Introduction
Temporomandibular disorders (TMD) are one of the most common chronic illnesses characterized by musculoskeletal pain that involves masticatory muscles, temporomandibular joints (TMJ), and other orofacial anatomical structures [
1]. Also, it is considered to be the second-most common skeletal-muscular issue. According to a recent study that examined the prevalence of TMD in the general population, TMD affected about 31% of adults and the elderly and 11% of children and adolescents [
2]. The etiopathogenesis of TMD remains unclear. In general, TMD is considered to be a disease caused by a variety of pathogenic factors, including psychological, physiological, anatomical structural, trauma, and genetic conditions [
3]. These factors initiate and exacerbate the development of TMD, which causes the emergence of TMD signs and symptoms [
4]. The main clinical symptoms of TMD are idiopathic and episodic musculoskeletal pain, a temporomandibular joint (TMJ) murmur (such as clicking, crepitating, and cracking), abnormal jaw movement, and associated dysfunction [
5]. The presence of these symptoms, especially pain, may affect and lower the quality of life of patients, interfering with their emotional and social lives [
6,
7].
In recent years, there has been a global increase in psychiatric disorders, including depression and anxiety, which pose a major burden on public health [
8,
9]. Depression is the most common mental disorder and is projected to become the leading global disease burden by 2030, according to the World Health Organization [
10]. A comprehensive review of 87 papers from 44 countries reported a worldwide prevalence of 7.30% for anxiety disorders [
11]. Except for the high prevalence, mental illness also increases susceptibility to other diseases, thereby placing a greater burden on society. Recent studies have indicated a genetic link between major depressive disorder (MDD) and coronavirus disease 2019 [
12], as well as between attention deficit hyperactivity disorder (ADHD) and diabetes [
13]. Previous research has identified psychiatric disorders as potential risk factors for TMD [
14,
15], with multiple observational studies demonstrating a strong association between TMD and mental symptoms like depression and anxiety [
16]. Notably, over half of TMD patients exhibit symptoms of depression ranging from mild to severe [
17]. Moreover, the severity of psychiatric disorders in TMD patients has been linked to treatment outcomes. Some researchers argue that psychiatric factors may impede the response of TMD patients to conservative treatment and increase their likelihood of developing chronic TMD, which can lead to disability and other adverse consequences [
18‐
20]. Consequently, it is crucial to thoroughly investigate various types of psychiatric factors when evaluating TMD patients in order to make informed clinical decisions and initiate appropriate management strategies.
The introduction of the large-scale available GWAS database and Mendelian randomization (MR) has made it possible to infer a causal relationship between complex traits and diseases [
21,
22]. MR is a method that uses genetic variants that are robustly associated with exposures as instrumental variables (IVs) to investigate the causal effects on outcomes [
23]. As a novel epidemiological method, MR may be considered conceptually as natural randomized controlled trials (RCTs) because genotypes are randomly distributed from parent to offspring. Compared with observational studies, MR uses genetic variants as IVs to effectively avoid the influence of confounding factors, such as underlying bias, measurement error, and reverse causality. These confounding factors are all inherent limitations of observational studies which are difficult to control in observational studies [
22]. Thus, the present study aimed to investigate the possible causation and their direction between TMD and eight psychiatric traits, including anxiety disorder (AD), panic disorder (PD), MDD, neuroticism, ADHD, autism spectrum disorder (ASD), bipolar disorder (BIP), and schizophrenia (SCZ) [
24‐
31].
Discussion
We applied two-sample MR to investigate the causal relationship between TMD and mental disorders in this study. The results showed that PD and MDD have risk effects on TMD. Neuroticism and SCZ had a suggestive causal effect on TMD, whereas no significant evidence for causal effects was found in which TMD is relevant to these psychiatric traits in the reverse MR analyses. These findings highlight the important and complex relationship between mental disorders and TMD.
Psychiatric and neurodevelopmental disorders such as depression and anxiety stand out as comorbidities frequently associated with TMD. Numerous studies have indicated that psychiatric factors such as depression, anxiety, and SCZ are associated with an increased risk of TMD [
41‐
44]. Through bi-directional MR studies, we have further confirmed the genetic correlation between these disorders. It has been observed that most TMD patients exhibit hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis. Mental disorders, acting as stressors, have the potential to upregulate the HPA axis in TMD patients, leading to the expression and release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol [
45]. This chronic activation may result in recurrent muscular hyperactivity, gradually causing damage to the joint and eventually manifesting as TMD symptoms [
46]. Additionally, mental disorders can also alter brain structures such as the hippocampus and hypothalamus, interfering with the central modulation of pain responses [
47]. Consequently, this can lead to an increased perception of pain, further exacerbating and promoting pain symptoms in individuals with TMD.
