Thyroid Hormone Mediates the Effect of Antidepressants on Cognitive Function in Patients with Depression: A Mediation Analysis in a Longitudinal Study

doi:10.21203/rs.3.rs-2321186/v1

Background: Patients with depression frequently experience cognitive impairment. Our purpose is to determine whether thyroid hormones mediate the effect of depression on cognitive impairment.

Methods: A total of 119 depressed patients were enrolled (mean age 32 years, 56.30% female). The Montreal Cognitive Assessment Scale, the 17-item Hamilton Depression Scale, and thyroid hormone levels, including free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH), were evaluated at intervals of 8 weeks. In order to describe the temporal relationship between depression and cognitive impairment, we initially used cross-lagged panel analysis. After that, linear regression analysis was utilized to show how depression and thyroid hormones are related to one another. To further investigate the causal role of thyroid hormones in depression and cognitive impairment, a causal mediation model was created.

Results: The cross-lagged panel analysis showed that there was a significant cross-lagged path coefficient from baseline depression to follow-up cognition(β=－0.284, P=0.002) . Baseline depression had an impact on FT3 (F = 1.880, P＜0.05) and FT4 (F = 2.466, P＜0.05), according to a linear regression analysis. Baseline depression were affected by baseline FT4 ( = 0.316, t = 2.687, P＜0.05). The link between baseline depression and follow-up cognitive performance was revealed to be partially mediated by serum FT4 levels, according to the causal mediation analysis (a=0.008, se=0.004, p=0.022, CI=0.001/0.016).

Conclusion: Serum FT4 levels may be biological markers of cognitive impairment in patients with depression and may mediate the effect of depression on cognitive impairment.

depression

cognitive dysfunction

thyroid Hormone

free thyroxine

causal mediation analysis

cross-lagged panel analysis

According to studies, depressed patients frequently have varying degrees of persistent cognitive impairment [1]. Patients' cognitive functions, such as psychomotor speed and delayed recall, improved significantly after antidepressant medication [2]. A better understanding of the underlying mechanisms would aid in the control and improvement of cognitive impairment in patients suffering from depression. Thyroid hormones have significant regulatory effects on many organs, including the brain [3–6]. According to current research, there is a strong link between changes in thyroid hormone levels and the development of depressive disorders [7]. Thyroid hormones are also linked to cognitive function [8]. However, whether there is a causal relationship between these three is unclear. One study, for example, discovered an increased prevalence of thyroid dysfunction in patients with depressive disorders [9]. Other studies have discovered a high prevalence of depression among thyroid disease patients [10]. Although these findings suggest a link between depression and thyroid hormones, direct evidence is lacking. Thyroid hormones, on the other hand, have an impact on mood and cognitive function [8, 11]. These findings imply that depressed mood, thyroid hormones, and cognitive function may all interact. By conducting a longitudinal study of depressed patients, we hoped to test whether thyroid hormones play a mediating role in the improvement of cognitive function.

Study Participants

From January 2022 to October 2022, 135 patients with major depressive disorder were hospitalized at Shandong Mental Health Center in Jinan, China. Inclusion criteria are: (1) conforming to the International Classification of Diseases-10 (ICD-10) diagnosis of depressive disorder; (2) aged 18–60 years; (3) expected to be hospitalized for at least 8 weeks and treated with only escitalopram antidepressant; (4) first did not use antidepressant treatment; and (5) patient or guardian informed consent, signed informed consent. Exclusion criteria include: (1) pregnant or lactating women; (2) patients with severe physical diseases or other severe mental disorders; and (3) patients who have recently received immunosuppressive agents or other hormone-affecting treatments. Although 16 patients were excluded because they had spent less than 8 weeks in the hospital, 119 eligible participants were included in the study. This study was carried out in accordance with the World Medical Association Declaration of Helsinki and was approved by the Ethics Committee of Shandong Mental Health Center. All participants provided written informed consent.

Measurement of Serum Thyroid Hormone

The patients were tested twice: on the second day of admission and eight weeks later. Blood samples were collected via venipuncture after fasting for at least 8 hours, and thyroid hormone levels (including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free tetraiodothyronine (FT4)) were measured using an Architect i2000sr immunoassay analyzer (Abbott Laboratories; Lake Bluff, IL, USA).

Assessment of Depression and Cognition

The patients were also tested twice: on the second day of admission and eight weeks later. The 17-item Hamilton Depression Scale (HAMD-17, HAMD) was used to assess depression in first-episode depressive disorder patients before and after treatment. The severity of HAMD was as follows: mild depression: HAMD17 score greater than 7 points, 17 points; moderate depression: HAMD17 score greater than 17 points, 24 points; severe depression: HAMD17 score greater than 24 points. The Montreal Cognitive Assessment Scale (MoCA) was used to assess patients' cognitive function before and after treatment, and the overall score was recorded.

Statistical Analysis

To determine the causal relationship between thyroid hormones and depression and cognitive impairment, we first used a cross-lagged panel to examine the temporal relationship between depression and cognitive impairment. The interaction between thyroid hormones and depression was studied using linear regression. Then, to help infer the role of thyroid hormones in the relationship between depression and cognitive impairment, we used causal mediation analysis. SPSS 26.0 and Mplus 8.7 were used for statistical analysis. A two-tailed P value less than 0.05 is considered statistically significant.

