The link between thyroid autoimmunity, depression and bipolar disorder

1 Introduction

Newly emerging data support the link between autoimmunity and mental illnesses which has been examined since the 1930s, when a schizophrenia patient was tested positive for autoantibodies [1,2]. The thyroid is the most common organ affected by autoimmunity [3], with up to 5% of the general population suffering from autoimmune thyroid diseases [4]. Thus, several studies have been conducted with the aim to discover whether there is a role for thyroid autoimmunity in psychiatric disorders. One of the main clinical manifestations of thyroid autoimmunity is Hashimoto’s thyroiditis (HT). Thyroid peroxidase antibodies (TPOAb) are considered to be the best serological marker of HT because about 95% of HT patients are TPOAb positive and false positive results are uncommon, whereas thyroglobulin antibodies (TGAb) are less sensitive and less specific compared with TPOAb [5]. Thyroid sonogram results and a combination of clinical features are required along with antibody positivity for the diagnosis of HT, however, the prevalence of increased TPOAb titers with no clinical manifestation is high and may reach up to 15% among females [5,6]. In this review we focus on the association between thyroid autoimmunity (both HT and asymptomatic elevated TPOAb levels) and two major psychiatric conditions: depression and bipolar disorder.

2 Major depressive disorder

Major depressive disorder (MDD), also referred to as clinical depression, is diagnosed when a distinct change of mood characterized by sadness or irritability occurs for at least 2 weeks, interferes with work and family relations and is accompanied by several psychophysiological changes (e.g., disturbances of sleep and appetite; suicidal thoughts; slowing of speech and action) [7]. MDD is associated with elevated risk of onset, persistence and severity of numerous secondary disorders (e.g., stroke, diabetes, coronary artery disease, certain types of cancer), increased suicide probability and many other issues (e.g., low education, marital disruption, unstable employment) [8]. A cross-national comparison from population-based surveys in 10 countries concluded that the lifetime prevalence of MDD varies substantially across countries and ranges from 3.0% in Japan to 16.9% in the US [9]. A specific form of MDD is postpartum depression (PPD) which is a major depressive episode with its onset within 4 weeks after delivery [10]. The prevalence of PPD is 10-15 % in Western countries, but globally it ranges from almost 0% to nearly 60% [11]. PPD affects not only the mother’s health, but also puts the offspring at risk by impairing their cognitive, social and emotional development [12].

In 1996 The World Health Organisation projected that by 2020 depression would be the second leading cause of disability worldwide [13], thereby encouraging further research concerning the causes of depression. However, due to the heterogeneity of MDD, its pathophysiology has been difficult to explain [14]. Newly emerging data indicate that the immune system may be a potential factor contributing to the development of depression [15]. Increased inflammatory cytokine levels in blood and cerebrospinal fluid as well as elevated acute phase protein concentrations in peripheral blood have been discovered in patients with MDD [16,17] and treatment with selective serotonin reuptake inhibitors has been reported to decrease serum levels of interleukin 6 [18]. It is hypothesized that the dysfunction of the immune system may lead to the reduction of monoamine synaptic availability, which is considered a fundamental mechanism in the pathophysiology of depression [15]. One of the first studies to show the connection between autoimmune thyroid disorders and depression was conducted in 1998 and included 583 perimenopausal women; after adjustment for psychosocial factors it was concluded that women with elevated TPOAb levels (≥100 IU/ml) are at risk for depression [19]. Afterwards the association between MDD and thyroid autoimmunity was further examined in different studies; some of them aimed to reveal the link between HT and depression (see Table 1), while others focused on the connection between increased TPOAb levels and depressive symptoms among the general population (see Table 2).

The results of one study showed a higher prevalence of MDD among euthyroid HT patients and the findings of another one indicated that HT may increase the predisposition to depression [20,21]. Even though HT patients have been reported to be at higher risk for depression, l-thyroxine (T4) treatment for more than one year was found to reduce the chance of MDD [22]. Robert Krysiak with colleagues [23] hypothesized that the development of depression in patients with HT may be linked to decreased sexual function. They observed more impaired sexual function among females with autoimmune subclinical hypothyroidism than among those with non-autoimmune subclinical hypothyroidism or euthyroid HT. Sexual dysfunction also correlated with the severity of depressive symptoms. It was concluded that both subclinical hypothyroidism and HT may have a negative effect on female sexual function and might contribute to the development of depressive symptoms [23]. The study on males with autoimmune hypothyroidism led to the conclusion that even mild forms of autoimmune hypothyroidism are followed by sexual function impairment and depressive symptoms, both of them were reduced after T4 treatment [24].

