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Thyroid hormone levels in patients with bipolar disorder: a systematic review and meta-analysis

BMC Endocrine Disorders volume 24, Article number: 248 (2024) Cite this article

Abstract

Purpose

To investigate the difference in blood (serum/plasma) thyroid hormone (TH) levels, including thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3), free thyroxine (FT4), and free triiodothyronine (FT3), in bipolar disorder (BD) during different mood episodes (depression and mania) compared with healthy control (HC) and between manic episodes (BD-M) and depressive episodes (BD-D).

Methods

As of September 1, 2024, the electronic databases PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, and Clinical Trials. Gov were systematically searched with no language limitations. Standardized mean differences (SMD) with 95% confidence interval (CI) were summarized using a random effects model. The chi-squared-based Q test and the I2 test assessed the size of heterogeneity.

Results

The 21 studies included a total of 3696 participants, Of the 2942 BD patients, 1583 were in depressive episodes 1359 were in manic episodes. The status of measuring blood TH levels included 2 studies in plasma and 19 in serum. Combined with the results of the sensitivity analyses, we obtained the following relatively reliable results: serum T3 (SMD: -0.63, 95%CI: -1.09 to -0.17) and FT3 (SMD: -0.42, 95%CI: -0.83 to -0.00) levels decreased significantly in BD-D compared to HC; serum T3 (SMD: -0.91, 95%CI: -1.49 to -0.32) levels decreased significantly and serum FT4 (SMD: 0.37, 95%CI: 0.14 to 0.60) levels increased significantly in BD-M than in HC; serum T3 (SMD: 0.87, 95%CI: 0.24 to 1.49) and FT3 (SMD: 0.27, 95%CI: 0.13 to 0.42) levels demonstrated a significant elevation in BD-M compared to BD-D. In the group of euthyroidism, apart from serum FT4 (SMD: 0.21, 95%CI: -0.15 to 0.58) levels showed no significant difference between BD-M and HC, other results above remained consistent.

Conclusion

Serum T3 and FT3 levels decreased significantly in BD-D compared to HC. Serum T3 levels decreased significantly and serum FT4 levels increased significantly in BD-M compared to HC. Serum T3 and FT3 levels increased significantly in BD-M than in BD-D. The temporality of changes in TH levels and BD progression demands further longitudinal studies to illustrate.

Trial registration

Number and date of registration for prospectively registered trials No. CRD42022378530.

Peer Review reports

Introduction

Bipolar disorder (BD) is a chronic, recurrent mental illness characterized by fluctuating mood states and energy, mainly manifested by alternating episodes of mania or hypomania (BD-M) and depression (BD-D), affecting 1–3% of the global population [1,2,3]. The psychosocial functioning of BD is greatly reduced, and suicide is one of the main causes of its high mortality rate, with a reduction in potential life expectancy of about 10–20 years [4]. According to the World Health Organization (WHO) World Mental Health (WMH) surveys, the days out of the role in BD was the second-highest among ten chronic physical disorders and nine mental disorders [5]. However, the diagnosis and treatment of BD continue to face challenges in clinical practice [3]. So, it is necessary to explore potential biomarkers for the disease.

