ORIGINAL
The association between thyroid hormone levels and psychiatric symptoms in patients with mania or depression
2026 年 73 巻 3 号 p. 399-404
詳細
2026 年 73 巻 3 号 p. 399-404
Thyroid hormones play a crucial role in regulating mood and cognitive function. However, the effect of thyroid function on psychiatric symptoms remains unclear. In this study, we investigated the association between psychiatric symptoms and thyroid hormone levels in patients with depression and mania. In this retrospective cross-sectional study, we enrolled patients with depression or mania admitted to the Department of Psychiatry of the National Kohnodai Medical Center from April 2014 to March 2023. We examined the association between thyroid function at admission and psychiatric symptoms using the Global Assessment of Functioning (GAF) score. A total of 309 patients with depression (199 females, mean age = 62 ± 15 years) and 91 patients with mania (60 females, mean age = 50 ± 16 years) were included. In the depression group, the median TSH level was 1.05 μIU/mL, the median free T3 level was 2.76 pg/mL, and the median free T4 level was 0.95 ng/dL. In the mania group, the median TSH level was 1.09 μIU/mL, the median free T3 level was 3.28 pg/mL, and the median free T4 level was 1.06 ng/dL. In patients with depression, the GAF score showed a weak but significant negative correlation with the free T4 level (r = –0.212, p < 0.001) and with the free T3 level (r = –0.253, p = 0.008). In patients with mania, the GAF score was negatively correlated with the free T4 level (r = –0.225, p = 0.033) and positively correlated with the TSH level (r = 0.226, p = 0.031). These findings suggest that higher thyroid hormone levels may be associated with more severe psychiatric symptoms. Our study presents possible associations between thyroid hormone levels and psychiatric symptoms.
Thyroid hormones play a crucial role in the regulation of various physiological functions, including metabolism and brain function. Some mental illnesses are typically associated with thyroid dysfunction [1]. Abnormal thyroid hormone levels, such as in hyperthyroidism [2, 3] and hypothyroidism [4, 5], can lead to a variety of psychiatric symptoms. Management of thyroid dysfunction often leads to the resolution or significant improvement of psychiatric symptoms, particularly in patients with refractory bipolar and depressive mood disorders [6]. However, the association between relevant psychiatric symptom scores and thyroid hormone levels has not been adequately investigated. In this study, we aimed to clarify the association between thyroid function and psychiatric symptoms in patients with depression and mania using the Global Assessment of Functioning (GAF) score.
This retrospective cross-sectional study included adult patients (aged 18 years or older) admitted to the psychiatric wards of the National Kohnodai Medical Center, located in Chiba Prefecture, Japan, between April 2014 and March 2023. Initially, 4,219 patients were screened for inclusion in this study. Among these, 2,527 patients (60%) underwent thyroid function testing, which included measurements of thyroid-stimulating hormone (TSH), free triiodothyronine (free T3), and free thyroxine (free T4). Patients were classified into four categories based on thyroid function: hyperthyroidism, hypothyroidism, euthyroid, and SITSH. Overt hyperthyroidism is characterized by suppressed TSH in combination with elevated levels of free T3 and free T4, whereas subclinical hyperthyroidism is defined as suppressed TSH with normal free T3 and free T4 levels. Overt hypothyroidism was defined as elevated TSH levels along with decreased levels of free T3 and free T4. Subclinical hypothyroidism was indicated by elevated TSH levels with normal free T3 and free T4 levels. SITSH was defined as inappropriately normal or elevated TSH levels despite elevated free T3 and/or free T4 levels. Euthyroidism was defined when all measured thyroid hormone levels were within the respective normal reference ranges.
Patients who were admitted for non-psychiatric reasons such as social adjustment or surgical procedures (n = 37), whose thyroid hormone profiles could not be classified into the four categories (n = 7), and those who had used lithium carbonate within 30 days before admission (n = 58; 30 patients with mania and 28 patients with depression) were excluded from the final analysis, as the potential confounding effects of lithium on thyroid hormone levels could not be eliminated.
The final cohort was limited to individuals diagnosed with bipolar disorder, mania, or major depressive disorder. Among 91 patients initially diagnosed with mania, 76 met the diagnostic criteria for bipolar disorder. Similarly, of the 309 patients initially diagnosed with depression, 75 were classified as having bipolar depression. A flow diagram depicting the patient selection process and inclusion criteria is shown in Fig. 1. Data collected from the electronic medical records included demographic characteristics (age and sex), psychiatric diagnoses made according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), thyroid function test results, and GAF scores at the time of admission.
This study was reviewed and approved by the Ethics Committee of the National Center for Global Health and Medicine (approval no. NCGM-S-004725) and conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.
