or slight improvement was reported (76). Our study has some impressive strength. It was a randomized, double-blind placebo-controlled clinical trial. Beck Depression Inventory and thyroid hormone parameters of the patients with subclinical hypothyroidism were compared to the age and sex-matched controls at the beginning and end of the study. All the recruited subjects completed the trial. Moreover, TSH levels in all subjects in the intervention group were normalized (TSH 54.5 mU/L) by the end of the study and no TSH suppression was observed in the levothyroxine group. There are, however, some limitations to this study. The study might not have sufficient ability to detect the differences between the groups in certain subscales of Beck Depression Inventory due to small sample size and short duration of treatment. We were also unable to analyze the effect of race/ethnicity or social economic status. In addition, the BDI suffers from the same defects as other self-report inventories, in that scores may be easily exaggerated or minimized by the person completing them.
Conclusions This study determined the efficacy of treatment of SCH patients with levothyroxine with regard to depressive symptoms. The findings highlight the importance of psychiatric evaluation in management of patients with SCH and that SCH might be considered as a possible risk factor for depression.
Acknowledgements The authors wish to thank the staff who greatly helped us to complete the project, especially Ms. Leila Mahmoodi.
DOI: 10.3109/07435800.2014.896924
In addition, we appreciate all people who contributed to this study.
Ethical approval This project was accepted by ethical committee of Tehran University of Medical Sciences; ethical code: 13/2/1390 and written informed consent was obtained from all participants.
Declaration of interest
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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. This study was funded and supported by Tehran University of Medical Sciences (TUMS); Grant No. 90-01-122-12951.
Author contributions (1) Study conception/design: Khamseh, Malek, Najafi, Hadian, Ebrahim Valojerdi. (2) Data collection/analysis: Hadian, Najafi, Ebrahim Valojerdi. (3) Drafting of manuscript: Khamseh, Malek, Hadian, Najafi, Ebrahim Valojerdi. (4) Critical revisions for important intellectual content and administrative/technical/material support: Khamseh, Malek, Hadian. (5) Supervision: Khamseh, Malek, Hadian, Najafi. (6) Statistical expertise: Najafi, Ebrahim Valojerdi.
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