Hypothalamic-pituitary-thyroid (HPT) axis dysfunction is considered to be related to the mechanism of BD [6]. Thyroid dysfunction (TD) increases the risk of BD and contributes to its worsening clinical course [7]. It was reported that BD patients were 2.55 times more likely to develop TD than the general population [8]. Even mild alterations in thyroid function are associated with the risk of BD [9]. Thyroid hormone (TH), which is involved in central nervous system (CNS)—related processes such as neuronal survival and differentiation, energy expenditure, synapse establishment, and myelin formation, has a fundamental effect on brain development [10, 11]. It is well established that TH is critical for mood regulation and abnormal TH levels may play an important role in the pathophysiology or management of mood disorders [12, 13]. Kuś et al. [9] concluded that each standard deviation (SD) increase in free thyroxine (FT4) levels was associated with an 11% reduction in the overall risk of BD. Amann et al. [14] indicated that higher blood thyroid-stimulating hormone (TSH) levels increase the risk of manic episodes in BD. The results of the study by Krishna et al. [8] noted that mean triiodothyronine (T3) values were significantly higher in BD patients compared with age and sex-matched controls. Furthermore, there is also some evidence that TH-assisted therapy is beneficial to the remission of BD [15, 16]. These findings affirm that the pathophysiologic mechanism of BD involves the disturbance of TH levels [8]. Several studies have examined changes in TH levels of BD patients, but a consensus has not yet been met. Lai et al. [12] found that serum TSH levels were significantly decreased in BD-D compared to healthy control (HC), and the result of Albeh et al. [17] demonstrated serum TSH levels in BD-M were significantly elevated compared to HC, but inconsistent results were reported by Song et al. [18]. Additionally, Zhao et al. [19] reported a significant increase in serum-free triiodothyronine (FT3) levels in BD-M than in BD-D, which is different from the outcome of Li et al. [20]. Therefore, this study aimed to investigate the differences in blood (serum/plasma) TH levels, including TSH, thyroxine (T4), T3, FT4, and FT3, between BD-D or BD-M and HC, as well as between BD-M and BD-D.

Methods

The study was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Table S6) [21]. It has been registered in the PROSPERO (https://www.crd.york.ac.uk/prospero/), the International Prospective Register of Systematic Reviews platform with the number CRD42022378530.

Search strategy

The electronic databases PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, China Science and Technology Journal Database, Wanfang Database, and Clinical Trials. Gov were searched from inception to 1 September 2024, without language restriction. To ensure the quality of publication in Chinese form, we only included studies published in core or higher-tier publications recognized by Peking University. We also manually searched the references of relevant literature to avoid omissions. For studies where full text or useful data were not available, we tried to get it by contacting the authors. The search strategy was (bipolar disorder) AND (Thyroid hormones OR Thyrotropin OR TSH OR Thyroxine OR T4 OR Triiodothyronine OR T3 OR FT4 OR FT3) (Table S1).

Inclusion and exclusion criteria

Inclusion criteria were as follows:(1) studies provided diagnostic criteria for BD (current a depressive episode or a manic episode); (2) studies comparing blood TH levels between BD during depressive episodes or manic episodes and HC, or between depressive episodes and manic episodes in BD; (3) studies provided TH levels as mean and SD (or can be calculated).

Exclusion criteria were as follows: (1) reviews, conference abstracts, letters, and other non-primary studies; (2) non-human research, such as animal experiments; (3) the object of studies accompanied by other mental illness (such as schizophrenia); (4) rapid cycling BD; (5) studies during pregnancy or lactation; (6) treatment-induced changes in TH levels, such as lithium; (7) data or full text was not available.

Data collection and extraction

Data was extracted using a pre-designed form by two reviewers independently and disagreements were reconciled by discussing with a third author. The extracted information was included as follows: the first author, publication year, location, design type, diagnostic criteria for BD, demographic characteristics of participants (sample size, gender, age, education), outcome indicators, TH measurement method, thyroid function, treatments, reference range of TH levels, and any scale to assess the severity of depression or mania.

Quality assessment

The quality of the included studies was assessed independently by two reviewers and any differences were resolved by a third reviewer. The quality assessment of case–control or cohort studies with the Newcastle Ottawa Scale (NOS) [22] and cross-sectional studies with the Agency for Healthcare Research and Quality Scale (AHRQ) [23], of 0–3, 4–6, 7–9 stars in NOS and 0–3,4–7,8–11 in AHRQ scores represent the highest risk of bias and the lowest quality, the medium risk of bias and the medium quality, the lowest risk of bias and the highest quality, respectively.

