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

doi:10.21203/rs.3.rs-3332028/v1

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Research Article

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

https://doi.org/10.21203/rs.3.rs-3332028/v1

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Purpose

To investigate the difference of serum thyroid hormone (TH) levels in bipolar disorder (BD) during different mood episodes (depression and mania) compared with healthy control (HC) and among different mood episodes.

Methods

We systematically searched the electronic databases for studies on the relationship between BD and TH levels. The random effects model and the standardized mean difference were used to combine the effect sizes.

Results

Serum T3 (standard mean difference [SMD]: -0.52, 95% confidence interval [CI]: -0.86 to -0.18, P = 0.00), FT3 (SMD: -0.55, 95%CI: -1.06 to -0.04, P = 0.04) decreased significantly in BD-depression compared with HC. Serum TSH(SMD: 0.20, 95%CI: 0.04 to 0.36, P = 0.02), FT4 (SMD: 0.42, 95%CI: 0.17 to 0.66, P = 0.00) increased significantly and T3 (SMD: −0.73, 95%CI: −1.37 to -0.08, P = 0.03) decreased significantly in BD-mania compared with HC; FT4 (SMD: 0.85, 95%CI: 0.56 to 1.13, P = 0.00) increased significantly in males; TSH (SMD: 0.49, 95%CI: 0.21 to 0.78, P = 0.00) increased significantly, T3 (SMD: -0.57, 95%CI: -0.86 to -0.29, P = 0.00) and T4 (SMD: -0.68, 95%CI: -1.34 to -0.01, P = 0.05) decreased significantly in females. Serum T3 (SMD: 0.29, 95%CI: 0.12 to 0.46, P = 0.00), FT3(SMD: 0.55, 95%CI: 0.28 to 0.81, P = 0.00) increased significantly in BD-mania than in BD-depression.

Conclusion

Serum T3 and FT3 levels decreased significantly in BD-depression compared with HC. Serum TSH, FT4 levels increased significantly and T3 level decreased significantly in BD-mania compared with HC. Serum T3, FT3 levels increased significantly in BD-mania than in BD-depression. The fascinating thing was that gender differences may affect the compensatory secretion of BD-mania anterior pituitary hormone.

Trial registration number and date of registration for prospectively registered trials No. CRD42022378530 (4 December 2022)

Bipolar disorder

Depression

Mania

Thyroid hormone

Meta-analysis

Bipolar disorder (BD) is a type of chronic episodic mental disorder with both manic (bipolar I disorder) or hypomanic (bipolar II disorder) episodes and depressive episodes, affecting more than 1% of the world's population, with a lifetime prevalence of about 2.8–6.5%, and is a leading cause of disability among young people [1–3]. The potential life expectancy is reduced by about 10–20 years [4]. According to the World Health Organization (WHO) World Mental Health (WMH) surveys, BD had the second-highest on the individual-level effects (days out of role per year) among ten chronic physical disorders and nine mental disorders [5]. It has caused huge economic burden to patients, families and society [6]. Therefore, early diagnosis and effective intervention of BD are extremely important, but still face great challenges [7].

Hypothalamic-pituitary-thyroid (HPT) axis dysfunction is considered to be related to the pathological neural mechanism of BD development. Both hypothyroidism [8] and hyperthyroidism [9] are associated with an increased risk of BD, and can promote the deterioration of its clinical course [10]. Thyroid hormone (TH) is regulated by strict feedback on the HPT axis, which is a sensitive marker of thyroid dysfunction [11, 12]. TH crosses the blood-brain barrier into the brain with the help of transporters, which is involved in regulating the survival and differentiation of neurons as well as energy consumption, and its abnormal metabolism can affect the pathogenesis of central nervous system diseases such as depression and cognitive disorders by affecting the development of dendrite or axons, the establishment of synapses, and the formation of myelination. [13–15]. Marangell et al. [16] reported that peripheral TSH level was negatively correlated with cerebral blood flow (CBF) and cerebral glucose metabolism in patients with mood disorders (untreated BD and major depressive disorder (MDD)). Larsen et al. [17] showed that increased severity of mood symptoms in BD may be associated with decreased TSH responsiveness to TRH. Pompili et al. [18] pointed out that FT3 level was positively correlated with suicide risk in BD. Furthermore, there are also some evidences that TH-assisted therapy is beneficial to the remission of BD [19, 20]. These findings proved that the progression of BD is related to disturbances in peripheral TH metabolism [21]. Surprisingly, the fluctuation in TH levels within the normal range is also associated with an increased risk of certain psychiatric disorders [22]. Aleksander et al. [23] found that slight changes in FT4 level within the normal-range were significantly negatively correlated with the risk of developing BD by Mendelian randomization (MR) method, especially bipolar I disorder. Additionally, there is significant cognitive deficit in BD, while the correlation between subtle differences in normal TH levels and cognitive function in BD patients have also been described [2, 24]. Although a large number of studies have explored changes of TH levels in BD patients, no consensus has been reached and still with controversy. So, we conducted the first meta-analysis to determine whether the occurrence and development of BD is related to specific TH levels, so as to provide certain theoretical basis for the clinical diagnosis and treatment of BD.

The study was according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [25]. It has been registered in the PROSPERO (https://www.crd.york.ac.uk/prospero/), International prospective register of systematic reviews platform with the number is 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 Database were searched from inception to 23 November, 2022 without language restriction. We also manually searched the references of relevant literature to avoid omissions. For studies where full text or useful data is 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 in supplementary material).

Inclusion and exclusion criteria

Inclusion criteria were as follows:(1) The study provided diagnostic criteria for BD (current a depressive episode or a manic episode); (2) The study provided general data of participants and sufficient experimental data, including sample sizes、mean and standard deviation or median and quartile of baseline blood TH levels of both the study group (depressive episodes or manic episodes) and the healthy control (HC); (3) The BD patient was medication-free or discontinued psychiatric medications, such as mood stabilizers or antidepressants, for at least two weeks;(4) The design type of the study was observational, consisting of cohort studies, case-control studies, and cross-sectional studies.

Exclusion criteria were as follows: (1) Reviews, conference abstracts, letters and other non- primary studies; (2) Non-human research, such as animal experiments; (3) Studies during pregnancy or lactation; (4) studies that included subjects with thyroid dysfunction; (5) The object of studies accompanied with other mental illness (such as schizophrenia); (6) Data or full text was not available.

Data extraction

Data was extracted using a pre-designed form by two reviewers independently and disagreements were reconciled by discussing with third author. The extracted information was included as follows: the first author、publication year、design type、demographic characteristics of participants (sample size、gender、average age、education)、status of thyroid function、time without medication、serum TH levels、reference range of TH levels and any scale to assess the severity of depression or mania.

Quality assessments

The quality of included studies was assessed independently by two reviewers and any differences were resolved by third reviewer. The quality assessment of case-control or cohort studies with the Newcastle Ottawa Scale (NOS) and the Agency for Healthcare Research and Quality Scale (AHRQ) used to assess the quality of cross-sectional studies, of them 0–3, 4–6 and 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

We used standardized mean difference (SMD) with 95% confidence intervals to represent continuous variables. If the data in the study were expressed using median and quartile, they were converted to mean and standard deviation according to the method given by McGrath et al. [26]. The random effect model was selected to combine the effect sizes. The size of heterogeneity was assessed by I², 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. Subgroup analysis was performed by diagnostic criteria for BD、mean age of patients、and methods for measuring serum TH, thus, explore the source of heterogeneity. Sensitivity analysis was performed by eliminating each study in turn. The test of publication bias used Egger's test and funnel plot. A P value of < 0.05 was considered statistically significant. All of the above statistical analyses were performed in STATA/MP 16.0.

Study selection and characteristics

The flowchart of study selection is shown in Fig. 1. A total of 3983 studies were retrieved in this study. There were 1984 duplicated studies removed and 1917 studies inconsistent with the purpose of the study were excluded by reading the title and abstract. The remaining 55 studies were screened by reading the full text. Finally, 27 studies were included for this systematic review and meta-analysis.