Multiple meta-analyses have established that inflammation caused by mental disorders, as well as the release of inflammatory cytokines, plays a crucial role in the pathophysiology of TMD. The level of inflammation in the synovial fluid of TMD patients and the blood of patients with MDD was found to be higher compared to healthy controls [
48‐
51]. This increased cytokine activity and elevated inflammatory response can negatively affect the biomechanical properties of the disc, leading to the development and progression of TMD [
52,
53]. Currently, there are several cytokines that may be involved in the pathogenesis of TMD and their relationship with pain [
54]. Further analysis and exploration of these inflammatory cytokines can provide a clearer understanding of the impact of mental disorders in patients with TMD. Additionally, inhibiting these receptors may have the potential to alleviate symptoms and improve or even reverse pain conditions in patients with TMD.
In some clinical studies, other psychiatric disorders such as ADHD, ASD, and BIP have been closely associated with the prevalence of TMD. However, this MR analysis found no causal association between these three psychiatric traits and TMD. It is well known that TMD symptoms, especially pain, have also been suggested as causes or enhancers in the development of depression and psychiatric illnesses [
3]. This creates a cycle where TMD and psychiatric disorders exacerbate each other’s risk. However, our study did not find evidence supporting a causal effect of TMD on these psychiatric disorders in the context of genetic variation. Therefore, it is possible that psychiatric disorders are primarily triggered by psychological stress associated with TMD rather than by genetic susceptibility to TMD.
The presence of significant genetic correlations between TMD and psychiatric disorders suggests that they cannot be considered entirely independent disease entities. TMD is significantly associated with changes in the central nervous system, suggesting a common pathophysiologic basis involving psychosocial and neuroendocrine mechanisms. Therefore, there is a great challenge to diagnosing and treating TMD patients with psychiatric disorders. In general, oral professionals generally prioritize and value attention to structural damages and symptoms of TMJ region and may neglect the mental and emotional states of these people. In order to properly assess the inducements and symptoms of TMD patients, comprehensive clinical evaluations of the mental state of patients are required. In addition, a randomized controlled trial demonstrates that TMD patients classified based on psychosocial and behavioral factors will demonstrate a differential response to the same standardized treatment [
55]. The peculiarities of the psychiatric disorders may limit and influent some management of TMD, thus requiring more cooperation from the subject. In the future, a multidisciplinary collaboration between mental health professionals and oral professional teams is required to develop clinical guidelines and personalized treatment protocols for TMD patients with psychiatric disorders, in order to address the complexity of their needs and situations.
This is the first MR study to comprehensively evaluate the relationships between eight psychiatric traits and TMD. There were significant advantages to our bi-directional MR analysis. First, we selected genetic variations that were randomly assigned as IVs, to avoid the potential effects due to conventional confounders as well as reverse causation common in observational studies. Second, to prevent bias and ensure the robustness of the instruments in the MR analysis, no overlapping samples between exposures and outcomes were used [
56]. Thirdly, we could more clearly determine the causal relationship and causal direction between two features by using a bi-directional MR. Moreover, our findings were reached after comprehensive studies by three MR methods, including IVW, weighted median, and MR-Egger, and several sensitivity tests demonstrated the robustness of MR analysis.
Our study had several limitations as well. First off, the sample size of TMD is relatively small, which makes the loci studied relatively limited. So, we might miss weak associations between the reverse causal association of TMD with psychiatric traits. Second, because diverse environmental factors may have significant effects on psychiatric characteristics and TMD, the findings of this study may not be totally generalized to persons of non-European heritage. Finally, women are more likely than males to experience TMD symptoms, which may vary for both psychological and physical symptoms of TMD patients [
57]. Due to the GWAS summary statistics of TMD not being stratified by sex, we were unable to conduct analysis by sex stratification to confirm the sex-specific effects on causal effects between psychiatric characteristics and TMD.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.