Association between Meibomian Gland Dysfunction and Depressive Symptoms: A Multi-center Cross-sectional Study

Increased prevalence of depression has been found in patients with meibomian gland dysfunction (MGD); however, specic conditions of patients suffered from MGD and depression remains unclear. Our aim was to investigate the prevalence of depression in patients with MGD and analyze the risk factors of depression in MGD patients. In this multi-center cross-sectional study, we enrolled 830 MGD patients and 114 normal controls. Demographic information was collected by designed questionnaires about lifestyle habits, systemic and ocular medical history. Ophthalmic examinations were performed in a formal order. Depression symptoms were evaluated with a questionnaire survey using a modied self-rating depression scale (M-SDS). The correlations between the M-SDS score and demographic and clinical information were analyzed. The prevalence of hyperlipidemia and obstructive sleep apnea-hypopnea syndrome (OSAHS) was higher in the MGD group. There were 78 cases (9.4%) with depressive symptoms in the MGD group whereas there were 4 cases (3.5%) in controls. Similarly, M-SDS was higher in the MGD group. The characteristics of depression in the MGD group included: crying spells, sleep disturbance and depressed appetite. Some systemic diseases (OSAHS, allergy, skin disease) and the use of contact lenses was correlated with an increased risk of depressive symptoms in MGD patients. signicant. obstructive sleep apnea-hypopnea


Introduction
Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian gland, which can induce the alteration of tear lm lipids, a decrease of tear lm stability and symptoms of eye irritation. As a leading cause of dry eye disease (DED), MGD becomes a major public ocular health problem, which prevalence rate varies from 3.5% to almost 70% 1,2 . Its occurrence is always related to gender, age, and race, and a strikingly higher prevalence appeared in the Asia population (46.2-69.3%) [3][4][5] . In recent years, with the change of social lifestyle and the increase of video display terminal (VDT) viewing, the number of MGD patients has increased signi cantly 6 .
Clinically, persistent ocular surface discomfort from MGD, including ocular irritation, dryness, burning sensation, and blurring of vision, could always produce a negative impact on life quality. Notably, these symptoms from MGD may be overlap or very similar to those reported in DED patients 7 . Some studies reported the relationship between DED and psychiatric alteration. Especially, Inomata et al 5

used Dry Eye
Rhythm to collect real-world data and found that severe DE symptoms were correlated with an increased risk of depressive symptoms. This relationship was also con rmed by a meta-analysis 8 , which found a higher depression prevalence in DED patients (29%) than that in controls.
Although MGD becomes a leading cause of DED, few studies attempted to explore the relationship between mental health and MGD. Especially, a potential concern is that chronic symptoms from MGD could induce a negative impact on mental health and the treatment effect of MGD cannot be completely satisfactory 9 . Therefore, it is important to undertake a large-sample study to investigate the MGD patients' mental alteration to make clear the relationship between MGD and depression. With this multi-center epidemic research, we hope to nd the risk factors of depressive symptoms in MGD cases and achieve the purpose of early detection and intervention of depression in patients with MGD.

Patient characteristics
A total of 944 participants were included: 830 patients with MGD and 114 control subjects. The mean age was 42.6 ± 13.2 years (range, 18-87 years) in the MGD group and 40.3 ± 14.6 years (range, 18-76 years) in the control group. The number of women in the MGD group and control group was 540 (65.0%) and 84 (73.7%), respectively. There was no signi cant difference in age (P = 0.057), gender (P = 0.068) and living area (urban or rural, P = 0.188) between these two groups.
The demographic data and basic medical history of MGD patients and normal controls are summarized in Table 1. The survey of systemic diseases showed that the MGD group had higher prevalence of hyperlipidemia (8.8% vs. 0.8%, P = 0.003) and OSAHS (obstructive sleep apnea-hypopnea syndrome) (15.9% vs. 7.9%, P = 0.024) compared with controls. There was no signi cant difference for other disease prevalence (hypertension, diabetes mellitus, coronary heart disease, cerebral infarction, allergy, skin disease) within the two groups. Similarly, there was no difference in ocular medical history between the two groups (diabetic retinopathy, glaucoma, cataract, ametropia and contact lens wear). 3), higher than the control group (all P 0.05). Although the duration of sport and walking every day in these two groups were no signi cant different, the reading time in MGD (60% cases, almost every day), longer than that in the control group (48.2%, almost every day, P = 0.029, Table 2).