Of the 27 studies, which included 4 case-control studies [27–30] and 23 cross-sectional studies [31–53]. One study [53] was conducted in America, one [30] in Egypt, one in Canada [50], and three [35, 51, 52] in France, the others in China. In terms of language, there are 11 English [27–31, 33, 35, 50–53] and 16 Chinese articles [32, 34, 36–49]. The 27 studies included a total of 2380 participants. Of the 1451 patients with BD, 953 were in depressive episodes and 498 were in manic episodes. The remaining 929 were HC. The sample size for the original studies ranged from 16 [51] to 264 [31]. After excluding 2 studies [29, 52] that did not indicate the sex ratio of enrolled patients, the proportion of females of all remaining patients was 53%, the proportion of females was 56% during depressive episodes, and 47% during manic episodes. The mean age of patients ranged from 15.9 [40] to 53.3 [52]. The diagnostic criteria for BD included the Diagnostic and Statistical Manual of Mental Disorders (DSM) [27, 29, 30, 33, 35, 38, 41, 43, 44, 50–52], the International Classification of Diseases diagnostic Criteria, Edition10(ICD 10) [28, 31, 34, 36, 39, 40, 42, 48], the Chinese Criteria for Classification and Diagnosis of Mental Disorders, Edition3(CCCD-3) [32, 37, 45–47, 49], and the Diagnostic Criteria for Functional Psychoses (3rd) [53]. In most studies, euthyroid patients or no history of thyroid disease were required to be included, while two studies [27, 30] had no any description of thyroid function. Except for 2 studies [36, 47] that didn't mention it, and one study [35] just said it was immunoassay, methods for measuring serum TH included Electrochemiluminescence immunoassay (ECLIA) [28, 31, 34, 39–42, 44], Chemiluminescence immunoassay (CLIA) [27, 29, 30, 32, 33, 37, 38, 45], Radioimmunoassay (RIA) [46, 50–53], Enzyme linked immunosorbent assay (ELISA) [43, 48–50], Immunofluorescence (IF) [50], and most studies show that they were measured in the morning. In terms of drug expression, some studies directly specified medication-free [30, 31, 33, 34, 42, 45], the duration of drug discontinuation in other studies were separately 6 months [27, 29, 36], 3 months [32, 39], 2 months [43], 1 month [37, 40, 46, 50], and at least 2 weeks [28, 35, 38, 41, 44, 47–49, 51–53]; But the specific medications were not specified, some said they had stopped antipsychotics、antidepressants、or mood stabilizers, some claimed they had stopped any drugs that have an effect on endocrine function, and some were even first-episode and had no history of taking antipsychotics, it is worth noting that all studies were categorized by the shortest duration of discontinuation. HC was the healthy participant without psychiatric and thyroid disorders, most studies selected physical examination subjects in hospitals [28, 32, 34, 37, 38, 40, 41, 44–47], and a few studies were recruited through the community [39] or advertising [27, 29, 50], but also volunteers [33, 35] and medical staffs [30, 43, 48, 49, 53], while three [42, 51, 52] were unknown.

Quality assessment and risk of bias

As shown in Table 1, all of the 27 studies included were of medium to high quality, with a minimum score of 6, and among them 8 were of high quality (NOS of 7–8 and AHRQ of 8).

