Schizophrenia, a chronic mental disorder with a multifactorial neurodevelopmental etiology (1) affects almost one in 100 individuals worldwide (2). Research indicates that patients with schizophrenia may experience fragmented thinking, emotions, behaviors, and perceptions, along with discordance between their mental processes and the surrounding environment. The disease typically follows a protracted course and is prone to relapses, leading to significant impacts on patients’ physical and mental well-being, as well as their social functioning. Consequently, long-term treatment is necessary (3–5). Currently, the specific causes of schizophrenia remain unclear. However, it is widely believed that genetics, environmental factors, and dopamine receptors play pivotal roles in its development (6). In addition, schizophrenia is often accompanied by comorbidities such as depression, anxiety, sleep, circadian rhythm disorders (7), and even suicidal tendencies in patients. Patients with schizophrenia comorbidity may suffer from physical health problems, including skin disorders (8), due to decreased self-care and social isolation. Therefore, schizophrenia has been recognized as a lifelong condition associated with social challenges, constituting a significant global concern (9).

Lichen planus (LP) is an immune-inflammatory disease with an unknown etiology that affects the skin (10), mucous membranes, and skin appendages. It typically manifests in middle-aged individuals and presents as a characteristic rash of purplish-red, polygonal, flat papules, and plaques (11). LP is a chronic and recurring condition that currently lacks sufficient diagnostic tools and effective treatment protocols. Lesions of LP in the oral mucosa can hinder the patient’s ability to eat, while those on exposed skin can significantly disrupt their social and daily activities. Oral lichen planus, a potentially malignant disorder, has no known cure and carries the risk of progressing into oral squamous cell carcinoma (12, 13). Thus, early detection and appropriate management of oral lichen planus are crucial in preventing the development of oral cancer. However, there is a lack of clinical screening techniques for LP that are both non-invasive and provide early and objective detection.

Mental stressors have the potential to induce atypical alterations in inflammatory factors, leading to immune dysfunction, which may contribute to the development of LP, as immune-mediated mechanisms of LP are well recognized (14). Some studies have also suggested that people with schizophrenia may have a higher risk of autoimmune diseases (15). In addition, schizophrenia and LP may share some inflammatory pathways. For example, some studies have found that inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) may play an important role in both disorders (16, 17). LP may be accompanied by psychiatric comorbidities, and multivariable analysis has demonstrated a positive correlation between LP and an increased likelihood of depression and anxiety (18). Furthermore, schizophrenia has been found to significantly influence the development and severity of LP (19), with research indicating a correlation between schizophrenia and the occurrence of oral lichen planus (20–22). The pathogenesis of LP is influenced by various factors, including individual patients and their potential etiology. It has been established that anxiety, stress, and depression are associated with LP (23). Studies have shown that patients with LP are more susceptible to depression compared to those in the control group, highlighting the significant burden of LP on patients and its contribution to psychological distress and mental illness (24, 25).

To investigate the bidirectional causal relationship between schizophrenia and LP in the present study, we conducted a two-sample bidirectional Mendelian randomization study. To evaluate the causality of potential exposure pathways, the use of genome-wide association data (GWAS) may be considered as a way to overcome the limitations of observational studies. An instrumental variable used in MR is genetic variation. The purpose is to develop a causal link between exposure and outcome using genetic variation as an instrument (26). When randomized controlled trials are not feasible, MR serves as an alternative approach for investigating potential causal links between exposure and outcome. Therefore, we employed a bidirectional MR design to examine the bidirectional causal association between schizophrenia and LP (Figure 1), thereby addressing an existing research gap and investigating the effects of LP on individuals with schizophrenia.

In this study, bidirectional MR was used to analyze published GWAS datasets to determine whether schizophrenia and LP have a bidirectional causal relationship. According to our results, we found that schizophrenia can reduce the incidence of LP. However, our findings do not support a causal relationship between genetic susceptibility to LP and increased risk of schizophrenia. Moreover, as a result of the sensitivity analysis, we were able to validate that the study results were robust and reliable.

At present, there is no clear etiology or pathogenesis of LP, and there has been considerable discussion about the relationship between schizophrenia and LP, but it still bears some controversy. As soon as some patients are exposed to mental stress, the condition becomes worse regarding lesion size, form, and pain (38). However, our reverse MR analysis contradicted those of prior observational studies (5), this may be because physician-dependent assessments can vary widely in observational studies. In addition, current studies have not been able to establish a direct cause-and-effect relationship between schizophrenia and LP.