Only one general population study showed a possible link between thyroid autoantibodies and depression (see Table 2): Itterman et al. [25] revealed that increased TPOAb levels were associated with MDD in the 12 months preceding the examination. However, that was not confirmed for TPOAb positivity (TPOAb+) and no connection was found between recurrent depression and TPOAb titer or TPOAb+. Thus, the authors concluded that it may be just a chance finding.

To our knowledge, a single study has provided an insight on the effect of thyroid autoimmunity on the response to antidepressants. In order to examine the connection, Eller and colleagues [28] compared the response to escitalopram treatment for MDD between TPOAb+ (>100 IU/ml) and TPOAb negative (TPOAb-) individuals. Although no significant differences were found, the non-responder group showed a trend for a higher prevalence of TPOAb+ compared with responders.

The findings of studies on TPOAb+ and PPD development are summarised in Table 3. Two of these studies identified an association between TPOAb+ during pregnancy and the development of PPD [29,30], while another one revealed that TPOAb values immediately after delivery do not affect PPD development [31]. Thus, it might be concluded that the development of PPD is associated with TPOAb values during pregnancy, but not shortly after delivery.

3 Bipolar disorder

Bipolar disorder (BD) is a chronic, relapsing illness characterized by recurrent episodes of manic or depressive symptoms, with intervening relatively asymptomatic periods [32]. The aggregate cross-study estimate of the lifetime prevalence of bipolar disorder is 1.2% [33], with a range of 0.1% in China [34], 1.0% in Germany [35] and up to 3.3% in the United States [36].

The interaction between genetic, environmental and psychosocial factors is believed to lead to the development of BD, but the exact cause remains unknown. Recent evidence suggests that the dysfunction of the immune system is linked to the pathophysiology of BD. A meta-analysis of 30 studies showed increased concentrations of proinflammatory cytokines among bipolar patients compared with healthy controls [37], another one also found some support for immune dysregulation in BD [38]. This data leads to inquirer whether BD may be associated with organ-specific autoimmune disorders, including thyroid autoimmunity. The link between thyroid function and BD is usually explained by the use of lithium and its effect on the thyroid. For more than 60 years lithium has been the gold standard for BD treatment [39,40]. It is now known that lithium definitely affects thyroid function [41], probably by inhibiting T3 and T4 release [42], but the exact mechanism remains elusive. During the first years of treatment, the patients are more prone to develop hypothyroidism, whereas hyperthyroidism and thyroid cancer are uncommon [43]. The association between lithium treatment and thyroid autoimmunity has been studied, but the question whether lithium per se can induce an increase in anti-thyroid antibody titers remains open to discussion [43]. Thyroid autoimmunity has been found to be more prevalent among BD affected individuals, irrespective of treatment. In 2002, Kupka with colleagues [44] reported that 28% of their studied bipolar patients were positive for TPOAb (≥10IU/ml), compared with 3-18% for population and psychiatric controls; this increased prevalence was not associated with lithium treatment. Afterwards a group of researchers conducted three consecutive studies and concluded that their findings point to a possible increased inherited risk of the co-occurrence of BD and AIT [45, 46, 47]. However, their results were contradictory to the ones of another study which showed no familial association between BD and thyroid autoimmunity [48] (see Table 4).

4 Conclusions

The results of most studies point towards the conclusion that thyroid autoimmunity is associated with both MDD and BD. Euthyroid HT patients have been shown to be more prone to depression, thus, MDD may be linked to the presence of high TPOAb titers among HT patients irrespective of their thyroid function. However, current data show no link between slightly elevated TPOAb levels and depressive symptoms among the general population. TPOAb+ during pregnancy has been linked to PPD development, but the presence of TPOAb shortly after delivery has not been found to be associated with PPD. In addition, further research is needed to assess the effect of TPOAb+ on the response to antidepressants.

Unfortunately, the association between BD and thyroid autoimmunity still remains unclear. The offspring of bipolar parents have shown higher rates of TPOAb+ and the twin study has led to the theory that BD and thyroid autoimmunity may be a result of the same genetic disturbance, but other scientists report to have found no association between BD and TPOAb levels. Thus, further large-scale research is needed to reach final conclusions.