Table 1

Characteristics of the included population
Study	Location	Design type	TH measurement method	Diagnostic criteria for BD	State	Number (Male/Female)	Average age(years)	Education(years)	Thyroid function in BD	Withdrawal time	Rating scale (Mean ± SD)	Reference range of TH	Scale of quality score
Study	Location	Design type	TH measurement method	Diagnostic criteria for BD	State	Number (Male/Female)	Average age(years)	Education(years)	Thyroid function in BD	Withdrawal time	Rating scale (Mean ± SD)	Reference range of TH	NOS	AHRQ
Chen et al. 2022 [27]	China	Case-control	Direct chemiluminescence method	DSM-V	BD-D	59(23/26)	23.81 ± 5.87	14.04 ± 2.44	No description on thyroid function.	≥ 6 months	24-item HDRS ( 27.05 ± 5.87)	TSH:0.49–4.91mIU/L TT4:69.97–152.52nmol/L TT3:1.01–2.48nmol/L FT4:7.64–16.03pmol/L FT3:3.09–7.42pmol/L	7
			Direct chemiluminescence method	DSM-V	HC	52(27/25)	24.62 ± 5.55	15.58 ± 2.53	No description on thyroid function.	≥ 6 months	24-item HDRS (1.80 ± 2.34)
Zhao et al. 2021 [31]	China	Cross-sectional	Electrochemiluminescence (TSH: electrochemiluminescence double antibody sandwich method;TT3、FT3、TT4、FT4:Quantitative analysis by electrochemical luminescence)	ICD-10	BD-M	136(71/65)	27.81 ± 8.62	N/A	No history of thyroid disease.	drug-naïve	YMRS (28.57 ± 12.00)	TSH:0.27–4.20mIU/L TT462.00–164.00nmol/L TT3:1.30–3.10nmol/L FT4:12.00–22.00pmol/L FT3:3.60–7.50 pmol/L		8
				ICD-10	BD-D	128(53/75)	26.91 ± 7.04		No history of thyroid disease.	drug-naïve	MADRS (25.74 ± 11.79)
Lai et al. 2021 [33]	China	Cross-sectional	Direct chemiluminescence method	DSM-IV	BD-D	69(32/37)	26.23 ± 8.98	13.62 ± 2.65	All subjects were euthyroid.	drug-naïve	24-item HDRS ( 26.72 ± 5.76)	TSH:0.49-4.91mIU/L TT4:69.97-152.52µg/dl TT3:1.01–2.48 ng/ml FT4:7.64–16.03 ng/dl FT3:3.09–7.42 pg/ml		7
			Direct chemiluminescence method	DSM-IV	HC	53(29/24)	36.23 ± 13.95	14.49 ± 3.12	All subjects were euthyroid.	drug-naïve	24-item HDRS (2.49 ± 2.05)
Han et al. 2021 [28]	China	Case-control	Electrochemiluminescence immunoassay (Roche Cobas e601 automatic electrochemiluminescence immunoassay system)	ICD-10	BD-M	70(35/35)	24.3 ± 5.1	N/A	No history of thyroid disease.	> 2 weeks	YMRS ( 28.2 ± 3.4)	TSH:0.27–4.20mIU/L TT4:66–181nmol/L TT3:1.3–3.1nmol/L FT4:12–22pmol/L FT3:2.8–7.1pmol/L	6
				ICD-10	HC	70(35/35)	24.7 ± 4.3		No history of thyroid disease.	> 2 weeks
Shi et al. 2021 [32]	China	Cross-sectional	Automatic chemiluminescence immunoanalyzer (Xiamen Haifei Biotechnology Co., LTD., Model: SMART 3000)	CCMD-3	BD-D	40(20/20)	33.68 ± 1.70	6.96 ± 2.60	All subjects were euthyroid.	> 3 months	N/A	N/A		6
				CCMD-3	HC	40(18/22)	33.69 ± 1.71		All subjects were euthyroid.	> 3 months		N/A
Fei et al. 2021 [34]	China	Cross-sectional	Electrochemiluminescence [Automatic biochemical analyzer (Model: AU583, USA Beckman Coulter Co.)]	ICD-10	BD-D	45(16/29)	21.53 ± 8.38	N/A	No history of thyroid disease.	drug-naïve	N/A	N/A		7
				ICD-10	HC	94(32/62)	22.72 ± 3.76		No history of thyroid disease.	drug-naïve		N/A
Duval et al. 2020 [35]	France	Cross-sectional	Assay by immunoassay technique with enhanced luminescence	DSM-IV	BD-D	13	34.3 ± 10.8	N/A	All subjects were euthyroid.	> 2 weeks	N/A	N/A		6
			Assay by immunoassay technique with enhanced luminescence	DSM-IV	HC	13	33.2 ± 9.2		All subjects were euthyroid.	> 2 weeks		N/A
Zhong et al. 2019 [29]	China	Case-control	Direct chemiluminescence method	DSM-V	BD-D	57	26.74 ± 8.73	14.03 ± 2.83	No history of thyroid disease; All subjects were euthyroid.	≥ 6 months	24-item HDRS ( 27.10 ± 5.69)	TSH:0.38-4.31mIU/L TT4:4.9–11.0µg/dl TT3:0.79-1.58ng/ml FT4:0.82-1.63ng/dl FT3:2.10-3.80pg/ml	8
			Direct chemiluminescence method	DSM-V	HC	20	28.32 ± 9.01	14.72 ± 2.76		≥ 6 months
Xing et al. 2019 [36]	China	Cross-sectional	N/A	ICD-10	BD-M	62(33/29)	39.06 ± 11.96	N/A	All subjects were euthyroid.	> 6 months	N/A	N/A		7
			N/A	ICD-10	BD-D	30(15/15)	34.50 ± 13.87		All subjects were euthyroid.	> 6 months		N/A
Wang et al. 2019 [37]	China	Cross-sectional	Automatic chemiluminescence immunoanalyzer (ARCHITECT i2000SR, Abbott Laboratories)	CCMD-3	BD-D	82(23/59)	36.0 ± 10.4	9.7 ± 5.3	All subjects were euthyroid.	> 1months	N/A	N/A		7
				CCMD-3	HC	53			All subjects were euthyroid.	> 1months		N/A
Khaled et al. 2018 [30]	Egypt	Case-control	The Immulite 1000 chemiluminescent immunoassay system	DSM-IV	BD-M	30(21/9)	23.6 ± 6.2	N/A	No description on thyroid function.	drug-naïve	N/A	N/A	6
			The Immulite 1000 chemiluminescent immunoassay system	DSM-IV	HC	15	24.4 ± 6.5		No description on thyroid function.	drug-naïve		N/A
Chen et al. 2018 [38]	China	Cross-sectional	Chemiluminescence method	DSM-V	BD-D	48(25/23)	39.3 ± 5.6	N/A	All subjects were euthyroid.	> 2 weeks	N/A	N/A		6
			Chemiluminescence method	DSM-V	HC	15(8/7)	41.5 ± 4.9		All subjects were euthyroid.	> 2 weeks		N/A
Zhu et al. 2017 [39]	China	Cross-sectional	Electrochemiluminescence immunoassay (ECLIA)	ICD-10	BD-M	40(20/20)	43 ± 13.35	N/A	No history of thyroid disease; All subjects were euthyroid.	> 3 months	N/A	N/A		8
			Electrochemiluminescence immunoassay (ECLIA)	ICD-10	HC	40(20/20)	41.2 ± 8.5			> 3 months		N/A
Shi et al. 2017 [41]	China	Cross-sectional	Electrochemical luminescence immunoanalyzer	DSM-IV	BD-D	50(17/33)	37.23 ± 15.61	11.03 ± 1.51	All subjects were euthyroid.	> 2 weeks	HAMD (30.50 ± 3.84)	N/A		7
			Electrochemical luminescence immunoanalyzer	DSM-IV	HC	50(20/30)	36.58 ± 16.94		All subjects were euthyroid.	> 2 weeks		N/A
Jiang et al. 2017 [42]	China	Cross-sectional	Electrochemiluminescence immunoassay [Roche Cobase601 fully automatic Electrochemical luminescence immunoassay system (ECLIA)]	ICD-10	BD-M	65(35/30)	24.3 ± 5.2	N/A	No history of thyroid disease; All subjects were euthyroid.	drug-naïve	N/A	TSH:0.27-4.2uIU/ml T4:66-181nmol/l T3:1.3-3.1nmol/l FT4:12-22pmol/l FT3:2.8-7.1pmol/l		8
				ICD-10	HC	62(35/27)	23.9 ± 4.4	N/A		drug-naïve
Chen et al. 2017 [43]	China	Cross-sectional	Enzyme linked immunosorbent assay [STEKOL1300 spectrophotometer, Thermo Multiskan MK3 enzyme label instrument (ELISA)]	DSM-Ⅳ	BD-M	26(15/11)	32 ± 12	N/A	All subjects were euthyroid.	> 2 months	N/A	TSH:0.34-5.6mIU/L TT4:60.9-122.3µg/L TT3:0.87–1.78 µg/L FT4:6.1-11.2ng/L FT3:2.5ཞ3.9 ng/L		8
					BD-D	33(16/17)	34 ± 12
					HC	41(17/24)	31 ± 5
Zhang et al. 2017 [40]	China	Cross-sectional	Electrochemiluminescence (Roche-Cobase601)	ICD-10	BD-M	49(26/23)	15.90 ± 1.83	N/A	All subjects were euthyroid.	≥ 1 months	N/A	TSH:0.27-4.2uIU/ml T4:68-181nmol/l T3:1.3-3.1nmol/l FT4:12-22pmol/l FT3:3.1-6.8pmol/l		8
					BD-D	80(39/41)	16.60 ± 1.09
					HC	50(23/27)	15.72 ± 1.47
Wang et al. 2015 [44]	China	Cross-sectional	Electrochemical luminescence immunoassay (Roche automatic electrochemiluminescence immunoanalyzer made in Germany)	DSM-Ⅳ	BD-D	42(16/26)	38.45 ± 14.34	9.38 ± 3.30	All subjects were euthyroid.	> 2 weeks	N/A	N/A		7
				DSM-Ⅳ	HC	69(24/45)	37.67 ± 14.41	9.74 ± 2.46	All subjects were euthyroid.	> 2 weeks		N/A
Zhang et al. 2007 [46]	China	Cross-sectional	Radioimmunoassay	CCMD-3	BD-D	30(15/15)	22ཞ68	N/A	All subjects were euthyroid.	> 1months	N/A	N/A		6
			Radioimmunoassay	CCMD-3	HC	30(15/15)	22ཞ65	N/A	All subjects were euthyroid.	> 1months		N/A
Zhan et al. 2007 [45]	China	Cross-sectional	Chemiluminescence (Bayer ACS: 180 SE automatic chemiluminescence analyzer)	CCMD-3	BD-D	42(20/22)	36 ± 8	N/A	All subjects were euthyroid.	drug-naïve	N/A	N/A		6
				CCMD-3	HC	30(15/15)	34 ± 6	N/A	All subjects were euthyroid.	drug-naïve		N/A
Du et al. 2005 [47]	China	Cross-sectional	N/A	CCMD-3	BD-D	32(16/16)	37 ± 8	N/A	All subjects were euthyroid.	> 2 weeks	N/A	FT3:1.4-4.2pg/ml FT4:0.8-2.2ul/L TSH:0.4-6.0uIU/ml		6
			N/A	CCMD-3	HC	30(15/15)	34 ± 10	N/A	All subjects were euthyroid.	> 2 weeks		FT3:1.4-4.2pg/ml FT4:0.8-2.2ul/L TSH:0.4-6.0uIU/ml
Jia et al. 2004 [48]	China	Cross-sectional	Enzyme linked immunosorbent assay (ELISA)	ICD-10	BD-D	23(11/12)	32.2 ± 12.4	N/A	All subjects were euthyroid.	> 2 weeks	N/A	N/A		7
			Enzyme linked immunosorbent assay (ELISA)	ICD-10	HC	30(13/17)	34.2 ± 10.0	N/A	All subjects were euthyroid.	> 2 weeks		N/A
Li et al. 2003 [49]	China	Cross-sectional	Enzyme linked immunosorbent assay	CCMD-3	BD-D	25(11/14)	33 ± 9	N/A	All subjects were euthyroid.	≥ 2 weeks	N/A	N/A		8
			Enzyme linked immunosorbent assay	CCMD-3	HC	30(13/17)	34 ± 10	N/A	All subjects were euthyroid.	≥ 2 weeks		N/A
Sokolov et al.1994 [50]	Canada	Cross-sectional	TSH-Enzyme linked immunosorbent assay; T4, T3- Immunofluorescence; FT4- Radioimmunoassay	DSM-III	BD-M	13(6/7)	17.3 ± 1.2	N/A	All subjects were euthyroid	≥ 1 months	N/A	N/A		7
				DSM-III	HC	13(5/8)	17.3 ± 1.6	N/A	All subjects were euthyroid	≥ 1 months		N/A
Souetre et al. 1988 [51]	France	Cross-sectional	Radioimmunoassay	DSM-III	BD-D	8(2/6)	52.8 ± 7.4	N/A	All subjects were euthyroid	≥ 2 weeks	HDRS (24.4 ± 3.8);	N/A		7
			Radioimmunoassay	DSM-III	HC	8	N/A	N/A	All subjects were euthyroid	≥ 2 weeks	(6.1 ± 3.5)	N/A
Souetre et al. 1986 [52]	France	Cross-sectional	Radioimmunoassay	DSM-III	BD-D	8	53.3 ± 4.49	N/A	All subjects were euthyroid	≥ 2 weeks	HDRS (22.89 ± 4.7);	N/A		6
			Radioimmunoassay	DSM-III	HC	13(8/5)	48.85 ± 6.91	N/A	All subjects were euthyroid	≥ 2 weeks	(5.7 ± 2.3)	N/A
Linnoila et al. 1982 [53]	America	Cross-sectional	Radioimmunoassay	Diagnostic Criteria for Functional Psychoses (3rd)	BD-M	7	38.3 ± 17.6	N/A	All subjects were euthyroid	≥ 2 weeks	N/A	N/A		7
					BD-D	9
					HC	8	37.0 + 10.4
DSM-V: the Diagnostic and Statistical Manual of Mental Disorders (5 Edition); DSM-Ⅳ: the Diagnostic and Statistical Manual of Mental Disorders (4 Edition); DSM-III: the Diagnostic and Statistical Manual of Mental Disorders (3 Edition); ICD-10: the International Classification of Diseases diagnostic Criteria(10 Edition); CCMD-3: Chinese Criteria for Classification and Diagnosis of Mental Disorders(3 Edition); BD: bipolar disorder; BD-D: BD-depression; BD-M: BD-mania; HC: healthy control; 24-item HDRS: 24-item Hamilton depression rating scale; YMRS: Young Mania Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; HAMD-24: Hamilton Depression Scale-24; TH: thyroid hormone; TSH: thyroid-stimulating hormone; T4: thyroxine; T3: triiodothyronine; FT4: free T4; FT3: free T3; NOS: The Newcastle-Ottawa Scale; AHRQ: Agency for Healthcare Research and Quality; N/A: not available