Baseline Characteristics of Study Participants

Our study included 119 people (mean age 32 years, female 56.30%). Table 1 shows the clinical characteristics at baseline and after 8 weeks of treatment. The serum TSH level increased significantly (P<0.05) after an average of 8 weeks of treatment, while the serum FT3 and FT4 levels decreased significantly (P<0.001). The total score of HAMD decreased significantly after 8 weeks of average treatment, while the total score of MoCA increased significantly (all P<0.001).

Table 1

Baseline Characteristics of Study Participants (n = 119)
Characteristics	Baseline	Follow-Up	P
Age, years	31.91 ± 11.34	-	-
Sex, female (%)	67(56.30)	-	-
Course,months	4.85 ± 5.81	-	-
TSH,uIU/mL	2.72 ± 2.07	3.09 ± 1.93	0.045
FT3, pg/mL	2.88 ± 0.50	2.54 ± 0.48	<0.001
FT4,ng/dL	1.06 ± 0.27	0.87 ± 0.25	<0.001
HAMD	22.60 ± 5.81	6.88 ± 2.62	<0.001
MoCA	20.53 ± 5.29	24.70 ± 3.96	<0.001

Temporal Relationship Between Depression and Cognition

As illustrated in Fig. 1, there was a significant correlation between depression and cognition at baseline(r = 0.350, P < 0.001). There was also a significant correlation after treatment (r = 0.568, P<0.001). The cross-lagged path coefficient from baseline depression to follow-up cognition was significant (β=-0.284, P = 0.002), but it was not significant from baseline cognition to follow-up depression (β = 0.015, P = 0.875). This points to cognitive changes following a depressive episode.

Relationship between baseline depression and thyroid hormones

Depression and thyroid hormone were studied using regression analysis. With depression as the independent variable and thyroid hormone as the dependent variable, a linear regression analysis was performed. Baseline depression had an effect on FT3 (F = 1.880, P<0.05) and FT4 (F = 2.466, P<0.05), as shown in Table 2. Table 3 shows the results of a linear regression analysis with thyroid as the independent variable and depression as the dependent variable. Depression was affected by baseline FT4 ( β = 0.316, t = 2.687, P<0.05).

Table 2

Effect of baseline depression on thyroid hormones
Independent Variable	Dependent Variable	F	P
Depression	TSH,uIU/mL	0.617	0.923
	FT3, pg/mL	1.880	0.014
	FT4,ng/dL	2.466	0.001

Table 3

Effect of baseline thyroid hormone on depression
Independent Variable	Dependent Variable	β	t	P
TSH,uIU/mL	Depression	0.090	0.969	0.334
FT3, pg/mL		-0.114	-0.998	0.321
FT4,ng/dL		0.316	2.687	0.008

Results of Causal Mediation Analysis

We also looked into whether thyroid hormones mediated the link between depression and cognitive impairment. We used baseline depression as an independent variable, follow-up cognition as a dependent variable, and follow-up FT3 and FT4 as mediators, as shown in Fig. 2. Depression had a significant direct effect (c = -0.220, se = 0.060, t = -3.688, p<0.001, CI = -0.338 / -0.102) and total indirect effect (c'= -0.215, se = 0.059, p<0.001, CI = -0.331 / -0.100) on cognition. Depression, on the other hand, had an indirect effect on cognition only via FT4 (a = 0.008, se = 0.004, p = 0.022, CI = 0.001 / 0.016), not via FT3 (a = 0.012, se = 0.007, p = 0.102, CI = -0.002 / 0.025).

For the first time, we systematically investigated the temporal consequences of depression and cognitive impairment, as well as the role of thyroid hormones in their regulation. Between 8 weeks, these participants had depression, cognition, and thyroid hormone levels measured again. First, we used cross-lagged panel analysis to determine the temporal relationship between depression and cognition. According to the findings, cognitive impairment followed depressed mood. Then, we used linear regression to examine the relationship between depression and thyroid hormones and discovered that depression and FT4 interact. Finally, using causal mediation analysis, the role of thyroid hormones in the association between depression and cognitive impairment was investigated. The findings revealed that depression's causal effect on cognitive impairment was mediated in part by FT4 reduction. Based on these findings, thyroid hormone-targeting strategies may be useful in the prevention and control of cognitive impairment in depressed patients, but more research is needed.

Although the temporal relationship between depression and cognitive impairment has not been extensively studied, many studies have confirmed the hypothesis that depression is a risk factor for dementia [12, 13]. According to a Danish study of 18,226 depressed patients, the average depressed person had a 13% increase in dementia rate for each episode [14]. It was also discovered that the severity of depressive symptoms predicted the diagnosis of mild cognitive impairment 6 years later [15]. Our findings, along with those of previous studies, point to a temporal relationship between depression and cognitive impairment.