Data synthesis and analysis

Standardized mean difference (SMD) with 95% confidence interval (CI) was used to represent continuous variables. If data in the study was not expressed as mean and SD, they were converted according to the method given by McGrath et al. [24]. The size of heterogeneity was assessed by the chi-squared-based Q test and the I2 test, studies with an I2 value of < 25%, 25%-50%, 50%-75%, or 75%-100% were considered to have no, low, moderate, or high heterogeneity, respectively. A random effects model was chosen to combine effect size, regardless of heterogeneity. Subgroup analyses were conducted following treatment, gender, and location. Sensitivity analysis was performed by eliminating each study in turn. Additionally, we only included those studies that demonstrated all included patients were euthyroid sound for sensitivity analysis. The test of publication bias used a funnel plot (number of studies at least 10) and Egger's test. If publication bias existed, the trim-and-fill method was used to reconfirmation the stability of statistical results. A P value of < 0.05 was considered statistically significant. All of the above statistical analyses were performed in STATA/MP 15.

Result

Study search and inclusion

The flowchart of study selection is shown in Fig. 1. A total of 6011 studies were retrieved in this study. There were 2227 duplicated studies removed and 3751 studies inconsistent with the purpose of the study were excluded by reading the title and abstract. The remaining 33 studies excluded 12 by full-text reading for the following reasons: reviews (n = 1), conference abstracts (n = 4), no BD diagnostic criteria (n = 1), not BD-D or BD-M (n = 4), under the influence of drugs (n = 1), no extractable data (n = 1). Finally, 21 studies were included in the systematic review and meta-analysis.

Fig. 1
figure 1

Flow chart of study screening

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Study characteristics and quality assessment

The detailed characterization of the study population is shown in Table 1. Of these 21 studies, all but one prospective cohort study [25] and five case–control studies [20, 25,26,27,28] were cross-sectional. The study sites included India [29], France [30,31,32], Egypt [17], Poland [33], Canada [26], America [34], and China. In terms of language, there were 17 English and 4 Chinese articles [35,36,37,38]. The sample size for the original studies ranged from 16 to 828. The 21 studies included a total of 3696 participants, Of the 2942 BD patients, 1583 were in depressive episodes 1359 were in manic episodes, and the remaining 754 were HC. After excluding 3 studies [32, 38, 39] that did not indicate the sex ratio of enrolled patients, the proportion of females of all remaining patients was 47%, the proportion of females was 46% during depressive episodes and 48% during manic episodes. Apart from 2 studies [31, 38] not mentioned, the mean age of subjects ranged from 17.3 to 53.3. It should be noted that BD-D and HC were not matched for age in 2 studies [12, 27] and BD-D and BD-M were not matched for age in 1 study [20]. The diagnostic criteria for BD included the Diagnostic and Statistical Manual of Mental Disorders, Third, Fourth, and Fifth Edition (DSM-III, DSM-IV, and DSM-V, respectively), the International Classification of Diseases Diagnostic Criteria, Edition 10 (ICD-10), the Chinese Classification of Mental Disorders, Edition 3 (CCMD-3), and Research Diagnostic Criteria for a Selected Group of Functional Pqchoses, Edition 3 (RDC-III). The main methods for measuring TH levels included electrochemiluminescence immunoassay (ECLIA), chemiluminescence immunoassay (CLIA), radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA). The states in which blood TH levels were measured included plasma [31, 32] and serum. Apart from the 5 studies not mentioned [17, 27, 31, 37, 40] or 1 study unsure [34], and 3 studies [20, 29, 33] included subjects with TD, others described the thyroid status as “no endocrine disease”, “excluded of history of thyroid diseases” or “Euthyroidism” and so on. Except for 3 studies unknown [25, 33, 37], in terms of drug expression, these included “drug-naïve or medication-free for at least 3 months before hospitalization” “excluded of who received treatment for thyroid disease” “not receiving lithium carbonate or quetiapine that significantly affects the health of the patient” and “not receiving any psychiatric treatment”, etc.

Table 1 Characteristics of the included population
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The results of quality assessment by NOS for case–control or cohort studies showed a minimum of 6 stars and a maximum of 8 stars (Table S3), and AHRQ for cross-sectional studies showed a minimum score of 6 and a maximum score of 9 (Table S4). Overall, the included studies were medium to high.