Comparison of BD-depression and HC

A total of 19 studies [27, 29, 32–35, 37, 38, 40, 41, 43–49, 51–53] reported comparison of BD-depression and HC. Eighteen studies reported serum TSH level found no significant differences between groups (SMD: -0.15, 95%CI: -0.32 to 0.01, I² = 53.75%, P = 0.06). Eleven studies reported serum T3, T4 levels, no significant difference was observed in T4 level (SMD: -1.71, 95%CI: -4.87 to 1.45, I² = 99.82%, P = 0.29), however, serum T3 level decreased significantly in BD-depression compared with HC, the difference between groups was statistically significant (SMD: -0.52, 95%CI: -0.86 to -0.18, I² = 85.53%, P = 0.00, Fig. 2). Fifteen studies showed serum FT3, FT4 levels, no significant difference was observed in FT4 level (SMD: 0.29, 95%CI: −0.09 to 0.67, I² = 91.07%, P = 0.14), nevertheless, serum FT3 level decreased significantly in BD-depression compared with HC, the difference between groups was statistically significant (SMD: −0.55, 95%CI: −1.06 to -0.04, I² = 95.04%, P = 0.04, Fig. 3) (Table 2).

Comparison of BD-mania and HC

A total of 8 studies [28, 30, 39, 40, 42, 43, 50, 53] reported comparison of BD-mania and HC. Seven studies showed serum TSH level increased significantly in BD-mania compared with HC, the difference between groups was statistically significant (SMD: 0.20, 95%CI: 0.04 to 0.36, I² = 0.00%, P = 0.02, Fig. 4). Eight studies reported serum T3, T4 levels, no significant difference was observed in T4 level (SMD: −1.62, 95%CI: −4.39 to 1.14, I² = 99.50%, P = 0.25), whereas, serum T3 level decreased significantly in BD-mania compared with HC, the difference between groups was statistically significant (SMD: −0.73, 95%CI: −1.37 to -0.08; I² = 92.24%, P = 0.03, Fig. 5). Six studies reported serum FT4 level increased significantly in BD-mania compared with HC, the difference between groups was statistically significant (SMD: 0.42, 95%CI: 0.17 to 0.66, I² = 44.49%, P = 0.00, Fig. 6). Five studies showed serum FT3 level was no significant difference (SMD: 0.16, 95%CI: −0.14 to 0.46, I² = 64.50%, P = 0.29) (Table 2).

In males, no significant differences in TSH (SMD: -0.16, 95%CI: -0.43 to 0.11, I² = 0.00%, P = 0.23), T4 (SMD: -0.06, 95%CI: -0.83 to 0.71, I² = 86.39%, P = 0.88), T3 (SMD: -0.19, 95%CI: -0.56 to 0.19, I² = 44.42%, P = 0.32) and FT3 levels (SMD: 0.01, 95%CI: -0.26 to 0.28, I² = 0.00%, P = 0.96) between groups, whereas, the level of FT4 (SMD: 0.85, 95%CI: 0.56 to 1.13, I² = 0.00%, P = 0.00) increased significantly in BD-mania compared with HC, the difference between groups was statistically significant (Table 3).

In females, FT4 (SMD: 0.08, 95%CI: -0.20 to 0.36, I² = 0.00%, P = 0.57) and FT3 levels (SMD: -0.01, 95%CI: -0.29 to 0.28, I² = 3.72%, P = 0.96) were no statistical significance between groups, while, TSH level (SMD: 0.49, 95%CI: 0.21 to 0.78, I² = 0.00%, P = 0.00) increased significantly, meanwhile, T4 (SMD: -0.68, 95%CI: -1.34 to -0.01, I² = 79.64%, P = 0.05) and T3 levels (SMD: -0.57, 95%CI: -0.86 to -0.29, I² = 0.00%, P = 0.00) decreased significantly in BD-mania compared with HC, the difference between groups was statistically significant (Table 3).

Comparison of BD-mania and BD-depression

A total of 5 studies [31, 36, 40, 43, 53] reported comparison of BD-mania and BD-depression. Four studies in TSH level found no significant differences between groups (SMD: 0.04, 95%CI: -0.14 to 0.21, I² = 0.00%, P = 0.69). As far as 5 studies in T3 and T4 levels were concerned, no significant difference was observed in T4 level (SMD: 1.37, 95%CI: -0.78 to 3.52, I² = 98.96%, P = 0.21), however, serum T3 level increased significantly in manic episodes than in depressive episodes, the difference between groups was statistically significant (SMD: 0.29, 95%CI: 0.12 to 0.46, I² = 0.00%, P = 0.00, Fig. 7). Four studies showed serum FT3 and FT4 levels, no significant difference was observed in FT4 level (SMD: 0.31, 95%CI: -0.10 to 0.72, I² = 79.03%, P = 0.14), while serum FT3 level increased significantly in manic episodes than in depressive episodes, the difference between groups was statistically significant (SMD: 0.55, 95%CI: 0.28 to 0.81, I² = 47.63%, P = 0.00, Fig. 8) (Table 2).

Subgroup analysis

Subgroup analysis was based on diagnostic criteria for BD、mean age of patients、and methods for measuring serum TH revealed that these factors were the source of heterogeneity between studies. There were significant differences of TSH in subgroups of gender and mean age. T4 had significant intergroup differences in subgroups of mean age and measurement methods. There were significant subgroup differences in the diagnostic criteria, mean age and measurement methods of T3. There were significant differences of FT4 in subgroups of gender, mean age and measuring methods. FT3 had significant intergroup differences in subgroups of mean age. All of the above differences between subgroups were statistically significant (P < 0.05) (Table S3 in supplementary material).

Sensitivity analysis and public bias

The results of sensitivity analysis showed that most of the results were stable, and the statistical significance of a few unstable results was consistent with the original results after excluding the outlier study, indicating that the results were stable (Table S2 in supplementary material). Egger's test showed that all publication bias concentrated in T4 results (comparing BD-depression or BD-mania with HC). We continued to draw a funnel plot for comparing BD-depression with HC that included more than 10 studies, where publication bias disappeared (P = 0.87) and heterogeneity decreased (I² = 0.00%) after excluding studies that caused the apparent asymmetry, and the results were consistent with ours, suggesting that the existence of publication bias may not affect our results (Figure S1 in supplementary material).

