Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review
Abstract
:1. Introduction
Autoimmune Hypothyroidism (AHT) and Depression
2. Methods
2.1. Review Question
2.2. Searches
2.3. Search Strategy
2.4. Condition or Domain Being Studied
2.5. Participants/Population
2.6. Intervention(s), Exposure(s)
2.7. Comparator(s)/Control
2.8. Types of Study to Be Included
2.9. Main Outcomes
2.10. Measures of Effect
2.11. Data Extraction
2.12. Risk of Bias (Quality) Assessment
2.13. Certainty Assessment
2.14. Strategy for Data Synthesis
2.15. Registration
3. Results and Discussion
3.1. Inflammatory Processes, Cytokines and Growth Factors
3.2. Brain-Derived Neurotrophic Factor (BDNF) and Depression, AHT and Gender
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Symptoms | Assessment Findings | Diagnostic Findings |
---|---|---|
Depression | Dry, coarse skin | Hyponatremia |
Fatigue | Reduced body and scalp hair | Macrocytic anemia |
Weight gain | Dull facial expression | Decreased memory |
Constipation | Bradycardia | Hyperprolactinemia |
Muscle cramps, arthralgias | Goiter | Elevated creatine kinase level |
Menorrhagia | Macroglossia | Pituitary gland enlargement |
Infertility | Ascites | Delayed bone age |
Sexual dysfunction | Galactorrhea | Hypercholesterolemia |
Cold intolerance | Slow relaxation of tendon reflexes | |
Carpal tunnel syndrome | Nonpitting edema of lower extremities | |
Sleep disorders | Hoarseness |
Author | Year | Sample Size | Characteristic of Participants | Results and Conclusions | Reference |
---|---|---|---|---|---|
Pop et al. | 1998 | 583 women | A total of 58 women had elevated levels of anti-TPO antibodies. Age group: 47–54 years old. | This study showed that women with elevated levels of anti-TPO antibodies are more prone to developing depression, while postmenopausal age does not increase this risk. | [29] |
Zetting et al. | 2003 | 76 | A total of 41 patients with autoimmune thyroiditis and 35 patients in the control group. | Brain impaired perfusion has been confirmed in patients with AHT. The presence of cerebral hypoperfusion suggests cerebral vasculitis as the most likely pathogenic cause. | [30] |
Carta et al. | 2004 | 222 | In all, 16.6% of the studied patients had elevated levels of anti-TPO antibodies. | A relationship has been demonstrated between the presence of a lifetime diagnosis of depressive disorders and the level of anti-TPO antibodies. | [13] |
Carta et al. | 2005 | 190 | A total of 19 patients were diagnosed with Hashimoto’s disease (HD) in euthyroidism, 19 patients with euthyroid neutral goiter, 152 people in the control group. | Patients diagnosed with HD in euthyroidism showed a higher incidence of depressive episodes throughout life. | [11] |
Engum et al. | 2005 | 30,175 | In all 995 of the study group had elevated levels of anti-TPO antibodies. Age group: 40–84. | In the group with elevated levels of anti-TPO antibodies, the incidence of depression was not higher than in the general population. | [31] |
Gulseren et al. | 2006 | 160 | A total of 33 patients with overt hypothyroidism, 43 patients with subclinical hypothyroidism, 51 patients with overt hyperthyroidism, 13 patients with subclinical hyperthyroidism and a healthy control group of 20 patients. | Achieving euthyroidism reduces depressive symptoms. In this study, the causes of hypothyroidism were not mentioned—the levels of TSH, fT3 and fT4 were examined. | [32] |
Bunevicius et al. | 2007 | 474 | Of the 474 randomly selected primary care patients, 348 were female, 95 of them were postmenopausal, 67 had a history of endocrine disease; 68 patients had a history of mental disorders. 84 patients used psychotropic drugs, including 69 benzodiazepines; none of the patients used lithium. Six women were diagnosed with hypothyroidism and were treated with L-thyroxine. | The results of this study indicate that ultrasound-assessed thyroid autoimmunity is associated with the symptoms of mood disorders in primary care patients, especially in premenopausal women. | [33] |
van der Deure et al. | 2008 | 141 | Patients with AHT treated with levothyroxine or combination of levothyroxine and liothyronine. | OATP1C1 polymorphisms are associated with fatigue and depression in patients with primary autoimmune hypothyroidism. | [34] |
Schinhammer et al. | 2010 | 96 | 67 patients were diagnosed with HD and 30 patients in the control group, age group 18–80. | Patients with HD have an increased risk of developing depression. This study showed that the MTHRF 1298C/C gene polymorphism in patients with HD may be associated with the etiology of depression. There seems to be an association between the MTHFR 677C/C and COMT A/A polymorphisms and Hashimoto’s disease. Gene polymorphism in the folate/homocysteine system appears to play a role in HD and associated depressive disorders. | [35] |
Kirim et al. | 2012 | 201 | Patients diagnosed with HD in the euthyroid stage, age group 18–65 years. | Increased frequency and severity of symptoms of depression in patients diagnosed with Hashimoto’s disease in the euthyroid stage. | [8] |
Watt et al. | 2012 | 199 | Patients with AHT. | Health-related quality of life (Qol) in patients with autoimmune hypothyroidism was related to anti-TPO antibodies level but not to thyroid function. Level of anti-TPO antibodies was significantly associated with several QoL outcomes such as depressivity, anxiety, emotional susceptibility and impaired social life. In the multivariate model, the anti-TPO antibodies levels were related to e.g., depressivity and anxiety. | [36] |
