Depression Causes Hypothyroidism 'LINK'
Borna Belnas
To help your doctor figure out if your depression is because of hypothyroidism, they should test you for thyroid disorders. Blood tests can confirm them if they show low levels of a thyroid hormone called thyroxine and a high level of one called thyroid-stimulating hormone (TSH).
Studies show that if you have both hypothyroidism and depression, thyroid-replacement medications may work better than antidepressants. They boost levels of two major thyroid hormones: triiodothyronine (also called T3) and thyroxin (T4). When thyroid pills lower TSH levels, you may start feeling better.
Today, it is well recognized that disturbances in thyroid function may significantly affect mental status including emotion and cognition. Both excess and insufficient thyroid hormones can cause mood abnormalities including depression that is generally reversible with adequate thyroid treatment. On the other hand, depression can be accompanied by subtle thyroid dysfunction. Overt thyroid disease is rare in depression. One to 4% of patients with affective disorders are found to have overt hypothyroidism while subclinical hypothyroidism occurs in 4% to 40% of these patients [2]. Furthermore, thyroid hormones are reported by many authors to be an effective adjunct treatment for depression.
On the other hand, hypothyroid patients frequently demonstrate features of depression, cognitive dysfunction, apathy, and psychomotor slowing. In severe forms of hypothyroidism, clinical symptoms may mimic that of melancholic depression and dementia [12]. However, there is less evidence on the association of subclinical hypothyroidism with cognitive dysfunction and affective disorders particularly depression although recently, a prevalence of 63.5% of depressive symptoms was reported in an Italian population with subclinical hypothyroidism. Nevertheless, therapy with levothyroxine alone was not sufficient to induce a total remission of depressive symptoms in this population [13]. Furthermore, Bauer et al. showed that TSH levels in hypothyroidism correlated with disease severity [14] and Joffe and Levitt found a disparity in depressive symptoms manifestations and severity among patients with a low-normal TSH versus those with a high-normal TSH. However, in the latter study no difference in treatment outcome was observed between the two groups [15]. In patients treated with T4, psychological symptoms may persist even when they achieve a euthyroid state [16]. Impaired psychological wellbeing in these subjects may be related to the occurrence of genetic polymorphisms in the D2 gene [17] as well as the OATPC1 encoding gene [18].
One mechanism explaining the increase in T4 seen in depression is the activation of hypothalamic TRH producing neurons and subsequent increase in thyroid function secondary to the rise in cortisol associated with depression [19, 24, 33]. In addition, it has been shown that elevated serum T4 levels fall after successful treatment of depression. A direct effect of antidepressants on the TRH neuron has been demonstrated resulting in an inhibition of TRH secretion [34]. This suggests that the decrease in T4 levels with initiation of antidepressants could be secondary to a direct effect on TRH neuron and thus to a reduced stimulation of the thyroid axis.
The prolonged release of TRH in depression may be seen as a compensatory response to the decreased 5HT activity in an attempt to normalize 5HT function and maintain normal levels of thyroid hormones [59]. An alternative explanation is that the blunted TSH response may be induced by the hypercortisolism associated with depression or the elevated thyroid hormone levels mediated by adrenergic mechanisms [60, 61].
Fewer studies assessed the efficacy of T4 in the treatment of affective disorders. Joffe and Singer found a significantly higher response to tricyclic antidepressants with T3 (53%) compared to T4 (19%) [71]. However, use of T4 in supraphysiological doses to treatment-resistant unipolar and bipolar depression was effective in approximately 50% of patients as reported by Baumgartner in a review of eight open clinical trials (N = 78) [72]. Surprisingly, T4 in high doses was well tolerated even in patients treated for up to 51 months. However, in healthy subjects, supraphysiological T4 doses were less well tolerated due to higher increments in thyroid hormones after supplementation [73]. A possible explanation would be a greater inactivation of T4 to rT3 in depressed patients compared to healthy subjects [74].
The inconsistency in the above findings can be accounted for by the variability in the degree of hypothyroidism and the differences in the etiology and duration of the disease in the various studied populations.
Changes in hormone levels such as somatostatin and serotonin in the central nervous system can result in neuropsychiatric disturbances [15]. Existing research also implies that these pathways may influence the HPT axis, explaining the link between subclinical hypothyroidism and depression. Somatostatin levels in the cerebrospinal fluid are lower in those with depression, resulting in higher TSH levels [15,16]. On the other hand, serotonin insufficiency, which is frequent in those who suffer from depression, has been related to changes in the HPT axis such as suppression of TSH release [17].
