Gender differences in the prevalence and clinical correlates of thyroid dysfunction in patients with first-episode and drug-naïve major depressive disorder with comorbid suicide attempts: a large cross-sectional study

Major depressive disorder (MDD) is a serious public health problem with a significant disease burden worldwide [1]. MDD has many potential risk factors, including chronic disease, metabolic syndrome, smoking, frequent alcohol consumption, and low physical activity [2]. The prevalence of MDD is approximately twice as high in women as in men [3]. Most risk factors have a greater impact on MDD risk in women than in men, and cross-gender risk factors typically have a deeper effect on potential recurrent MDD than on the first episode of MDD [4]. Although overall gender differences in prevalence of MDD have been well explored, gender differences in other aspects have received limited attention historically.

Suicide is prevalent in MDD [5‐7]. The results of a study conducted in Brazil showed that the cumulative prevalence of suicide attempts in MDD patients was 10.1%, and that people who were previously at risk for suicide were more likely to attempt suicide [8]. Another study of depressed patients in China showed that the prevalence of suicidal ideation among depressed patients was 53.4%, and that women were more likely to have suicidal ideation than men [9].

The relationship between thyroid dysfunction and mood disorders has been extensively studied over the past few decades. Both deficiency and excess of thyroid hormones may be accompanied by various neuropsychiatric symptoms, including depression. Patients with MDD have significantly lower free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin (TSH) compared to healthy controls [10]. Even variations in thyroid function within the normal range have been associated with the risk of MDD [11]. It has been proposed that MMD is associated with changes in the hypothalamic-pituitary-thyroid (HPT) axis and hypercortisolism [12]. A previous study found that suicide attempts and psychotic symptoms were associated with MDD patients with severe subclinical hypothyroidism [13].

Thyroid disease is a very prevalent disorder that influences the entire body, both in cognitive function and mental health. Therefore, thyroid disorders are involved in a variety of neuropsychiatric disorders. Patients with suicidal behavior demonstrate significantly reduced mean FT3 and TT4 levels compared to patients without suicidal behavior [14]. Liu et al. concluded that patients with abnormal TSH must be thoroughly screened for suicidal ideation [15]. Heiberg et al. found that Hashimoto’s thyroiditis may play an important role in the pathophysiological underlying mechanisms of suicidal behavior [16]. The pathophysiology of suicidal behavior may be related to simultaneous alterations in the dopaminergic (DA) and hypothalamic-pituitary-thyroid systems [17]. In view of the above studies, suicide and ATF are closely related with each other and have a complex impact on MDD. Therefore, comorbid ATF in suicide attempts has important research value.

Gender differences play an important role in depression comorbidity and influence the course of the disease. MDD comorbid suicide attempts are common in both men and women, but suicide attempts in female MDD patients are reported at a higher rate compared to male MDD patients [18]. Previous studies compared gender difference in the thyroid dysfunction between male and female patients with psychiatric disorders are still controversial. For example, data from a Korean National Health and Nutrition Examination Survey found that gender may play an important role in the relationship between TSH and depressive symptoms. The highest TSH tertile in men was 1.92 times more likely to have depressive symptoms than the lowest TSH tertile, while the highest TSH tertile in women was associated with an approximately 35% lower prevalence of depressive symptoms in women [19]. Varella et al. showed that low TSH concentration were linked with incident depression in women but not in men [20]. The prevalence of thyroid disorders is much higher in women than in men with bipolar disorder and increases with age. The most common abnormality is subclinical hypothyroidism, which occurs in up to 20% of postmenopausal women [21].

To our knowledge, this is the first large clinical study to examine sex differences in ATF in FEDN MDD patients with comorbid suicide attempts. Our findings included: (1) the prevalence of ATF was high in both sexes, up to 76.0%; (2) there was no gender difference in the prevalence of ATF in MDD patients with suicide attempts; and (3) there were gender differences in risk factors for ATF in MDD patients with suicide attempts.

Our study found no difference in the prevalence of ATF between male and female MDD patients with comorbid suicide attempts. A large study of depressed inpatients by Zhao et al. found that the prevalence of subclinical hypothyroidism was approximately twice as high in female depressed inpatients as in male depressed inpatients [30]. Also, another large study by Engum et al. showed that in individuals with normal TSH and no known thyroid disease, the prevalence of TPOAb was 14.2% in women and 4.3% in men [31]. They reported that among participants with biochemical thyroid dysfunction, the prevalence of TPOAb was 59.0% in females and 38.9% in males. In the present study, the prevalence of ATF in MDD patients with comorbid suicide attempts was higher in both male and female patients than in previous studies. In contrast, no gender difference in ATF was found in the present study. This difference may be due to the different diagnostic criteria in the present study and previous studies. In the present study, we included only patients with severe MDD. On the other hand, the included patients were MDD patients with suicide attempts, therefore, suicide attempts may be an important factor influencing the gender difference in ATF.