Schizophrenia is a multifaceted psychiatric disorder with a diverse etiology, encompassing a cluster of psychiatric disorders of indeterminate origin. Currently, antipsychotic medications are the primary treatment modality for schizophrenia. Certain clinical studies indicate that the combination of antipsychotic drugs with nonsteroidal anti-inflammatory drugs and anti-inflammatory agents can ameliorate symptoms in individuals with schizophrenia (39). Over time, research has revealed intricate connections between the immune system, inflammation, and alterations in mood, cognition, and behavior. Cytokines, which are closely linked to neuroinflammatory mechanisms, can impact neurotransmission involving dopamine, 5-HT, and norepinephrine, resulting in psychiatric or depressive symptoms (40). One study suggests that abnormal functioning of the hypothalamic–pituitary–adrenal (HPA) axis may be involved in the pathogenesis of schizophrenia (41), leading to the development of several negative clinical conditions (e.g., suicidal behavior), but there is also another study that suggests that HPA-axis activity is associated with negative clinical outcomes regardless of the presence of psychiatric conditions (42). Therefore, we suggest that schizophrenia is a complex disorder whose pathogenesis involves the interaction of several factors, of which the HPA axis may be one of the important ones. In addition, elevated inflammatory mediators in the periphery and brain may be related to the pathogenesis of schizophrenia, as increased inflammatory mediators may lead to neurotransmitter disorders, abnormal neuronal function, and neurological damage, which in turn may affect the normal functioning of the brain (43). The study by Serafini et al. (44) demonstrated that higher average concentrations of inflammatory mediators were found in both the periphery and the brain of individuals at risk of suicide compared to non-suicidal subjects. A multitude of investigations have concentrated on the correlation between cytokines and schizophrenia, aiming to pinpoint potential etiologies and establish efficacious interventions to alleviate the disease’s impact. An increasing number of studies have attempted to prospectively identify populations at ultra-high risk for schizophrenia to enhance their protective factors and provide effective early intervention methods to delay or reduce the onset of schizophrenia and improve its prognosis (45). Because of the lack of biomarkers for ultra-high-risk of schizophrenia, the most effective way to recognize schizophrenia is through prodromal symptoms and recognition tools that take into account the impact of multiple risk factors including family history, family and psychosocial stressors. Due to abnormal mental activity, low volitional activity, long duration of illness, laziness, and reduced salivary secretion caused by some antipsychotic drugs, schizophrenic patients are prone to accumulation of plaque, calculus, and soft scale in their oral cavity, which eventually leads to an increase in the incidence of oral diseases. Oral problems not only greatly affect patients’ eating and speech functions, but also interfere with social and psychological activities. While our MR study findings do not provide evidence for a causal relationship between LP and schizophrenia, it is incontrovertible that individuals with LP experience significant psychological distress during their illness (46). Additionally, prior research indicates that emotional stress, including insomnia and anxiety, is prevalent among LP patients and may contribute to the onset and progression of the condition (47). Consequently, we contend that addressing the mental stressors underlying LP is an essential component of the treatment regimen for individuals with schizophrenia, in conjunction with pharmacological interventions.

Lichen planus is an immune-inflammatory skin disease, and inflammatory skin disease will appear as a rash on the skin mucosa, and oral lichen planus is an immune-mediated condition affecting the mucosa of the mouth (48), often presenting with white striae, and occasionally accompanied by ulcers and erosions, resulting in discomfort and impaired oral intake (49). There is still no clear understanding of how LP develops but is thought to be influenced by a complex interplay of cellular immunity, genetic predisposition, environmental factors, and psychological stressors, including drug exposure, viral infections, consumption of irritating foods, and emotional distress. Current treatments for LP are mainly symptomatic, with glucocorticoids being the first-line drug of choice for the treatment of LP, and specialized treatments are lacking (50). It has been found that LP and mood disorders may be caused by a common immune activation state in which T-cell subsets change and activate interferon family cytokines. Specifically, IFN-α and IFN-γ were identified as critical immune regulators of LP and mood disorders (51). In addition, the prevalence of psychological disorders, including stress, depression, anxiety, and schizophrenia, is higher in patients with LP (52), but our results of the present MR study do not support that at the genetic level, LP increases the risk of psychotic schizophrenia, and interestingly, our MR results support that schizophrenia reduces the risk of LP. In addition, psychological changes may lead to immune dysfunction and influence the development of autoimmune diseases (53). T cells, chemokines, interleukins, and tumor necrosis factors are involved in the pathological damage process of LP. By detecting the cellular immune function and cytokine levels of patients, the condition and prognosis of LP patients can be evaluated and clinical treatment can be guided. However, further studies are needed to fully understand the specific process of immune factor-mediated LP pathogenesis and pathological development (14).