Depression is associated with neuroendocrine disturbances such as thyroid hormone disorders. Missing a diagnosis of subclinical hypothyroidism (SCH) can possibly be a cause of depression or mood cycling, as well as a delayed response to therapy [18]. Because MDD is frequently associated with autoimmune thyroiditis, it might be considered an autoimmune condition or an immune system disorder. Antithyroid antibodies are elevated in many people with depression [12]. Microsomal antibodies are also commonly seen in patients with chronic lymphocytic thyroiditis. Additional thyrotropin receptor (TSHR) antibodies that block TSH function can cause hypothyroidism [8]. A reduced TSH response to TRH has been linked to increased suicide risk, suicidal intent, violent suicide attempts, and greater lethality, mainly in depressed women [19]. TSH, antithyroglobulin (TgAb), and TPOAb levels have all been proposed as potential indicators of suicidality in MDD [19]. Thyroid-binding inhibitory immunoglobulins block TSH from binding to its receptor, causing hypothyroidism to develop. Atypical depression is associated with high levels of immunoglobulins and microsomal antibodies linked to treatment resistance [20].
Furthermore, higher TRH concentrations have consistently been reported in the cerebrospinal fluid of individuals with depression, indicating that depression is associated with a changed TRH response [12,21]. On the other hand, depression has been linked to developing hypothyroidism. The most widely accepted explanation is a thyroid axis disruption, which blunts the TSH response to TRH stimulation [22]. Patients with atypical depression have higher levels of microsomal antibodies and TSH-blocking immunoglobulin while their free triiodothyronine (FT3), free thyroxine (FT4), and TSH levels are within normal limits [21]. Overt hypothyroidism and SCH are common concomitant illnesses associated with MDD, particularly in women [23]. Treatment-resistant MDD, increased severity of MDD, psychotic phenomenology, and somatic symptoms are all possible consequences of this comorbidity [24]. Patients with MDD may have immune system activation, which can develop into autoimmune thyroiditis and thyroid dysfunction [25]. Thyroid hormone replacement therapy has been shown to benefit individuals with hypothyroidism and MDD, particularly treatment-resistant patients or/and those with unusual symptoms [24]. Overt hypothyroidism, on the other hand, is associated with effective and broader neuropsychiatric symptomatology [26]. It has been proposed that subclinical autoimmune thyroid dysfunction may play a causative role in MDD [21].
According to a reversal hypothesis, the pathogenetic mechanism of MDD might be related to a condition of local cerebral hypothyroidism with normal peripheral thyroid hormone concentrations. Many researchers have used the phrase "brain hypothyroidism" to describe this idea, based on the discovery of type II deiodinase inhibition in the brain and reduced T4 transport across the blood-brain barrier in depressed individuals. Furthermore, functional changes such as loss of nocturnal thyrotropin (TSH) increase, reduced TSH response to thyrotropin-releasing hormone (TRH) stimulation, and mild elevation of serum thyroxine (T4) have been documented [27]. The DeltaDeltaTSH (TSH) test is a better way to detect dysregulation of the HPT axis in MDD [28]. It calculates the difference in TSH response to TRH tests between 23:00 and 08:00 hours on the same day. Therapy resistance was linked to changes in the HPT axis after two weeks of antidepressant treatment. Clinical remission did occur once the HPT axis activity was restored chronobiologically [29]. In individuals with MDD, however, monitoring thyroid axis hormones at different times of the day is not accurate [29].
In the year 2021, Diaz et al. did research to determine the association between TSH levels and health related quality of life (HRQL). Hypothyroid individuals who had received sufficient treatment for hypothyroidism were included in the research. HRQL was measured using the specific thyroid disease ThyPRO-39 questionnaire in 218 consecutive patients with primary hypothyroidism of any cause who attended an endocrinology department in a single center. The study's findings revealed that increased TSH levels resulted in a worsening of HRQL. TSH has also been found to be linked to ratings of tiredness and emotional sensitivity assessments [35]. Shivaprasad et al. in 2018 did research to measure HRQL in hypothyroid individuals. The SF-36 questionnaire was used to examine 244 individuals in the research, and all of the individuals in the trial were older than 18 years. Six of the eight SF-36 measures had significantly lower scores for hypothyroidism patients compared to healthy controls in the research. There were no significant intergroup variations in the domains of "role effective" and "social functioning" [36]. In 2016, Winther et al. published research that looked at disease-specific (ThyPRO) and general (SF-36) HRQL in those who had hypothyroidism owing to autoimmune thyroiditis after initiating levothyroxine therapy. A prospective cohort study was conducted on 78 individuals at two Danish university hospitals' endocrine clinics. According to ThyPRO and SF-36, HRQL was considerably impaired in this group of hypothyroid patients before treatment, with fatigue being the most significant impairment. Several aspects of HRQL improved throughout the first six months of LT4 therapy, albeit complete recovery was not achieved [37]. Tan et al. researched Asian patients in 2019 to see if there was a relationship between hypothyroid symptoms, comorbidities, quality of life (QOL), and hypothyroid-related symptoms in patients on LT4 medication. In Asian hypothyroid individuals, weight gain, weariness, weakness, dry or coarse skin, leg edema, and increased comorbidities and symptoms were all linked to a decreased QOL [38].
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