In the present study, women reported higher SBP in ATF subgroup in MDD patients with comorbid suicide. Consistent with our findings, Duan et al. found a significantly higher incidence of hypertension in the subclinical hypothyroidism group than in the non- subclinical hypothyroidism group only in female MDD patients, while no significant difference was found between the two groups in male subjects, suggesting that SCH was an independent predictor of elevated SBP and pulse pressure only in women [32]. However, Langén et al. demonstrated that TSH was negatively associated with 11-year changes in blood pressure in men, but not in in women [33]. Some studies found no difference in systolic BP between male and female ATF patients. For example, Gu et al. found a positive association between FT3 or FT4 and elevated blood pressure in adults with normal thyroid function, but no significant relationship between TSH and elevated blood pressure [34]. These differences may be due to the fact that our sample was FEND MDD patients with comorbid suicide attempts, whereas the samples of other studies were only MDD patients or depressed patients. Therefore, our results need to be interpreted with caution.

Another major finding of this study was that there were gender differences in the clinical variables associated with ATF in MDD patients with suicide attempts. In male patients, three clinical variables and metabolic indicators-HAMD score, SBP, and blood glucose levels-significantly predicted ATF in MDD patients with suicide attempts, whereas in anxiety, SBP, psychotic symptoms, TPOAb, and glucose levels significantly predicted ATF in MDD patients with suicide attempts. Interestingly, similar results have been observed in other recent studies, showing that depressed patients with comorbid anxiety were more likely to have a higher risk of suicide attempts and psychotic features [35, 36]. Mowla et al. showed that depressed patients with hypothyroidism had more anxiety symptoms [37]. Sigman et al. found that patients with autoimmune thyroiditis were at increased risk of developing symptoms of depression and anxiety or being diagnosed with depression and anxiety [38]. Compared with healthy controls, female adolescents meeting nonsuicidal self-injury criteria exhibited altered HPT axis function due to a reduced fT3/fT4 ratio [39]. Steiner et al. indicated that MDD patients who were thyroid antibody positive had higher HAMD-21 score [40]. It is well known that there are gender differences in depressive symptoms and psychotic symptoms in patients with depression. Previous study has consistently found that coexisting depressive symptoms and psychotic features are more common in women than in men [41]. Stanton et al. showed that women reported significantly higher levels of psychotic-like experiences and associated distress than men [41]. In addition to steroid hormones, TSH may also be one of the key signaling molecules that regulate different brain signals in a male- and female-specific manner. Thyroid-related and neurological disorders exhibit sex-specific differences in prevalence [42]. The reasons for these differences are complex and may include differences in brain structure, function, and stress response, as well as differences in reproductive hormone exposure, social expectations, and experience [43]. However, the molecular mechanisms behind this have not been clarified. Our findings contribute to the understanding of the role of biological sex, physiological, psychological and metabolic factors in mediating the correlation between depressive/suicidal symptoms and ATF. Our results suggest that further studies are needed to explore these potentially relevant risk factors that may influence clinical outcomes.

In conclusion, one of the main novel findings of this study was that there were no gender differences in the prevalence of ATF in MDD patients with comorbid suicide attempts. Our study also found that SBP was higher in female FEND MDD patients than in male patients. Moreover, HAMD score, SBP and fasting glucose levels predicted ATF in both male and female MDD patients with comorbid suicide attempts, while severe anxiety, psychotic symptoms and higher TPOAb level were correlated with ATF in female MDD patients, but not in male MDD patients. A longitudinal observation of the HAMD, SBP and glucose concentration in both male and female MDD with comorbid suicide attempts will provide the necessary help to prevent thyroid dysfunction. Our study focused on the thyroid dysfunction in male and female MDD with comorbid suicide attempts in the Chinese Han population to minimize the potential confounding influences. Therefore, for both male and female, our results are more likely to be meaningful in clinical practice. It may be useful to predict the severity of thyroid function in MDD with comorbid suicide attempts, and enables to the conduction of proper evidence-based clinical prevention or intervention.