Table 2

Presentation of the results for the primary outcome indicators
	Outcome indicators	N	SMD	95%CI	I² (%)	P-value
BD-D and HC	TSH	18	-0.15	(-0.32 to 0.01)	53.75	0.06
	T4	11	-1.71	(-4.87 to 1.45)	99.82	0.29
	T3	11	-0.52	(-0.86 to -0.18)	85.53	0.00
	FT4	15	0.29	(-0.09 to 0.67)	91.07	0.14
	FT3	15	-0.55	(-1.06 to -0.04)	95.04	0.04
BD-M and HC	TSH	7	0.20	(0.04 to 0.36)	0.00	0.02
	T4	8	−1.62	(− 4.39 to 1.14)	99.50	0.25
	T3	8	−0.73	(− 1.37 to -0.08)	92.24	0.03
	FT4	6	0.42	(0.17 to 0.66)	44.49	0.00
	FT3	5	0.16	(-0.14 to 0.46)	64.50	0.29
BD-M and BD-D	TSH	4	0.04	(-0.14 to 0.21)	0.00	0.69
	T4	5	1.37	(-0.78 to 3.52)	98.96	0.21
	T3	5	0.29	(0.12 to 0.46)	0.00	0.00
	FT4	4	0.31	(-0.10 to 0.72)	79.03	0.14
	FT3	4	0.55	(0.28 to 0.81)	47.63	0.00
BD: bipolar disorder; BD-D: BD-depression; BD-M: BD-mania; HC: healthy control; N: sample size; SMD: standard mean difference; CI: confidence interval; TSH: thyroid-stimulating hormone; T4: thyroxine; T3: triiodothyronine; FT4: free T4; FT3: free T3

Table 3

Presentation of the results for the comparison of gender in BD-mania and HC
	Outcome indicators		N	SMD	95%CI	I² (%)
Males	TSH	4	-0.16	(-0.43 to 0.11)	0.00	0.23
	T4	4	-0.06	(-0.83 to 0.71)	86.39	0.88
	T3	4	-0.19	(-0.56 to 0.19)	44.42	0.32
	FT4	4	0.85	(0.56 to 1.13)	0.00	0.00
	FT3	4	0.01	(-0.26 to 0.28)	0.00	0.96
Females	TSH	4	0.49	(0.21 to 0.78)	0.00	0.00
	T4	4	-0.68	(-1.34 to -0.01)	79.64	0.05
	T3	4	-0.57	(-0.86 to -0.29)	0.00	0.00
	FT4	4	0.08	(-0.20 to 0.36)	0.00	0.57
	FT3	4	-0.01	(-0.29 to 0.28)	3.72	0.96
N: sample size; SMD: standard mean difference; CI: confidence interval; TSH: thyroid-stimulating hormone; T4: thyroxine; T3: triiodothyronine; FT4: free T4; FT3: free T3

In this study, we systematically gathered related studies about serum TH levels in patients with BD. The following results were obtained after meta-analysis: Serum T3 and FT3 levels decreased significantly in BD-depression compared with HC. Serum TSH, FT4 levels increased significantly and T3 level decreased significantly in BD-mania compared with HC; serum FT4 increased significantly in males; while in females, serum TSH increased significantly and T4, T3 decreased significantly. Serum T3, FT3 levels increased significantly in BD-mania than in BD-depression. No significant changes were observed in other TH levels.

BD and TH

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 deiodinase to function [54, 55]. T3 is essential for the development and differentiation of neurons and neuroglia [56]. T3 in the brain comes from a dual source of circulating T4 (type 1 deiodinase (D1)) and T4 in astrocyte (type 2 iodothyronine deiodinase (D2)) [57]. Circulating T4 enters the brain by transthyretin, together with T3, acts on thyroid receptors β and α (TRβ and TRα) in the brain [58]. TR are abundant in the hippocampus [59]. T3 can induce hippocampal neurogenesis by affecting type 2b and type 3 progenitor cells, accompanied by significantly induced specific transcription factors [60, 61]. A lack of T3 can slow the growth of the hippocampus and reduces the number of cells in the dentate gyrus [62]. Of note, reduction in hippocampal volume is a hallmark of BD [63]. Decreased brain-derived neurotrophic factor (BDNF) is another characteristic of BD, in which TH maybe also involved in its downregulation [64, 65]. Furthermore, Fernandes et al. [66] pointed out that C-reactive protein (CRP) would increase no matter BD was in what kind of mood state, and BD-mania was the most significant one. While decreased TH levels increase serum CRP levels due to decreased CRP clearance or slow uptake by target cells;in addition, increased TH levels can also increase serum CRP levels due to stimulation of the adrenalin system and immune system, as well as increased peripheral blood flow [67]. Take together, there is a certain relationship between BD and TH levels.

BD-depression and HC

In our study, serum T3 and FT3 levels decreased significantly in BD-depression compared with HC. It was consistent with the results of Joffe et al. [68]. Kjellman et al. [69] showed that T3 level was inversely associated with depression severity. Chen et al. [27] found a negative correlation between serum T3 level and total HDRS scores in BD-depression. Mendonca et al. [70] indicated that the degree of reduction FT3 level decreased in BD-depression was positively correlated with the severity of the disease. It can be concluded that the reduction of serum T3 or FT3 level may contribute to the worsening of BD-depression. Previous studies have shown that depression can cause overactivation of the 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 level [35, 71, 72]. Perhaps it is the reason why T3 treatment is superior to T4 in depression [73]. Moreover, the serotonin deficiency hypothesis has also been reported in depression, and the key is that plasma serotonin (5-HT) levels are positively correlated with T3 level [74]. What counts is that the excellent efficacy of T3 as an adjunct therapy for bipolar depression has been reported, the mechanism of which may be through the regulation of neurogenesis by influencing 5-HT and dopamine (DA) [75]. In addition, T3 may represent a biological difference between unipolar and bipolar depression [68]. Specifically, BD-depression, which is the most common form in BD, is highly similar to unipolar depression, resulting in a high misdiagnosis rate of BD [76]. Therefore, the detection of T3 level may be helpful for the diagnosis of BD.

BD-mania and HC

Our data showed that, compared with HC, serum TSH, FT4 levels increased significantly and T3 level decreased significantly in BD-mania. The important point was that the above changes of TH seemed to be closely related to gender. Specifically, FT4 increased significantly only in the male subgroup, while TSH increased significantly and T4, T3 decreased significantly in the female subgroup. Elevated FT4 was consistent with manic-like symptoms, and FT4 has been reported as a risk factor for core characteristics (physical violence) in BD-mania [77]. For the particularity of female BD-mania, it can be explained by the self-protective regulatory mechanism of BD-mania, which alleviates symptoms by reducing TH levels and then stimulates TSH secretion through negative feedback as well as increasing sensitivity of the anterior pituitary gland [78]. In addition, certain abnormalities in the hypothalamic-pituitary axis in patients with manic states may be related to plasma prolactin (PRL) [79]. Two studies [28, 80] have shown that gender differences affected anterior pituitary hormone compensatory secretion in BD-mania, meanwhile there was a certain relationship (inverse) between increased TSH and PRL levels in female BD-mania. The potentially mechanism of TSH and PRL can be explained as TSH is estradiol-dependent, whereas PRL is a typical estradiol up-regulated hormone that rises rapidly during female adolescence; and that TSH can also promote the release of PRL by stimulating the expression of PRL mRNA in pituitary gland [28, 81]. The above not only verified the sex-specific difference of TH in BD, but also the correlation between mood episodes and estrogen in female BD [82, 83]. To sum up, it is speculated that the reason for the increase of TSH in female BD-mania: the one hand is the decrease of compensatory secretion of T4 and T3, and then negative feedback stimulates the release of TSH; the other hand is the indirect induction by PRL.

BD-mania and BD-depression

In our study, serum T3, FT3 levels increased significantly in BD-mania than in BD-depression. 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 (norepinephrine (NE) and DA) activity [84]. Due to their the common synthetic precursor tyrosine, T3 is structurally similar to catecholamines [85]. Moreover, immunohistochemistry showed that T3 is concentrated in the NE system and can directly produce neurotransmitter effects [86, 87]. There was also evidence of a transition to manic symptoms in drug-resistant bipolar depression after adjuvant therapy with T3, which was speculated to be a TH-catecholamine receptor interaction [88]. In addition, Muller et al. [89] showed that the increase of peripheral deiodination may be the mechanism by which the level of T3 was higher in mania than in depression with the level of T4 was decreased. Above arguments indicate that the elevation of T3 may promote the transformation of DB from depression to mania. Adding to the evidence was the study by Khaled et al. [30] showed that cortisol levels reduced and serotonin levels increased in BD-mania. However, the result of T4 was inconsistent with Muller et al. [89],considering the small number of included studies and significant heterogeneity (I² = 98.96%), it should be interpreted with caution. The result in FT3 was consistent with Zhao et al. [31], which highlighted that the antithyroid effects of psychotropic drugs may be beneficial in BD-mania, while should be avoided in BD-depression. However, Li et al. [90] found no significant difference in TH levels between BD-mania and BD depression. Based on the above reasons, a large number of prospective studies are needed in the future to demonstrate whether the TH levels of BD patients exist discrepancy in different emotional episodes, and provide a theoretical basis for more effective treatment of BD.