Laboratory MethodsThyroid hormone levels were analyzed by SRL, Inc. (Tokyo, Japan) using chemiluminescent enzyme immunoassays. TSH was measured using the Lumipulse Presto TSH kit (Fujirebio Inc., Kanagawa, Japan; reference range: 0.5–5.0 μIU/mL). Free T3 was measured using the Lumipulse free T3-N kit (Fujirebio Inc., Kanagawa, Japan; reference range: 2.3–4.3 pg/mL). Free T4 was measured using the Lumipulse Presto Free T4 kit (Fujirebio Inc., Kanagawa, Japan; reference range: 0.9–1.7 ng/dL). The thyroid function was defined based on these values.
Psychiatric EvaluationPsychiatric diagnoses were performed by board-certified psychiatrists using the DSM-5 criteria. The GAF scale was used to assess psychological, social, and occupational functioning upon admission. The attending psychiatrist assigned the GAF scores based on structured clinical interviews, direct behavioral observations, and corroborative information from family members or caregivers [7]. A detailed explanation of the GAF scoring system, including score ranges and clinical interpretations, is provided in the Supplementary File 1.
Statistical AnalysisAll statistical analyses were performed using IBM SPSS Statistics for Windows (version 22.0; IBM Corp., Armonk, NY). Pearson’s correlation analysis was used to explore the association between thyroid hormone levels and GAF scores. Differences in categorical variables between groups (such as the prevalence of overt hyperthyroidism) were evaluated using Fisher’s exact test. Statistical significance was set at a two-tailed p-value of <0.05.
Patient characteristics are summarized in Table 1. We enrolled 309 patients with depression (199 females, mean age = 62 ± 15 years) and 91 patients with mania (60 females, mean age = 51 ± 16 years).
| depression group n = 309 |
manic group n = 91 |
|
|---|---|---|
| age (year) (mean ± SD) |
62 ± 15 | 50 ± 16 |
| Gender (male/female) |
110/119 | 31/60 |
| GAF (at the time of admission) (median (min–max)) |
30 (1–75) | 25 (0–61) |
| Free T3 (pg/mL) (median (min–max)) |
2.76 (1.18–4.69) | 3.28 (2.61–3.78) |
| Free T4 (ng/mL) (median (min–max)) |
0.95 (0.54–2.2) | 1.06 (0.36–1.93) |
| TSH (μIU/mL) (median (min–max)) |
1.05 (0.03–15.85) | 1.09 (0.12–7.08) |
In the depression group, the median free T3 level was 2.76 pg/mL (range, 1.18–4.69), the median free T4 level was 0.95 ng/dL (range, 0.54–2.20), and the median TSH level was 1.05 μIU/mL (range, 0.03–15.85). The median GAF score was 30 (range, 1–75).
In the mania group, the median free T3 level was 3.28 pg/mL (range, 2.61–3.78), the median free T4 level was 1.06 ng/dL (range, 0.36–1.93), and the median TSH level was 1.09 μIU/mL (range, 0.12–7.08). The median GAF score was 25 (range, 0–61).
The numbers and proportions of patients in each thyroid function category are shown in Table 2.
| depression group (n = 309) | mania group (n = 91) | |||
|---|---|---|---|---|
| Thyroid Status | GAF score median (min–max) | GAF score median (min–max) | ||
| Hyperthyroidism | ||||
| overt hyperthyroidism | 4 (1.3%) | 23 (10–30) | 0 (0%) | |
| subclinical hyperthyroidism | 39 (12.6%) | 25 (5–70) | 11 (12.1%) | 20 (5–51) |
| Hypothyroidism | ||||
| overt hypothyroidism | 5 (1.6%) | 31 (15–63) | 0 (0%) | |
| subclinical hypothyroidism | 9 (2.9%) | 25 (1–61) | 0 (0%) | |
| Normal thyroid function | 206 (66.7%) | 30 (3–70) | 71 (78.0%) | 25 (0–61) |
| SITSH | 46 (14.9%) | 29 (5–75) | 9 (9.9%) | 31 (20–51) |
In the depression group, the GAF score was negatively correlated with free T4 levels (r = –0.212, p < 0.001) and free T3 levels (r = –0.253, p = 0.008). GAF was not correlated with TSH levels (r = 0.036, p = 0.530). In the mania group, the GAF score was negatively correlated with free T4 (r = –0.225, p = 0.033) and positively correlated with TSH (r = 0.226, p = 0.031) levels. However, there was no significant correlation between the GAF score and free T3 levels (r = –0.284, p = 0.109). Fig. 2A, B show scatter plots of TSH, free T3, and free T4 levels versus GAF scores in patients with depression and mania.