Meta-analysis

Comparison of TH levels between BD-D and HC

A total of 12 studies [12, 18, 25, 27, 30,31,32, 34,35,36, 39, 40] compared TH levels between BD-D and HC. The pooled result of 11 studies showed no significant differences in the blood (9 in serum and 2 in plasma) TSH levels between BD-D and HC (SMD: -0.20, 95%CI: -0.44 to 0.03, I2 = 72.10%, P = 0.089). A total of 8 studies comparing serum T4 and T3 levels, the pooled results displayed that T4 and T3 levels decreased significantly in BD-D compared to HC ((SMD: -0.44, 95%CI: -0.79 to -0.08, I2 = 87.50%, P = 0.017), (SMD: -0.63, 95%CI: -1.09 to -0.17, I2 = 92.30%, P = 0.007, Fig. 2), respectively). Nine studies showed serum FT4 and FT3 levels, no significant difference was observed in FT4 levels, while FT3 levels displayed a significant decrease in BD-D compared to HC ((SMD: 0.12, 95%CI: -0.16 to 0.40), I2 = 81.80%, P = 0.403), (SMD: -0.42, 95%CI: -0.83 to -0.00, I2 = 91.20%, P = 0.049), respectively) (Table 2).

Fig. 2
figure 2

Forest plot for comparing serum T3 levels in BD-D and HC (SMD: standard mean difference; CI: confidence interval)

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Table 2 Presentation of outcome indicators in all subjects
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For sensitivity analysis in the group of euthyroidism, the pooled results of TSH, T4, T3, FT4, and FT3 levels all remained consistent with the original results ((SMD: -0.18, 95%CI: -0.48 to 0.11, I2 = 76.20%, P = 0.224), (SMD: -0.58, 95%CI: -1.03 to -0.12, I2 = 89.60%, P = 0.014), (SMD: -0.80, 95%CI: -1.44 to -0.15, I2 = 94.50%, P = 0.015), (SMD: 0.01, 95%CI: -0.30 to 0.31, I2 = 77.90%, P = 0.969), (SMD: -0.47, 95%CI: -0.82 to -0.12, I2 = 83.00%, P = 0.009), respectively) (Table 3).

Table 3 Presentation of outcome indicators in the group of euthyroidism in sensitivity analysis
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Comparison of TH levels between BD-M and HC

A total of 8 studies [17, 18, 25, 26, 28, 34, 35, 38] compared TH levels between BD-M and HC. The pooled result of 7 studies showed no significant differences in serum TSH levels between BD-M and HC (SMD: -0.03, 95%CI: -0.48 to 0.41, I2 = 89.90%, P = 0.878). A total of 7 studies comparing serum T4 and T3 levels, the pooled results displayed that T4 and T3 levels had no significant differences between BD-M and HC ((SMD: -0.34, 95%CI: -0.91 to 0.24, I2 = 92.60%, P = 0.252), (SMD: -0.51, 95%CI: -1.12 to 0.09, I2 = 93.30%, P = 0.096), respectively). Six studies showed serum FT4 levels, no significant difference was observed in FT4 levels between BD-M and HC (SMD: 0.23, 95%CI: -0.08 to 0.55, I2 = 77.90%, P = 0.144). The pooled results of 5 studies displayed showed no significant differences in serum FT3 levels between BD-M and HC (SMD: 0.04, 95%CI: -0.09 to 0.18, I2 = 0.00%, P = 0.537) (Table 2).

For sensitivity analysis in the group of euthyroidism, the pooled results of TSH, T4, FT4, and FT3 levels were consistent with the original results ((SMD: 0.05, 95%CI: -0.40 to 0.49, I2 = 88.20%, P = 0.839), (SMD: -0.10, 95%CI: -0.64 to 0.43, I2 = 91.70%, P = 0.708), (SMD: 0.21, 95%CI: -0.15 to 0.58, I2 = 81.90%, P = 0.255), (SMD: 0.02, 95%CI: -0.12 to 0.16, I2 = 0.00%, P = 0.779), respectively); however, T3 levels decreased significantly in BD-M compared to HC (SMD: -0.74, 95%CI: -1.47 to -0.01, I2 = 95.30%, P = 0.048) (Table 3).