Treatment of BD

At present, BD is mainly treated with drugs. While the use of psychotropic drugs alone or in combination all inhibits the function of the HPT axis, causing differences in neuroendocrine hormone levels from baseline and even central hypothyroidism [91, 92]. Especially lithium therapists, it has proven to be the treatment of choice for BD, but its effect on thyroid function is explicit, due to the antithyroid effects of it, hypothyroidism is a common complication of it. [93, 94]. What's more, supraphysiological doses of TH also appeared to be an excellent option for BD treatment [95, 96]. The reason maybe that BD has mitochondrial dysfunction and low ATP cellular state, while the uptake of TH in the cell is energy dependent. Therefore, insufficient ATP will lead to cellular hypothyroidism, and that serum TH levels are normal. In other words, the level of serum TH in BD patients cannot accurately reflect the functional status of thyroid [97, 98]. Another reason maybe that CSF transthyretin in BD is decreased, and TH levels within the blood-brain barrier are disrupted despite sufficient serum TH levels [99]. In short, it is still unclear whether the level of serum TH in BD can guide its clinical treatment, which need to be further studied. In addition, more prospective randomized controlled trials are still needed to evaluate the safety and efficacy of TH-assisted therapy in BD patients.

Strengths and limitations

Despite this study is the first to systematically review levels of serum TH levels in patients with BD, and it excluded the influence of drugs on the serum TH levels of BD patients as far as possible. For the following reasons, the results of this study need to be interpreted with caution. Firstly, there was no distinction between the subtypes of BD, namely, bipolar I disorder or bipolar II disorder. Secondly, the results of some statistical analyses were highly heterogeneous, especially those of T4. Thirdly, most of the studies are cross-sectional, which cannot precisely demonstrate the causal relationship between BD and the HPT axis. Fourthly, the measurement methods of serum TH were inconsistent in some studies, which may result in data mild differences between studies, so we conducted subgroup analysis according to different measurement methods. Fifthly, there was no restriction on the age of the patients, perhaps with error due to age difference; thus, subgroup analyses were performed for different age groups to further identify the sources of heterogeneity in our study. Sixthly, the experimental research site was mainly in China, and there might have regional differences, which may be the objective reason why T4 cannot explain publication bias. Seventhly, although euthyroid patients were required to be included in most studies, the possibility that other studies (three studies included patients who excluded a history of thyroid disease and two studies did not describe thyroid function) enrolled patients with thyroid dysfunction cannot be totally ruled out, thus distorting the overall results.

In summary, serum T3 and FT3 levels decreased significantly in BD-depression compared with HC. Serum TSH, FT4 levels increased significantly and T3 level decreased significantly in BD-mania compared with HC. Serum T3, FT3 levels increased significantly in BD-mania than in BD-depression. The fascinating thing was that gender differences may affect the compensatory secretion of BD-mania anterior pituitary hormone. The potential link between TSH and PRL in female BD-mania needs to be further verified. Further longitudinal studies are needed to prove the causal relationship between the change of TH levels and the occurrence and development of BD. Moreover, the clinical applicability of TH therapy for BD remains to be conducted by more prospective randomized controlled trials.

Acknowledgments 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).

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

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

Conflict of interest The authors have no competing interests

Author 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.