Franke et al. | 2013 | 57 | 36 patients diagnosed with HD and 21 patients diagnosed with neutral goiter. | The study shows increased expression of the ADA (adenosine deaminase gene) and ADAR (adenosine deaminase gene, RNA specific) genes in patients diagnosed with HD compared to patients with neutral goiter, which may explain the increased incidence of depression in patients with HD. | [37] |
Giynas Ayhan et al. | 2014 | 164 | 51 patients diagnosed with HD in euthyroidism, 45 patients with euthyroid neutral goiter, 68 patients in the control group. | Depressive disorders are more common in euthyroid patients diagnosed with HD, suggesting that they may be associated not only with abnormal levels of thyroid hormones, but also with the process of autoimmunity. | [38] |
Medici et al. | 2014 | 7983 | 1503 people had the level of anti-TPO tested, the study included Caucasian people aged 55+ (people with dementia were excluded). | Older people with low normal TSH levels have more comorbid depressive symptoms and a significantly increased risk of developing a depressive syndrome later in life. Low TSH levels are an important risk factor for the development of depression in the elderly. Autoimmunity of the thyroid gland (as assessed by elevated levels of anti-TPO antibodies) was not associated with an increased risk of depression. | [39] |
Demartini et al. | 2014 | 246 | A total of 123 patients with subclinical hypothyroidism, including 106 patients diagnosed with HD, 12 with non-autoimmune hypothyroidism and 5 with nodular goiter, and 123 controls without diagnosed thyroid disease. Patients diagnosed with intellectual disability and dementia were excluded. | More than twice more patients diagnosed with subclinical hypothyroidism had at least mild depression. | [40] |
Quinque et al. | 2015 | 36 | 18 patients treated for AHT and 18 patients in the control group. Structural and functional MRI and neuropsychological tests were performed to assess mood and cognitive function. | Properly treated patients report more depressive symptoms compared with healthy controls. Mood changes were not associated with brain structure and function in brain regions specific to depression. Higher levels of anti-TPO antibodies are associated with higher gray matter density in the right amygdala and increased connections between the cortex subcallosum and the left post-hippocampal gyrus. Duration of treatment was associated with the development of structural and functional changes in brain areas associated with depression and untreated hypothyroidism. Autoimmunity and the duration of treatment are possible factors explaining the occurrence of psychiatric symptoms in patients receiving long-term treatment for hypothyroidism. | [41] |
Itterman et al. | 2015 | 2142 | The analysis included 498 patients with previously diagnosed thyroid dysfunction—247 people were taking medication, 223 had thyroid nodules, 74 were diagnosed with hyperthyroidism, and 70 with hypothyroidism—without specifying the causes of the disorders. | Untreated, diagnosed hypothyroidism is associated with a higher risk of depressive symptoms. TSH and anti-TPO levels were not significantly associated with the risk of depression. | [42] |
Fjaellegaard et al. | 2015 | 8214 | The patients were divided into four groups: 1. Euthyroid patients with normal levels of anti-TPO antibodies (7015 patients), 2. Euthyroid patients with elevated levels of anti-TPO antibodies (619 patients), 3. Patients with subclinical hypothyroidism and normal levels of anti-TPO antibodies (378 patients), 4. Patients with subclinical hypothyroidism and elevated levels of anti-TPO antibodies (202 patients). | This study showed no significant differences in the incidence of depression in euthyroid patients and patients diagnosed with subclinical hypothyroidism. Euthyroid women with elevated levels of anti-TPO antibodies had statistically significantly better well-being than patients with normal levels of anti-TPO antibodies. | [43] |
Van de Ven et al. | 2016 | 906 | Age group 50–70, relationship between the presence of anti-TPO antibodies, TSH and fT4 levels and the risk of depression was examined. | Presence of anti-TPO antibodies may be a marker of susceptibility to depression. Lack of correlation between thyroid function and incidence of depression. | [44] |
Krysiak et al. | 2016 | 86 | Age group: women aged 20–40, 68 patients were divided into four groups: 1. Patients in euthyroidism diagnosed with HD, 2. Patients with non-autoimmune hypothyroidism, 3. Patients with autoimmune hypothyroidism, 4. Control group—18 patients. | The Beck Depression Inventory (BDI) total score was highest in group 3, and higher in groups 1 and 2 than in group 4. Anti-TPO antibody levels were directly proportional to serum TSH levels and the BDI total score and the number of patients with depressive symptoms. | [45] |