In this study, we assessed the association between relevant psychiatric symptom scores and thyroid hormone levels, an area which remains scantly researched. Our findings provide evidence that higher thyroid hormone levels lead to worse psychiatric symptoms. In overt hyperthyroidism as well as hypothyroidism, TSH and thyroid hormone levels are outside the normal limits. In overt thyroid dysfunction, TSH cannot fully regulate the free thyroid hormone levels; therefore, both TSH and thyroid hormone levels deviate from the normal range. Conversely, in subclinical thyroid abnormalities, TSH compensates enough to maintain free thyroid hormones within the normal range, resulting in abnormal TSH levels, while free hormones remain normal. As summarized in Table 2, the prevalence of overt and subclinical thyroid dysfunction was higher in both the depression and mania groups compared with the general Japanese population [8]. In particular, subclinical hyperthyroidism was more common, whereas hypothyroidism was mainly observed in the depression group. This difference between the depression and mania groups was not statistically significant (Fisher’s exact test, p = 0.578). These findings indicate that thyroid dysfunction, especially hyperthyroidism, was more frequent among psychiatric patients than in the general population.
None of the patients with mania were categorized as having overt hyperthyroidism or hypothyroidism. However, subclinical hyperthyroidism was more common in the mania group, whereas hypothyroidism was observed mainly in the depression group. Mania may be the initial presenting symptom of Graves’ disease [9, 10]. Elevated thyroid hormone levels, a characteristic of hyperthyroidism, were associated with worsening psychiatric symptoms in both the mania and depression groups. This was supported by a negative correlation between GAF scores and free T4 levels, indicating that higher thyroid hormone levels correspond to more severe psychiatric symptoms (lower GAF scores indicate greater symptom severity). Similarly, Zhang et al. reported a positive correlation between the Young Mania Rating Scale scores and baseline free T4 levels (r = 0.349, p = 0.010) in patients with manic bipolar disorder [11]. Adrenergic hyperactivity in hyperthyroidism has been identified as a key driver of psychiatric symptoms, and normalization of thyroid function can improve mental health outcomes [1, 12]. In addition, altered central serotonin levels may contribute to hyperthyroidism-associated psychiatric symptoms. In patients with depression and hyperthyroidism, decreased serotonin activity in the central nervous system can reduce the inhibition of TRH secretion, leading to increased TSH release and subsequently elevated thyroid hormone production [13].
Hypothyroidism has traditionally been considered as a risk factor for depression [14], but recent studies have challenged this view [15]. In our study, hypothyroidism was observed only in the depression group. It has been hypothesized that depression involves decreased T3 levels due to the inhibition of the Type II iodothyronine deiodinase enzyme responsible for converting T4 to T3, which may be influenced by elevated cortisol levels caused by stress. Cortisol also increases T4 levels [16], which may explain why only a correlation between GAF scores and T4 levels was observed.
The “low T3 syndrome,” characterized by low free T3 with normal-to-low free T4 and TSH levels, occurs in severe physical illnesses [17]. However, because the patients in our study did not have severe physical diseases, this syndrome is unlikely to explain our findings.
Certain psychiatric medications such as lithium can affect thyroid hormone levels [18]. However, we could not assess the effects of medication due to the lack of drug information. Furthermore, anti-thyroid antibodies are rarely measured in psychiatric patients. Previous studies demonstrated the clinical relevance of thyroid function in psychiatric disorders. For instance, elevated TSH levels in patients with subclinical hypothyroidism have been associated with treatment-resistant depression, whereas higher total thyroxine levels have been correlated with more severe depressive states [19].
In addition, 55 patients in this study were classified as having syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH). Because this was a retrospective observational study of hospitalized psychiatric patients, we were not able to investigate the underlying causes of SITSH in detail. Nevertheless, it is possible that psychiatric disorders themselves may have influenced TSH levels. The inclusion of SITSH patients therefore represents a limitation of this study, and we consider this an important issue that should be addressed in future investigations with larger datasets.
As this was a retrospective cross-sectional study, we could not infer any causal relationship between thyroid hormone levels and psychiatric symptoms. Therefore, the observed associations should be interpreted as correlations rather than as evidence of direct causation. In addition, information regarding the past medical history of thyroid diseases (e.g., thyroid dysfunction, thyroid tumors, or prior thyroid surgery) was not available. This limitation prevented us from considering the potential influence of such conditions on thyroid function tests in our analysis. Likewise, family history data were also not available in this study and thus, could not be included in the analysis.
In this retrospective cross-sectional study, a significant association was observed between thyroid hormone levels and the severity of psychiatric symptoms in patients with mania or depression. Although the mean serum-free T4 levels remained within the normal reference range and only four patients presented with overt hyperthyroidism, higher serum-free T4 levels were still correlated with lower GAF scores. This finding suggests that even within the normal range, relatively higher thyroid hormone activity may contribute to deteriorating mental functioning. Overall, these results emphasize the importance of routine thyroid function assessment in patients with psychiatric disorders. Early detection and management of thyroid abnormalities may play a critical role in comprehensive mood disorder treatment and in improving psychiatric outcomes.
These findings are summarized schematically in the Graphical Abstract, which illustrates the potential relationships between thyroid hormone levels and psychiatric symptom severity in patients with mania or depression.
We thank the staff of the Division of Research Support, Japan Institute for Health Security National Kohnodai Medical Center. This work was supported by the JIHS Intramural Research Fund (23A3002).
The authors have no conflicts of interest directly relevant to the content of this article.