Ethics approval Not applicable

Consent to participate Not applicable

Consent to publish Not applicable

Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Bipolar disorders. Nat Rev Dis Primers. 2018. https://doi.org/10.1038/nrdp.2018.8.
Lima IMM, Peckham AD, Johnson SL. Cognitive deficits in bipolar disorders: Implications for emotion. Clin Psychol Rev. 2018. https://doi.org/10.1016/j.cpr.2017.11.006.
Bauer M, Pfennig A. Epidemiology of bipolar disorders. Epilepsia. 2005. https://doi.org/10.1111/j.1528-1167.2005.463003.x.
McIntyre RS, Berk M, Brietzke E, Goldstein BI, López-Jaramillo C, Kessing LV, et al. Bipolar disorders Lancet. 2020. https://doi.org/10.1016/s0140-6736(20)31544-0.
Alonso J, Petukhova M, Vilagut G, Chatterji S, Heeringa S, Üstün TB, et al. Days out of role due to common physical and mental conditions: results from the WHO World Mental Health surveys. Mol Psychiatry. 2011. https://doi.org/10.1038/mp.2010.101.
Kleinman L, Lowin A, Flood E, Gandhi G, Edgell E, Revicki D. Costs of bipolar disorder. PharmacoEconomics. 2003. https://doi.org/10.2165/00019053-200321090-00001.
Malhi GS. Bipolar disorders: key clinical considerations. Lancet. 2016. https://doi.org/10.1016/s0140-6736(15)01045-4.
Thomsen AF, Kvist TK, Andersen PK, Kessing LV. Increased risk of developing affective disorder in patients with hypothyroidism: a register-based study. Thyroid. 2005. https://doi.org/10.1089/thy.2005.15.700.
Hu LY, Shen CC, Hu YW, Chen MH, Tsai CF, Chiang HL, et al. Hyperthyroidism and risk for bipolar disorders: a nationwide population-based study. PLoS ONE. 2013. https://doi.org/10.1371/journal.pone.0073057.
Sierra P, Cámara R, Tobella H, Livianos L. What is the real significance and management of major thyroid disorders in bipolar patients? Rev Psiquiatr Salud Ment. 2014. https://doi.org/10.1016/j.rpsm.2013.07.005.
Sapin R, Schlienger JL. [Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function]. Ann Biol Clin (Paris). 2003;61(4):411–20.
Zheng X, Jin Y, Xu T, Xu H, Zhu S. Thyroid function analysis after roxadustat or erythropoietin treatment in patients with renal anemia: a cohort study. Ren Fail. 2023. https://doi.org/10.1080/0886022x.2023.2199093.
Bernal J, Morte B, Diez D. Thyroid hormone regulators in human cerebral cortex development. J Endocrinol. 2022. https://doi.org/10.1530/joe-22-0189.
Sawicka-Gutaj N, Zawalna N, Gut P, Ruchała M. Relationship between thyroid hormones and central nervous system metabolism in physiological and pathological conditions. Pharmacol Rep. 2022. https://doi.org/10.1007/s43440-022-00377-w.
Prezioso G, Giannini C, Chiarelli F. Effect of Thyroid Hormones on Neurons and Neurodevelopment. Horm Res Paediatr. 2018. https://doi.org/10.1159/000492129.
Marangell LB, Ketter TA, George MS, Pazzaglia PJ, Callahan AM, Parekh P, et al. Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. Am J Psychiatry. 1997. https://doi.org/10.1176/ajp.154.2.224.
Larsen JK, Faber J, Christensen EM, Bendsen BB, Solstad K, Gjerris A, et al. Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder. Psychoneuroendocrinology. 2004. https://doi.org/10.1016/j.psyneuen.2003.08.004.
Pompili M, Gibiino S, Innamorati M, Serafini G, Del Casale A, De Risio L, et al. Prolactin and thyroid hormone levels are associated with suicide attempts in psychiatric patients. Psychiatry Res. 2012. https://doi.org/10.1016/j.psychres.2012.05.010.
Walshaw PD, Gyulai L, Bauer M, Bauer MS, Calimlim B, Sugar CA et al. Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T(4)) and triiodothyronine (T(3)). Bipolar Disord. 2018. https://doi.org/10.1111/bdi.12657.
Seshadri A, Sundaresh V, Prokop LJ, Singh B. Thyroid Hormone Augmentation for Bipolar Disorder: A Systematic Review. Brain Sci. 2022. https://doi.org/10.3390/brainsci12111540.
Krishna VN, Thunga R, Unnikrishnan B, Kanchan T, Bukelo MJ, Mehta RK, et al. Association between bipolar affective disorder and thyroid dysfunction. Asian J Psychiatr. 2013. https://doi.org/10.1016/j.ajp.2012.08.003.
Soheili-Nezhad S, Sprooten E, Tendolkar I, Medici M. Exploring the Genetic Link Between Thyroid Dysfunction and Common Psychiatric Disorders: A Specific Hormonal or a General Autoimmune Comorbidity. Thyroid. 2023. https://doi.org/10.1089/thy.2022.0304.
Kuś A, Kjaergaard AD, Marouli E, Del Greco MF, Sterenborg R, Chaker L, et al. Thyroid Function and Mood Disorders: A Mendelian Randomization Study. Thyroid. 2021. https://doi.org/10.1089/thy.2020.0884.
Barbero JD, Gutiérrez-Zotes A, Montalvo I, Creus M, Cabezas Á, Solé M, et al. Free thyroxine levels are associated with cognitive abilities in subjects with early psychosis. Schizophr Res. 2015. https://doi.org/10.1016/j.schres.2015.04.030.
Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021. https://doi.org/10.1136/bmj.n160.
McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Methods Med Res. 2020. https://doi.org/10.1177/0962280219889080.
Chen P, Chen GM, Zhong SM, Chen F, Ye T, Gong JY, et al. Thyroid hormones disturbances, cognitive deficits and abnormal dynamic functional connectivity variability of the amygdala in unmedicated bipolar disorder. J Psychiatr Res. 2022;150:282–91.
Han Y, Zhang HH, Huang T, Wang F, Zhu YC. A retrospective study of pituitary-thyroid interaction in patients with first-episode of bipolar disorder type I in Mania State. Med (Baltim). 2021. https://doi.org/10.1097/md.0000000000024645.
Zhong SM, Chen GM, Zhao LP, Jia YB, Chen F, Qi ZZ, et al. Correlation between Intrinsic Brain Activity and Thyroid-Stimulating Hormone Level in Unmedicated Bipolar II Depression. Neuroendocrinology. 2019. https://doi.org/10.1159/000497182.
Khaled A, Albeh Y, Elserogy, Tahra M, Sherif MM, Noaman H, Khalifa. Esam. N. Hormonal level and serum serotonin in patients with first episode mania: a case–control study. Middle East Current Psychiatry. 2018;25(3):116–21.
Zhao SN, Zhang X, Zhou Yl, Xu H, Li YW, Chen YX, et al. Comparison of thyroid function in different emotional states of drug-naïve patients with bipolar disorder. BMC Endocr Disord. 2021. https://doi.org/10.1186/s12902-021-00869-5.
Shi NN, Han ZW, Fan YN. Analysis of serum significance of thyroid hormone levels in patients with depression. Chin Med guide. 2021. https://doi.org/10.15912/j.cnki.gocm.2021.17.050.
Lai SK, Zhong SM, Zhang Y, Wang Y, Zhao H, Chen GM, et al. Association of altered thyroid hormones and neurometabolism to cognitive dysfunction in unmedicated bipolar II depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021. https://doi.org/10.1016/j.pnpbp.2020.110027.
Fei YL, Yu EY. Comparison of thyroid hormone levels in peripheral blood of patients with first unipolar depression and bipolar depression. Zhejiang Med J. 2021;43(7):726–9.
Duval F, Mokrani MC, Erb A, Danila V, Gonzalez Lopera F, Jeanjean L, Dopaminergic. Noradrenergic, Adrenal, and Thyroid Abnormalities in Psychotic and Affective Disorders. Front Psychiatry. 2020. https://doi.org/10.3389/fpsyt.2020.533872.
Xing ZQ, Li L, Chen YH. Correlation analysis between clinical features and thyroid function in patients with bipolar disorder. Mod Med. 2019;19(7):1044–5.
Wang ZS, Wang XQ, Shen YH, Sun CF, et al. Detection and clinical study of serum thyroid hormone level in patients with depression. Int J Lab Med. 2019;40(2):149–52.
Chen S, Deng B, Bi B, Liu Y, Li SS, Wang L, et al. Serum BDNF and TSH levels in bipolar and unipolar depressive episodes. J Taishan Med Coll. 2018;39(4):365–7.
Zhu YC, Li GH, Ma XY, Xue LX, Wang F. Study on serum thyroid hormone and pituitary prolactin levels in bipolar manic episode patients. J Clin Psychiatry. 2017;27(2):111–3.
Zhang L, Li YE, Yang C. Differences in thyroid function before and after treatment in adolescent patients with different subtypes of first-episode bipolar disorder. Chin J Health Psychol. 2017. https://doi.org/10.13342/j.cnki.cjhp.2017.08.003.
Shi L. Comparative analysis of the correlation between thyroid function and bipolar disorder. Electron J Cardiovasc Dis Integr Chin Western Med. 2017. https://doi.org/10.16282/j.cnki.cn11-9336/r.2017.10.008.
Jiang QQ, Zhu YC, Ma XY, Yan WJ, Zeng T, Liu L, et al. Correlation between pituitary prolactin and thyroid axis in patients with first manic episode of bipolar disorder. Chin J Health Psychol. 2017. https://doi.org/10.13342/j.cnki.cjhp.2017.10.002.
Chen K, Zhang RZ, Fu WD, Feng W, Chen DC. A controlled study of the correlation between thyroid function level and bipolar disorder. Neurol Dis mental health. 2017;17(1):24–7.
Wang XQ, Wang ZS, Hou ZH, Liang KM, Song CF, Li JY. Comparison of clinical features and serum thyroid hormone levels in mono - and bipolar depression. J psychiatry. 2015;28(3):182–5.
Zhan H, Dai Y, Yuan B, He Y, Xiong J, Xing HY. Relationship between thyroid function and autonomic nerve function in patients with depression. J Clin Intern Med. 2007;24(10):685–7.
Zhang XF. Analysis of serum free thyroid hormone levels in patients with bipolar depression. Jiangxi Med examination. 2007;25(1):31–2.
Du ZH, Chen GY, Wu SL. Determination of thyroid hormone levels in patients with depression and its clinical application. Lab Med. 2005;20(3):275–7.
Jia FJ, Zhang HY, Guo XS, Li HZ. Thyroid function and cytokines in patients with depression. Shanghai psychiatric Medicine. 2004;16(5):277–9.
Li HZ, Jia FJ, Li HF, Guo XS, Zhang YL, Zhang XM, et al. The observation of thyroid hormone level in patients with mono - and bipolar depression. Chin J Psychiatry. 2003;36(1):27.
Sokolov ST, Kutcher SP, Joffe RT. Basal thyroid indices in adolescent depression and bipolar disorder. J Am Acad Child Adolesc Psychiatry. 1994. https://doi.org/10.1097/00004583-199405000-00004.
Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G. Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry. 1988. https://doi.org/10.1176/ajp.145.9.1133.
Souetre E, Salvati E, Pringuey D, Krebs B, Plasse Y, Darcourt G. The circadian rhythm of plasma thyrotropin in depression and recovery. Chronobiol Int. 1986. https://doi.org/10.3109/07420528609066367.