In addition, we have combined other existing studies to formulate some plausible hypotheses for our current findings. The first is the medication factors, patients with schizophrenia are usually treated with a number of antipsychotic medications that have anti-inflammatory and immunomodulatory effects (54). And another study has shown that psychiatric drugs are also one of the common medications used by people with LP (55), which could be one of the risk factors for schizophrenia to reduce the development of LP. Second, there are neurotransmitter modulation factors, and studies have shown that schizophrenia is usually associated with neurotransmitter disorders, especially dopamine and acetylcholine (56, 57). Whereas the development of LP is similarly associated with neurotransmitter disorders, we hypothesized that neurotransmitter abnormalities in patients with schizophrenia might reduce the risk of developing LP (58). In summary, mental factors have a close relationship with the occurrence and development of LP, and stress, emotional disorders, and personality traits play an important role in the pathogenesis of LP. Although our study crossed to show that schizophrenia decreases the risk of LP occurrence, there is no doubt that schizophrenia can cause great mental suffering to LP patients. Therefore, we believe that in addition to the pharmacological treatment of LP patients related to psychiatric factors, the development of LP patients’ own psychological qualities and character traits should be enhanced to achieve better treatment outcomes and improve the prognosis of the disease.

The utilization of genetic variants in MR enables the estimation of health outcomes associated with phenotypes that are influenced by said variants. MR, an established genetic epidemiology technique, emulates a lifelong randomized controlled trial by leveraging natural genetic variation. The IVW method, for instance, concentrates on the integration of numerous genetic variants to ascertain the causal relationship between exposure factors and outcome outcomes. The present study’s outstands are as follows. Research on psychiatric disorders through MR has increased in recent years (59–61), also because, by randomizing groups, MR allows potential confounders to be evenly distributed between test and control groups. This can minimize the interference of other factors on the effect of interventions on mental illness, and MR can improve the reproducibility of the study through rigorous experimental design and methodology, which is highly scientific and reliable and can provide strong evidence to support the assessment of the effect of interventions on mental illness (62). This study represents a pioneering effort in examining the association between LP and schizophrenia through the utilization of MR methods, thereby broadening the scope of conventional observational studies. Furthermore, the reliability of this study is underscored by the use of multiple MR methods that yielded largely congruent results. The utilization of MR analysis confers the benefit of circumventing reverse causal associations and confounding variables, while also conserving time and resources relative to observational studies. Finally, the absence of cross-sectional pleiotropy in this study serves to affirm the soundness of our conclusions.

There are limitations to this MR study. First, our biggest limitation is that we are using a single sample of European ancestry with limited representativeness, so the extent to which our results generalize to other ancestral groups is uncertain. Second, we did not stratify the causal effects between schizophrenia and LP by gender or age. Finally, it is necessary to perform a large-scale GWAS for MR to determine more genetic variation due to the IV’s strength based on sample size. Therefore, we encourage other researchers to conduct similar studies to validate and replicate the results of our Mendelian randomization study. The generalizability of results is more convincing if multiple independent studies reach similar conclusions. In addition, the results of the Mendelian randomization study are synthesized with the results of other related studies to obtain more comprehensive and reliable conclusions.

In summary, our two-sample Mendelian randomization study provides strong evidence for a causal relationship between LP and schizophrenia. Surprisingly, we found that schizophrenia actually decreases the incidence of LP, which contradicts previous findings and offers new insights into this complex relationship. However, it is important to note that our analysis does not establish a causal link between genetic susceptibility to schizophrenia and an increased risk of LP. Therefore, further comprehensive investigations are needed to fully understand the limitations of our study.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/participants or patients/participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

G-YC: developing the conceptual framework, investigating the methodology, gathering data, and writing the original draft. L-lF: developing the conceptual framework, investigating the methodology, and gathering data. MA, BY, and MY: investigation, review, and editing. H-CF: conceptualizing, reviewing, and editing. All authors contributed to the article and approved the submitted version.

Guizhou Provincial Health Commission provided support through its Science and Technology Fund (gzwkj2022-431). MY was supported by the Merit Scholarship of Hamburg University for International Students (No. 7238065). L-lF was supported by the Chinese Government Scholarship (CSC Scholarship; No. 202208520014).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.