Delitala et al. | 2016 | 3138 | The group included patients who were not taking thyroid medications or antidepressants. The levels of TSH, fT4 and anti-TPO antibodies were assessed. | No relationship was found between the level of anti-TPO antibodies and the occurrence of depressive symptoms. On the other hand, a U-shaped relationship was found between the level of fT4 and the occurrence of depressive symptoms in comparison with the average values of fT4—both high and low values of fT4 were associated with a greater number of depressive symptoms. | [46] |
Yalcin et al. | 2017 | 124 | 93 patients diagnosed with euthyroid HD for at least 3 months and 31 patients in the control group. | The level of TSH was statistically higher in patients diagnosed with HD, no differences in the level of fT4 were observed in the group of patients with HD and in the control group. In 17.3% of patients diagnosed with HD and in 4.3% of patients in the control group, depression was diagnosed. Autoimmunity itself may have an impact on the risk of depression in patients diagnosed with HD in the euthyroid stage. | [47] |
Bhagwat et al. | 2017 | 66 | 33 patients with autoimmune hypothyroidism and 33 patients from the control group. | In 57% of patients diagnosed with AHT, mild to moderate depression was diagnosed (MADRS > 11 points). After 6 months of treatment with tyroxin, 42% of these patients had remission of symptoms. The decrease in inflammatory markers correlated with the remission of depression. | [4] |
Lee et al. | 2019 | 1651 | The study group was divided into three groups depending on the level of TSH. Anti-TPO antibodies and fT4 levels were also tested in all patients. | Depressive symptoms were observed less frequently in patients with positive anti-TPO antibodies and the highest TSH concentrations than in the group of patients with the lowest TSH concentrations. Men with the highest TSH level were less than twice as likely to develop depressive symptoms than in the group with the lowest TSH levels. In women with the highest TSH level 35% less often depressive symptoms than in the group with the lowest TSH level. Gender may play an important role in the relationship between TSH levels and depressive symptoms. | [48] |
Dersch et al. | 2020 | 100 | 100 patients with unipolar endogenous major depression or treatment-resistant depression, including: 25 patients with first depressive episode (6 of them patients with psychotic symptoms) and 75 patients with recurrent depression (18 of them were patients with psychotic symptoms). | This study provides evidence of intrathecal synthesis of anti-thyroid antibodies in a subset of patients with unipolar depression. This may indicate central immunization in a subset of patients diagnosed with HD. | [49] |
Minaldi et al. | 2020 | 2932 | A meta-analysis of five studies (449 women with anti-TPO antibodies and 2483 women without anti-TPO antibodies). | Thyroid autoimmunity (anti-TPO antibodies -positive) during pregnancy and in the weeks after childbirth is associated with an increased risk of developing post-partum depression. | [50] |
Hirtz et al. | 2021 | 360 | Adolescents (11–19 years) with at least mild depression (BDI-II score > 13) compared to a representative reference cohort without evidence of mental health impairment. | Study found a higher prevalence of thyroid peroxidase antibody positivity in depressed adolescents compared to mentally healthy participants. The prevalence of subclinical hypothyroidism was higher in depressed adolescents vs. mentally healthy participants, but no other types of thyroid dysfunction had a higher prevalence. The prevalence of subclinical hypothyroidism and of thyroid autoimmunity in depressed adolescents is increased. | [51] |
Kamyshna | 2022 | 153 | Patients with various forms of thyroid pathology including AHT. | The CT genotype of the glutamate ionotropic receptor NMDA type subunit 1, GRIN1 (rs4880213) was predominant in the patients with autoimmune diseases of the thyroid gland. GRIN2B (glutamate ionotropic receptor NMDA type subunit 2B) serum levels in ELISA were probable increased in AHT by 1.58 times compared with controls, while significantly (by 3.45 times) decreased in patients with postoperative hypothyroidism. The C allele of rs4880213 was more frequent than the T allele among patients with thyroid disease. GRIN2B levels were significantly different in patients of different groups depending on thyroid pathology. Study found direct close correlation (r = 0.635) between GRIN2B and anti-TPO levels (p < 0.001) and direct close correlation (r = 0.527) between GRIN2B and anti-TG levels in the blood (p < 0.001). | [52] |
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Kotkowska, Z.; Strzelecki, D. Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review. Pharmaceuticals 2022, 15, 391. https://doi.org/10.3390/ph15040391
Kotkowska Z, Strzelecki D. Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review. Pharmaceuticals. 2022; 15(4):391. https://doi.org/10.3390/ph15040391
Chicago/Turabian StyleKotkowska, Zofia, and Dominik Strzelecki. 2022. "Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review" Pharmaceuticals 15, no. 4: 391. https://doi.org/10.3390/ph15040391
APA StyleKotkowska, Z., & Strzelecki, D. (2022). Depression and Autoimmune Hypothyroidism—Their Relationship and the Effects of Treating Psychiatric and Thyroid Disorders on Changes in Clinical and Biochemical Parameters Including BDNF and Other Cytokines—A Systematic Review. Pharmaceuticals, 15(4), 391. https://doi.org/10.3390/ph15040391