Linnoila M, Lamberg BA, Potter WZ. High reverse T3 levels in manic and unipolar depressed women. Psychiatry Res. 1982. https://doi.org/10.1016/0165-1781(82)90016-6.
Jing L, Zhang Q. Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion. Front Endocrinol (Lausanne). 2022. https://doi.org/10.3389/fendo.2022.992883.
Bárez-López S, Guadaño-Ferraz A. Thyroid Hormone Availability and Action during Brain Development in Rodents. Front Cell Neurosci. 2017. https://doi.org/10.3389/fncel.2017.00240.
König S, Moura Neto V. Thyroid hormone actions on neural cells. Cell Mol Neurobiol. 2002. https://doi.org/10.1023/a:1021828218454.
Chaalal A, Poirier R, Blum D, Laroche S, Enderlin V. Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and β-Amyloid Peptide Load in Hypothyroid Rats. Mol Neurobiol. 2019. https://doi.org/10.1007/s12035-018-1111-z.
Dolatshahi M, Salehipour A, Saghazadeh A, Sanjeari Moghaddam H, Aghamollaii V, Fotouhi A, et al. Thyroid hormone levels in Alzheimer disease: a systematic review and meta-analysis. Endocrine. 2023. https://doi.org/10.1007/s12020-022-03190-w.
de Jong FJ, den Heijer T, Visser TJ, de Rijke YB, Drexhage HA, Hofman A, et al. Thyroid hormones, dementia, and atrophy of the medial temporal lobe. J Clin Endocrinol Metab. 2006. https://doi.org/10.1210/jc.2006-0449.
Desouza LA, Ladiwala U, Daniel SM, Agashe S, Vaidya RA, Vaidya VA. Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci. 2005. https://doi.org/10.1016/j.mcn.2005.03.010.
Kapoor R, Desouza LA, Nanavaty IN, Kernie SG, Vaidya VA. Thyroid hormone accelerates the differentiation of adult hippocampal progenitors. J Neuroendocrinol. 2012. https://doi.org/10.1111/j.1365-2826.2012.02329.x.
Montero-Pedrazuela A, Venero C, Lavado-Autric R, Fernández-Lamo I, García-Verdugo JM, Bernal J, et al. Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior. Mol Psychiatry. 2006. https://doi.org/10.1038/sj.mp.4001802.
Haukvik UK, Gurholt TP, Nerland S, Elvsåshagen T, Akudjedu TN, Alda M, et al. In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group. Hum Brain Mapp. 2022. https://doi.org/10.1002/hbm.25249.
Yalcin Arslan Y, Ceylan D, Ozerdem A, Resmi H, Cimrin D, Tunca Z. Interaction between BDNF (brain derived neurotrophic factor) levels and thyroid hormones in adult bipolar disorder patients. Bipolar Disord. 2013. https://doi.org/10.1111/bdi.12084.
Shahyad S, Kheirabadi GR, Jahromi GP, Massaly M. Brain-derived Neurotrophic Factor and High Sensitive C-reactive Protein in Bipolar Depression and Unipolar Depression: The Practical Usage as a Discriminatory Tool. Clin Psychopharmacol Neurosci. 2023. https://doi.org/10.9758/cpn.2023.21.1.108.
Fernandes BS, Steiner J, Molendijk ML, Dodd S, Nardin P, Gonçalves CA, et al. C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry. 2016. https://doi.org/10.1016/s2215-0366(16)30370-4.
Czarnywojtek A, Owecki M, Zgorzalewicz-Stachowiak M, Woliński K, Szczepanek-Parulska E, Budny B, et al. The role of serum C-reactive protein measured by high-sensitive method in thyroid disease. Arch Immunol Ther Exp (Warsz). 2014. https://doi.org/10.1007/s00005-014-0282-1.
Joffe RT, Blank DW, Post RM, Uhde TW. Decreased triiodothyronines in depression: a preliminary report. Biol Psychiatry. 1985. https://doi.org/10.1016/0006-3223(85)90218-5.
Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L. Reverse T3 levels in affective disorders. Psychiatry Res. 1983. https://doi.org/10.1016/0165-1781(83)90022-7.
De Mendonça Lima CA, Vandel S, Bonin B, Bertschy G, Bizouard P. Thyroid function in depressed patients. Encephale. 1996;22(2):85–94.
Nemeroff CB. Clinical significance of psychoneuroendocrinology in psychiatry: focus on the thyroid and adrenal. J Clin Psychiatry. 1989; 50 Suppl: 13–20.
Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev. 2005. https://doi.org/10.1016/j.arr.2005.03.003.
Prange AJ Jr. Novel uses of thyroid hormones in patients with affective disorders. Thyroid. 1996. https://doi.org/10.1089/thy.1996.6.537.
Cleare AJ, McGregor A, O'Keane V. Neuroendocrine evidence for an association between hypothyroidism, reduced central 5-HT activity and depression. Clin Endocrinol (Oxf). 1995. https://doi.org/10.1111/j.1365-2265.1995.tb00540.x.
Parmentier T, Sienaert P. The use of triiodothyronine (T3) in the treatment of bipolar depression: A review of the literature. J Affect Disord. 2018. https://doi.org/10.1016/j.jad.2017.12.071.
Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016. https://doi.org/10.1016/s0140-6736(15)00241-x.
Li X, Gao Y, Liu Y, Wang Y, Wu Q. Clinical Markers of Physical Violence in Patients with Bipolar Disorder in Manic States. Risk Manag Healthc Policy. 2023. https://doi.org/10.2147/rmhp.S403170.
Goyal MK, Yadav KS, Solanki RK. A study of thyroid profile in patients suffering from the first episode of mania: A cross-sectional study. Indian J Psychiatry. 2021. https://doi.org/10.4103/psychiatry.IndianJPsychiatry_33_20.
Tanimoto K, Maeda K, Yamaguchi N, Chihara K, Fujita T. Effect of lithium on prolactin responses to thyrotropin releasing hormone in patients with manic state. Psychopharmacology. 1981. https://doi.org/10.1007/bf00431645.
Zhu Y, Ji W. Correlative study of anterior pituitary-thyroid axis and prolactin of patients with first-episode bipolar mania. J Am Acad Child Adolesc Psychiatry. 2017. https://doi.org/10.1016/j.jaac.2017.09.028.
Benvenga S, Di Bari F, Granese R, Borrielli I, Giorgianni G, Grasso L, et al. Circulating thyrotropin is upregulated by estradiol. J Clin Transl Endocrinol. 2018. https://doi.org/10.1016/j.jcte.2018.02.002.
Frey BN, Dias RS. Sex hormones and biomarkers of neuroprotection and neurodegeneration: implications for female reproductive events in bipolar disorder. Bipolar Disord. 2014. https://doi.org/10.1111/bdi.12151.
Baksi S, Pradhan A. Thyroid hormone: sex-dependent role in nervous system regulation and disease. Biol Sex Differ. 2021. https://doi.org/10.1186/s13293-021-00367-2.
van Enkhuizen J, Janowsky DS, Olivier B, Minassian A, Perry W, Young JW, et al. The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited. Eur J Pharmacol. 2015. https://doi.org/10.1016/j.ejphar.2014.05.063.
Weatherman RV. A triple play for thyroid hormone. ACS Chem Biol. 2007. https://doi.org/10.1021/cb700104v.
Dratman MB, Gordon JT. Thyroid hormones as neurotransmitters. Thyroid. 1996. https://doi.org/10.1089/thy.1996.6.639.
Rozanov CB, Dratman MB. Immunohistochemical mapping of brain triiodothyronine reveals prominent localization in central noradrenergic systems. Neuroscience. 1996. https://doi.org/10.1016/0306-4522(96)00186-8.
Evans DL, Strawn SK, Haggerty JJ Jr, Garbutt JC, Burnett GB, Pedersen CA. Appearance of mania in drug-resistant bipolar depressed patients after treatment with L-triiodothyronine. J Clin Psychiatry. 1986;47(10):521–2.
Müller B, Böning J. Changes in the pituitary-thyroid axis accompanying major affective disorders. Acta Psychiatr Scand. 1988. https://doi.org/10.1111/j.1600-0447.1988.tb05091.x.
Li C, Lai J, Huang T, Han Y, Du Y, Xu Y, et al. Thyroid functions in patients with bipolar disorder and the impact of quetiapine monotherapy: a retrospective, naturalistic study. Neuropsychiatr Dis Treat. 2019. https://doi.org/10.2147/ndt.S196661.
Zhao S, Zhang B, Sun X. A Retrospective Study of the Effects of Psychotropic Drugs on Neuroendocrine Hormones in Patients with Bipolar Disorder. Neuropsychiatr Dis Treat. 2021. https://doi.org/10.2147/ndt.S306458.
Keen F, Chalishazar A, Mitchem K, Dodd A, Kalhan A. Central hypothyroidism related to antipsychotic and antidepressant medications: an observational study and literature review. Eur Thyroid J. 2022. https://doi.org/10.1530/etj-21-0119.
Lazarus JH. Lithium and thyroid. Best Pract Res Clin Endocrinol Metab. 2009. https://doi.org/10.1016/j.beem.2009.06.002.
Joseph B, Nunez NA, Pazdernik V, Kumar R, Pahwa M, Ercis M, et al. Long-Term Lithium Therapy and Thyroid Disorders in Bipolar Disorder: A Historical Cohort Study. Brain Sci. 2023. https://doi.org/10.3390/brainsci13010133.
Zamar A, Lulsegged A, Kouimtsidis C. A new approach for the treatment of subthreshold bipolar disorders: Targeted high dose levothyroxine and repetitive transcranial magnetic stimulation for mitochondrial treatment. Front Psychiatry. 2022. https://doi.org/10.3389/fpsyt.2022.976544.
George S, Maiti R, Mishra A, Ranjan Mishra B, Jena M. Efficacy and safety of supraphysiologic doses of levothyroxine for patients with bipolar depression in adults: A systematic review. J Psychopharmacol. 2022. https://doi.org/10.1177/02698811221078758.
Kelly T. A hypothesis on the mechanism of action of high-dose thyroid in refractory mood disorders. Med Hypotheses. 2016. https://doi.org/10.1016/j.mehy.2016.09.022.
Gardea-Resendez M, Coombes BJ, Veldic M, Tye SJ, Romo-Nava F, Ozerdem A, et al. Antidepressants that increase mitochondrial energetics may elevate risk of treatment-emergent mania. Mol Psychiatry. 2023. https://doi.org/10.1038/s41380-022-01888-x.
Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord. 2009. https://doi.org/10.1016/j.jad.2008.12.010.

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

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Abstract

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Introduction

Methods

Search strategy

Inclusion and exclusion criteria

Data extraction

Quality assessments

Data synthesis and analysis

Result

Study selection and characteristics

Quality assessment and risk of bias

Comparison of BD-depression and HC

Comparison of BD-mania and HC

Comparison of BD-mania and BD-depression

Subgroup analysis

Sensitivity analysis and public bias

Discussion

BD and TH

BD-depression and HC

BD-mania and HC

BD-mania and BD-depression

Treatment of BD

Strengths and limitations

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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