Comparison of TH levels between BD-M and BD-D

A total of 9 studies [18,19,20, 25, 33,34,35, 37, 38] compared TH levels between BD-M and BD-D. The pooled result of 8 studies showed no significant differences in serum TSH levels between BD-M and BD-D (SMD: 0.06, 95%CI: -0.12 to 0.23, I2 = 73.00%, P = 0.514). A total of 8 studies comparing serum T4 and T3 levels, the pooled results displayed that T4 and T3 levels demonstrated a significant elevation in BD-M compared to BD-D ((SMD: 0.67, 95%CI: 0.08 to 1.26, I2 = 97.20%, P = 0.026), (SMD: 0.87, 95%CI: 0.24 to 1.49, I2 = 97.50%, P = 0.007, Fig. 3), respectively). Seven studies showed serum FT4 and FT3 levels, no significant difference was observed in FT4 levels (SMD: 0.48, 95%CI: -0.06 to 1.03, I2 = 96.90%, P = 0.083), however, FT3 levels had significant elevation in BD-M compared to BD-D (SMD: 0.27, 95%CI: 0.13 to 0.42, I2 = 54.70%, P = 0.000, Fig. 4) (Table 2).

Fig. 3
figure 3

Forest plot for comparing serum T3 levels in BD-M and BD-D (SMD: standard mean difference; CI: confidence interval)

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Fig. 4
figure 4

Forest plot for comparing serum FT3 levels in BD-M and BD-D (SMD: standard mean difference; CI: confidence interval)

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For sensitivity analysis in the group of euthyroidism, the pooled results of TSH, T4, T3, FT4, and FT3 levels were consistent with the original results ((SMD: 0.04, 95%CI: -0.20 to 0.28, I2 = 75.10%, P = 0.739), (SMD: 0.94, 95%CI: 0.03 to 1.86, I2 = 98.00%, P = 0.043), (SMD: 1.36, 95%CI: 0.33 to 2.40, I2 = 98.40%, P = 0.010), (SMD: 0.73, 95%CI: -0.08 to 1.55, I2 = 97.60%, P = 0.078), (SMD: 0.37, 95%CI: 0.26 to 0.49, I2 = 0.00%, P = 0.000), respectively) (Table 3).

Subgroup analysis

Subgroup analyses were based on treatment, gender, and location. There were significant differences in TSH and FT4 levels in the subgroup of treatment. T4, T3, and FT3 levels had significant intergroup differences in the subgroups of treatment, gender, and location (Table S5).

Sensitivity analysis and publication bias

The results of the sensitivity analysis are shown in Fig. S1. As demonstrated in Table 4, after omitting unstable studies in the sensitivity analysis, the following results have not changed, indicating relative stability: TSH levels showed no significant differences and FT3 levels showed a decrease significantly in BD-D compared with HC ((SMD: -0.16, 95%CI: -0.38 to 0.07, I2 = 44.00%, P = 0.172), (SMD: -0.77, 95%CI: -1.12 to -0.42, I2 = 83.90%, P = 0.000), respectively); but the following results have changed, indicating instability: (1) T4 levels had no significant differences between BD-D and HC (SMD: -0.06, 95%CI: -0.32 to 0.20, I2 = 44.40%, P = 0.649); (2) T3 levels showed decreased significantly and FT4 levels showed elevated significantly in BD-M than in HC ((SMD: -0.91, 95%CI: -1.49 to -0.32, I2 = 86.20%, P = 0.002), (SMD: 0.37, 95%CI: 0.14 to 0.60, I2 = 40.00%, P = 0.002), respectively); (3) T4 levels showed no significant differences between BD-M and BD-D (SMD: 0.16, 95%CI: -0.12 to 0.43, I2 = 77.60%, P = 0.267); sensitivity analyses indicated that the re-pooled results above after removing unstable studies were relatively robust (Fig. S2). Both the funnel plot (Fig. S3) and Egger's test (Table S2) showed that all results were free of publication bias.