Thyroid hormones and depression have been found to interact in many populations, which is consistent with our findings [16–18]. A meta-analysis, for example, discovered that patients with abnormal thyroid function were 3.5 times more likely than healthy controls to have clinically relevant depressive symptoms [19]. A study of 263 depressed patients found that 26.2% had abnormal thyroid function, with 12.2% having subclinical hypothyroidism, 4.9% having overt hypothyroidism, and 2.7% having overt hyperthyroidism [20]. As a result, thyroid hormones and depression are inextricably linked.

Given the significance of thyroid hormones in altered cognitive function [21–23], We hypothesize that thyroid hormones may, at least in part, mediate the effects of depression on cognitive impairment. However, the exact mechanism of action or how this is mediated is unknown. Using a longitudinal study, we investigated for the first time the role of thyroid hormones in mediating the causal relationship between depression and cognitive impairment. According to the findings of the causal mediation analysis, serum FT4 partially mediated the relationship between baseline depressive status and cognitive impairment at follow-up. These findings suggest that depression may contribute to the onset of cognitive impairment by dysregulating FT4 metabolism. According to these findings, dysregulated thyroid metabolism may already be present in people suffering from depression before cognitive impairment develops. This suggests that serum FT4 levels in depressed individuals should be monitored and controlled in order to prevent and control the development of cognitive impairment.

The potential mediating mechanism observed in our study merits discussion, and a better understanding of it could aid in the prevention and management of cognitive impairment in depressed patients. High levels of FT4 have been linked to atrophy of temporal lobe structures, including the hippocampus, according to research [24, 25]. Even when FT4 levels are normal, oxidative stress caused by FT4 can cause neuronal damage and increase the risk of accelerated degenerative changes due to increased oxidative processes [26, 27]. Thyroid hormones also influence the density of dopamine receptors and the activity of key enzymes in the catecholaminergic transmission pathway [28, 29]. Current research suggests that neurotransmitters such as dopamine, catecholamines, 5-hydroxytryptamine, norepinephrine, and acetylcholine are involved in the onset of depression [30–34]. And all thyroid hormones are involved in the neurotransmitter metabolic pathways mentioned above [28, 29, 35, 36]. Neurotransmitter disorders in depressed patients may result in compensatory changes in thyroid hormones, resulting in compensatory increases in FT3 and FT4 in some patients and compensatory decreases in FT3 and FT4 in others [37, 38]. Abnormal thyroid hormones act on the brain, causing neuronal damage and atrophy of some brain structures, ultimately leading to impaired cognitive function. This could be the mechanism by which thyroid hormones mediate impaired cognitive function in depressed patients. It is undeniable that thyroid hormones play a minor role in the causal relationship between depression and cognitive impairment, and that other mechanisms may be at work [39]. This is something worth investigating further.

The use of cross-lagged panel analysis and causal mediation analysis to describe the temporal and causal relationships between depression, thyroid hormones, and cognitive impairment in a longitudinal study design is one of the study's strengths. Furthermore, our study has some limitations. First, our study only included Chinese adults and did not take ethnicity into account. Furthermore, our study did not take into account the effects of age, gender, and other confounding factors on thyroid hormones [40]. Second, thyroid hormone is a process that changes with the seasons [41]. On two occasions, the measurement of hormone levels in patients has limitations. Although the current study suggests that FT4 levels may play a role in mediating the relationship between depression and cognitive impairment, more evidence from additional clinical trials is required to confirm this.

Thyroid hormones were found to partially mediate the relationship between depression and cognitive dysfunction in our study. Thyroid hormones may be biological markers of cognitive impairment in depressed patients.

FT3

free triiodothyronine

FT4

free thyroxine

TSH

thyroid stimulating hormone

ICD-10

International Classification of Disease-10

HAMD

17-item Hamilton Depression Scale

MoCA

Montreal Cognitive Assessment Scale.

Acknowledgments

We gratefully acknowledge the members of all depression patients who took part in this study. We would also like to express our gratitude to the clinical staff at our hospital for their contributions to this project.

Authors’ contributions

Zengxun Liu designed the study and reviewed the paper's content; Mingming Zhao analyzed and interpreted the results and wrote the paper; and all authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-forprofit sectors.

Availability of data and materials

The datasets used in this study are available upon reasonable request from the corresponding author.

Ethics approval and consent to participate

The Shandong Mental Health Center's ethics committee approved this study (2019-R103). For inclusion in the study, all patients provided informed written consent.

Consent for publication

Not applicable.

Competing interests

The authors report no conflicts of interest in this work.

Author details

¹Department of Psychiatry, Jining Medical University, Jining, 272067, People’s Republic of China;

²Department of Psychiatry, Shandong Mental Health Center, Jinan, 250014, People’s Republic of China

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No competing interests reported.

Thyroid Hormone Mediates the Effect of Antidepressants on Cognitive Function in Patients with Depression: A Mediation Analysis in a Longitudinal Study

Status:

Version 1

Abstract

Figures

Background

Methods

Study Participants

Measurement of Serum Thyroid Hormone

Assessment of Depression and Cognition

Statistical Analysis

Results

Baseline Characteristics of Study Participants

Temporal Relationship Between Depression and Cognition

Relationship between baseline depression and thyroid hormones

Results of Causal Mediation Analysis

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1