Depression analysis
In this study, M-SDS was used to evaluate depression and its severity. The score of M-SDS in the MGD group was 30.7 ± 7.7, signi cantly higher than that in normal controls (27.9 ± 6.2, P = 0.001). There were 78 cases (9.4%) with depressive symptoms in the MGD group, which was higher than that in controls (4 cases, 3.5%) (P = 0.036). Among MGD cases with depression symptoms, most of them appeared mild (49/78) and moderate (24/78) depressive symptoms. Between normal controls and the MGD group, the severity of depression symptoms was no signi cant difference (P = 0.517, Table 4). Severe Depression 0 (0) 5 (0.6%) Note: Depression was assessed using the Self-rating scale and de nite depression was de ned as having a depression score of 40 or higher. The severity of depression was rated as mild, 40-50 scores; moderate, 50-60 scores; and severe, above 60 scores. *P < 0.05 was considered statistically signi cant.
After analyzing each result of the 17 questions in the M-SDS questionnaire, three parameters (crying spells, sleep disturbance and depressed appetite) had a higher score in the MGD group with depression symptoms, comparing with normal controls with depression (P 0.001, 0.012, 0.008, Table 5).

Discussion
MGD had a high prevalence worldwide, and it is higher in Asians than in Caucasians 10-12 . As a leading cause of DED, MGD often presents chronic ocular health problems, especially eye pain, foreign body, and alterations of optical quality, etc. It not only can adversely affect anyone's life quality but also the mental health of patients. Moreover, depression symptoms also strengthen the subjective feeling about ocular surface discomfort and always coexist with other health conditions. Till now the risk factors and the correlation between MGD and depression remains unclear. Based on our study, the prevalence of depression in the MGD group was higher than normal controls. Risk factors such as OSAHS, allergy, skin disease, contact lens wearing, and inactive time were correlated with the depression symptoms of MGD patients. The results enabled early detection of the signs of mental changes in the MGD group and offer the appropriate support promptly.
In this study, the prevalence of depression in the MGD group was 9.3%, which is signi cantly higher than that in normal controls (3.5%). As a major cause of DED, MGD can increase the evaporation of tear and decrease the tear volume, which induce short tear breakup times and tear hyperosmolarity. Some studies declared that hyperosmolarity could cause ocular surface in ammation and/or nerve damage, which may increase symptoms by peripheral sensitization. With functional magnetic resonance imaging (fMRI), Yu et al 13 found regional homogeneity (ReHo) values of the middle frontal gyrus, inferior frontal gyrus, and superior frontal gyrus were signi cantly lower in dry eye patients compared to healthy controls. Symptoms of ocular surface injury in DED, especially MGD patients are associated with dysfunction in speci c brain regions. And rianopoulou et al 14 investigated brain function and microstructural changes in primary Sjögren syndrome (pSS) and found the functional connectivity abnormalities of the somatosensory cortex and microstructural abnormalities appeared in pSS, which were more pronounced in depression. In addition, depression could also increase the symptom of MGD. Mahmut et al 15 invited 40 newly diagnosed depression patients and found that patients without a history of psychiatric drug use showed dry eye symptoms. Some studies revealed that negative emotional states would induce or enhance the perception of pain and irritation 16 . And the symptoms of pain, dryness, itchiness, stinging, foreign body sensation and sensitivity to light and wind from MGD can also negatively impact the mood of patients and have potential consequences of depression. So, patients with dry eye symptoms but no signs would have the lowest happiness scores. Subjective happiness scores in DED cases were found to be inversely correlated with dry eye symptoms 17 . At last, several studies have con rmed antidepressants may play an important role in provoking DED. Emel et al 18 found that selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors increased the risk for eye dryness.
Furthermore, Zhang et al 19 proved that SSRIs could aggravate DED by activating the NF-κB pathway, which shows the interaction between dry eye and depression. Therefore, the depressive symptom could be alleviated by applying the managing MGD, which open the options of cooperative therapy between Ophthalmologists and psychiatrists to MGD cases.
Many risk factors make MGD patients more prone to develop depression, for instance, living in rural areas could be associated with depression in our study. However, results from a Korean elder cross-sectional study showed that living in the urban area is also strongly correlated with depression (P < 0.001) 3 . The economical differences between developed countries and developing countries may provide a reasonable explanation. Wang et al 20 conducted a study about socio-demographic characteristics of depressive symptoms and found that educational attainment, the economic level had a signi cant association between depressive symptoms, which may explain the different results between Chinese and Korean studies.
Moreover, our study found that some systemic diseases (OSAHS, allergy, skin disease) were also related to depression. The results of the current study are consistent with previous results 21,22 . A meta-analysis by Jennifer et al concluded that the risk of developing depressive disorders was two to three times more likely among individuals with two or more chronic conditions 23 . Just as MGD, OSAHS, allergy and skin disease are always chronic and incurable diseases. Chronic pain and irritation are associated with sleep de ciency, activity and mobility limitations, social withdrawal, and loneliness. All these negative effects will induce cognitive impairment, loss of self-con dence and self-esteem, even anxiety and depression 24 .
Wearing a contact lens could also be argued to have potential adverse towards the development of depression. Patients with MGD who also wears contact lenses revealed an increase in dry eye symptom and ocular surface staining 25,26 . Consequently, the shorter TBUT result suggests that MGD and contact lens both contributes to the negative outcome of tear lm integrity. Therefore, contact lens maybe induces depressive symptoms in MGD cases due to the aggravation of dry eye symptoms.
We articles and concluded that dry eye patients suffer more from bad quality sleep. Wu et al 30 also found that poor sleep quality may aggravate DED by affecting tear secretion and tear lm stability, even indirectly aggravate depression at the same time. The result from the M-SDS questionnaire showed the difference in frequent crying, sleep disturbance and depressed appetite between MGD patients and control. Another interesting point is that depressive patients in the MGD group may more easily lose hope for their aspirations (2.60 ± 1.00 vs. 1.75 ± 0.50, P = 0.095). In Van's study of patients with Sjögren's syndrome, these patients with a lower "cryability" had a higher score on frustration 31 . Gomes reported that the effect of the quality of life by dry eye may be underestimated 32 .
Our study offered insight into the importance of early detection and intervention of depressive disorder among MGD patients. Questionnaire results regarding sleep, eat changing and cry intention could help ophthalmologists screening depression patients. Such early conversation with the patient can not only prevent further prognosis but also facilitate a speedy recovery.
Even though this study is a focused multi-center cross-sectional study, the sample size could have improved to have more generalizability. Second, alongside the M-SDS questionnaire, other means of measure for the participants mental status could be employed. Third, this study is a cross-sectional study, more robust follow-up evidence is favorable for a deeper understanding of the relationship between MGD and depression.
In conclusion, this study served a pioneering role in connecting MGD and depression. Ophthalmologists should be aware of the association between MGD and depression, better understand patients' mental changes and better treat MGD patients with depression. Furthermore, the correlation between MGD patients with depression and the changing of their cytokines, chemokine, and in ammatory factors could be fascinating to investigate further. All participants were informed of the aims of the study and provided written informed consent was obtained from all subjects according to the declaration of Helsinki.