Table 4 Presentation of outcome indicators after omitting unstable studies in the sensitivity analysis
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Discussion

In this meta-analysis, we systematically compared blood TH levels between BD-D or BD-M and HC as well as between BD-M and BD-D, then the following relatively robust results were obtained: serum T3 and FT3 levels decreased significantly in BD-D compared to HC; serum T3 levels decreased significantly and serum FT4 levels increased significantly in BD-M compared to HC; serum T3 and FT3 levels were significantly higher in BD-M than in BD-D; there were no significant differences in other TH levels. Overall, the results of the present study deepened the understanding of the relationship between BD and thyroid function, which may be helpful in the diagnosis and treatment of BD in clinical practice.

In this study, serum T3 levels were significantly decreased in both BD-D and BD-M compared to HC, which was coherent with those of Song et al. [18]. It is a fact that significant cognitive impairment exists in BD [41]. The thyroid gland is stimulated by TSH to secrete TH, of which 93% are T4 and 7% are T3, and inactive T4 is converted to active T3 by types I, II iodothyronine deiodinase (D1, D2) [42, 43]. T3 is essential for the development and differentiation of neurons and neuroglia [44, 45]. T3 in the brain comes from a dual source of T4 in the circulation (D1) and astrocytes (D2), which functions by acting on thyroid receptors (TR) [46, 47]. TR is abundant in the hippocampus [48, 49]. T3 induces hippocampal neurogenesis by affecting Type 2b and Type 3 progenitors in the dentate gyrus [49,50,51]. It is well-established that hippocampal neurogenesis and cognitive function have an association [52]. Additionally, the lack of T3 decreases the growth rate of the hippocampus and the number of granule cells in the dentate gyrus [53, 54]. Of note, a reduction in hippocampal volume is a hallmark of BD [55]. Furthermore, T3 is sufficient to activate TR-specific gene pathways in the amygdala, and infusion of T3 into the amygdala is sufficient to rescue cognitive deficits in a mouse model of systemic hypothyroidism [56]. In brief, T3 levels in BD patients may be related to their cognitive function. Besides, we found that serum FT3 levels were significantly decreased in BD-D compared to HC, which was consistent with other studies [12, 18, 25, 40]. It has been found that T3 levels were negatively correlated with the Hamilton Depression Rating Scale (HAMD) in BD-D and the Young Mania Rating Scale (YMRS) in BD-M [18, 40]. However, the results of Zhang et al. [25] showed a positive correlation between FT3 levels and the Montgomery and Asberg Depression Rating Scale (MADRS) in BD-D. Moreover, depressive episodes are the most typical clinical feature of BD patients, leading to a high rate of misdiagnosis of BD due to its high similarity to unipolar depression [3]. Su et al. [27] noted that serum T3 and FT3 levels may represent biological differences between unipolar and bipolar depression. Therefore, measuring serum T3 or FT3 levels in BD may be beneficial in diagnosis as well as prediction and prevention of serious consequences in future disease processes.

Similar to the findings of previous studies, we found that serum T3 and FT3 levels were significantly higher in BD-M than in BD-D [18, 19]. It has been reported that the mechanism by which BD fluctuates between polar and opposing emotional states has a hypothesis of the adrenergic-cholinergic, with depressive episodes based on increased cholinergic function and manic episodes based on increased catecholamine activity [57]. T3 is an aromatic amino acid analog of tyrosine that undergoes decarboxylation to form biogenic amine neurotransmitters such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT), and so T3 is regarded as a precursor of catecholamine-like amines [58, 59]. Moreover, T3 has neurotransmitter-and/or neuromodulator-like effects in the adrenergic system of the brain [59]. Indeed, the pathophysiologic changes in depression are associated with 5-HT deficiency [60]. It is known that there is a link between 5-HT levels and circulating T3 levels, and that depressive-like behavior in hypothyroid rats is strongly associated with reduced 5-HT levels [61,62,63]. Besides, previous studies have shown that depression can cause overactivation of the hypothalamic–pituitary–adrenal (HPA) axis and then increase cortisol levels, which in turn may reduce TH conversion in peripheral tissues by inhibiting deiodinase activity, leading to decreased T3 levels [30, 64, 65]. Khaled et al. [17] showed that cortisol levels reduced and 5-HT levels increased in BD-M. The excellent efficacy of T3 as an adjunctive treatment for BD-D has been reported, and the mechanism may be through the modulation of neurogenesis by affecting 5-HT and DA [66]. There was also evidence of a transition to manic symptoms in drug-resistant BD-D after adjuvant therapy with T3, which was speculated to be a TH-catecholamine receptor interaction [67]. Taken together, BD mood fluctuation may be associated with serum T3 and FT3 levels. Therefore, it is necessary to consider differences in TH levels in BD patients with different emotional states in clinical practice.

After omitting unstable studies of Zhang et al. [25] in the sensitivity analysis, serum FT4 levels displayed a significant increase in BD-M than in HC. At present, BD is mainly treated with drugs. It is known that psychotropic drugs affect the function of the HPT axis [68, 69]. Especially for lithium, has proven to be the treatment of choice for BD, but its effect on thyroid function is explicit [7, 70]. However, the treatment condition of BD patients was not shown in the study by Zhang et al. [25], which may be a reason for its instability. It is known that TH has a profound effect on mood and behavior. Elevated peripheral FT4 levels may be associated with symptoms specific to manic episodes in BD, such as elevated mood and increased activity [71]. A study by Li et al. [72] found that serum FT4 levels were a risk factor for the core features of BD-M (physical violence). Additionally, it was reported that FT4 levels were positively correlated with YMRS in BD-M patients [25]. Therefore, FT4 levels may correlate with disease severity during manic episodes in BD. Our results were similar to those of Han et al. [28]. Notely, Han et al. [28] indicated that there may be gender differences in the neuroendocrine regulation of BD-M, with elevated FT4 levels restricted to males, and that the specific changes in TH levels in females need to be explained by thyroid compensatory mechanisms. Classical neuroendocrine feedback theory suggests that physiologic feedback systems are regulated primarily by negative feedback and self-protection. BD-M has been reported to alleviate symptoms by lowering TH levels through self-regulatory mechanisms and stimulating regulation of the pituitary axis through a negative feedback mechanism, a process that increases TSH secretion as well as the sensitivity of the anterior pituitary gland [73,74,75]. Besides, Özerdem et al. [74] emphasized that female BD patients were more likely to have elevated TSH levels. However, due to the limitations of the included studies, further analysis by gender was not conducted in this study. Furthermore, several studies have reported that low TSH levels may be possibly associated with cognitive impairment in BD-D patients [12, 39, 40]. But, our study did not find significant changes in TSH levels in BD patients. Currently, studies on BD and thyroid-related studies focus on the therapeutic aspects, such as exploring the benefits of TH therapy for BD or exploring the effects of antipsychotics on thyroid function in BD patients, whereas there are a limited number of studies exploring the changes in TH levels in BD patients alone. Therefore, more future studies are necessary to explore TH levels in BD patients and then better testify to the potential value of TH for the diagnosis and treatment of BD.

The strengths of this meta-analysis were that it provided the most comprehensive and up-to-date assessment of blood TH levels in BD patients by rigorously quantifying and analyzing inconsistent results, leading to more persuasive conclusions. Additionally, we only included those studies that demonstrated all included patients were euthyroid sound for sensitivity analysis, which added to the reliability of our findings. Nonetheless, there were several limitations. Firstly, due to the cross-sectional nature of the included studies, the causal relationship between BD patients and TH levels cannot be well illustrated. Secondly, the small number of studies included may affect the robustness of the pooled results. Thirdly, the pooled results demonstrated high heterogeneity, which may be related to different subject characteristics such as age and gender. Fourthly, the generalizability of the results may be limited by the fact that the experimental study sites were mainly in China. For the above reasons, the results of this study need to be interpreted with caution. Thus, more relevant studies to verify the feasibility of our results are necessary.