Subjects
According to the diagnosis criteria de ned by the International Workshop 33 on MGD in 2011, the inclusion criteria of MGD were as follows: (1) aged ≥ 18 years; (2) presence of at least one subjective symptom, such as ocular fatigue, dryness, foreign body sensation, pain, burning sensation, itching, redness and visual uctuation; (3) more than one lid margin abnormalities under slit-lamp examination: palpebral margin hyperemia, irregular lid margin, vascular engorgement, plugged meibomian gland ori ces, and anterior or posterior replacement of the mucocutaneous junction. Participants with one or more of the following criteria were excluded: (1) eyelid and conjunctival scar; (2) ocular surface abnormalities that may affect the corneal integrity; (3) unwilling or unable to stop medicine that can cause or aggravate dry eye disease; (4) pregnant and lactating women.
The inclusion criteria of the control group were as follows: (1)

Depression symptom Evaluation
Depression symptoms were evaluated with a questionnaire survey using a modi ed self-rating depression scale (M-SDS), which was adapted from the Zung self-rated depression scale and had been applied in The Beijing Eye Study. 35 Total scores (range 20-80) were counted by summing the results of each 9 positive questions and 11 negative questions. The 1 to 4 responses to the negative question and positive question using an inverted recording method from 4 to 1. De nite depression was de ned as having an M-SDS score of 40 or higher. The severity of depression was rated as mild (40 ~ 50 scores), moderate (50 ~ 60 scores), and severe (above 60 scores).

Data analysis
Statistical analysis was performed with R software (www.r-project.org). For each patient, the right eye was chosen for statistical analysis. Kolmogorov-Smirnov test was used for testing the normality of each variable. Mean values and standardized deviations were used to make the basic statistical description for normally distributed continuous variables, otherwise, median values and interquartile range (IQR) were used. Frequency and percentile were used to make a basic statistical description for categorical variables.
An independent two-sample t-test was used to make the comparison of normally distributed continuous variables between the MGD group and control group, while the Wilcoxon rank-sum test was used to make the comparison for non-normally distributed continuous variables. A Chi-square test was used to make the comparison of categorical variables between the MGD group and the control group. Logistic regression analysis was used to explore the association between the M-SDS score, clinical indicators, and depression. The signi cance level was set to be 0.05.

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