The present study did have several questions that were not addressed owing to deficiencies in the design type, number, subject population, and location of included studies. Given these shortcomings, more large prospective cohort studies and clinical trials are needed to provide reference values for specific TH as circulating biomarkers for BD, encompassing specific age groups, different genders, and more ethnically diverse BD patients, respectively.

Conclusion

In conclusion, serum T3 and FT3 levels decreased significantly in BD-D compared to HC. Serum T3 levels decreased significantly and serum FT4 levels increased significantly in BD-M compared to HC. Serum T3 and FT3 levels increased significantly in BD-M than in BD-D. Whether changes in TH levels occur after or before BD pathology needs to be assessed by longitudinal studies. TH levels in BD patients with different emotional states need to be considered in clinical management. Certainly, the clinical applicability of TH therapy for BD remains to be validated by additional large multicenter trials.

Data availability

All available data analyzed in this study are included in the manuscript and its supplementary materials.

Abbreviations

BD:

Bipolar disorder

BD-D:

Bipolar depression

BD-M:

Bipolar mania

HC:

Healthy control

WHO:

World Health Organization

WMH:

World Mental Health

HPT:

Hypothalamic-pituitary-thyroid

HPA:

Hypothalamic–pituitary–adrenal

TD:

Thyroid dysfunction

TH:

Thyroid hormone

TSH:

Thyroid-stimulating hormone

T4:

Thyroxine

T3:

Triiodothyronine

FT4:

Free thyroxine

FT3:

Free triiodothyronine

TR:

Thyroid receptor

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

NOS:

Newcastle Ottawa Scale

AHRQ:

Agency for Healthcare Research and Quality Scale

SD:

Standard deviation

SMD:

Standardized mean difference

Cl:

Confidence interval

DSM:

Diagnostic and Statistical Manual of Mental Disorders

ICD-10:

International Classification of Diseases Diagnostic Criteria, Edition 10

CCMD-3:

Chinese Classification of Mental Disorders, Edition 3

RDC-III:

Research Diagnostic Criteria for a Selected Group of Functional Pqchoses, Edition 3

ECLIA:

Electrochemiluminescence immunoassay

CLIA:

Chemiluminescence immunoassay

RIA:

Radioimmunoassay

ELISA:

Enzyme-linked immunosorbent assay

D1:

Types I iodothyronine deiodinase

D2:

Types II iodothyronine deiodinase

YMRS:

Young Mania Rating Scale

HAMD:

Hamilton Depression Rating Scale

MADRS:

Montgomery and Asberg Depression Rating Scale

CNS:

Central nervous system

DA:

Dopamine

NE:

Norepinephrine

5-HT:

Serotonin

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Acknowledgements

We are grateful for the contributions of the researchers and study participants, and the grant from the National Natural Science Foundation of China (No.82060152).

Clinical trial number

Not applicable.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No.82060152).

Author information

Authors and Affiliations

  1. The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, China

    Shanshan Liu & Limin Tian

  2. Department of Endocrinology, Gansu Provincial Hospital, Lanzhou, Gansu, China

    Shanshan Liu, Xiaoai Chen, Xiaotao Li & Limin Tian

  3. School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China

    Xiaoai Chen

  4. The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, China

    Xiaotao Li

  5. Clinical Research Center for Metabolic Diseases, Lanzhou, Gansu, China

    Shanshan Liu, Xiaoai Chen, Xiaotao Li & Limin Tian

Authors
  1. Shanshan Liu
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  2. Xiaoai Chen
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  3. Xiaotao Li
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  4. Limin Tian
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Contributions

All authors were involved in the conception and design of the study. SL, XC and XL completed the data preparation, data extraction and data analysis. SL wrote the first draft. The draft was reviewed and revised by LT and XC. All authors read and finalized the final version of the manuscript.

Corresponding author

Correspondence to Limin Tian.

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Liu, S., Chen, X., Li, X. et al. Thyroid hormone levels in patients with bipolar disorder: a systematic review and meta-analysis. BMC Endocr Disord 24, 248 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12902-024-01776-1

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12902-024-01776-1

Keywords

BMC Endocrine Disorders

ISSN: 1472-6823

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