The association between glaucoma and risk of depression: a nationwide population-based cohort study

Glaucoma is the most common cause of irreversible blindness [1]. Glaucoma patients must cope with visual impairment, the anxiety associated with blindness, long-term follow-up and a heavy economic burden. In addition, prior studies have shown an association between β-blocker eye drops (a common glaucoma treatment) and depression [2, 3]. In all, there are many factors associated with glaucoma that may lead to depression.

Previous studies have shown that the prevalence of depression among the glaucoma patients is higher than that among the non-glaucoma individuals [4‐8]. The risk factors associated with depression among glaucoma patients have also been identified [6, 8‐14]. However, the majority of the studies have been conducted in hospital settings with a small sample size. Moreover, most studies have been cross-sectional studies and as such cannot address the timeline between glaucoma and the development of depression.

To investigate the relationship of glaucoma and subsequent development of depression, we conducted a population-based, retrospective cohort study with an 11-year follow-up period. A glaucoma group and non-glaucoma group were explored through the National Health Insurance Research Database (NHIRD) in Taiwan to see whether the risk of developing depression differed between groups. In addition, risk factors associated with the development of depression among glaucoma patients were explored.

We conducted an 11-year follow-up study on population-based data from the Taiwan LHID. Compared to those without glaucoma, patients with glaucoma had a significantly higher risk (HR = 1.71) of developing depression. Among glaucoma patients, older age, female gender, lower income, living alone, and substance abuse were significant risk factors for developing depression. Neither the number nor the types of glaucoma eye drops were significant risk factor of depression.

The majority of the prior studies regarding the association between glaucoma and depression used different kinds of self-report questionnaires to assess depression symptoms rather than a clinical diagnosis [4‐10, 12, 13, 18], limiting comparisons between studies. In our study, diagnoses of glaucoma, depression, and systemic comorbidities were made by board-certificated doctors, increasing the validity of the results in the present study. Besides, the follow-up cohort design of our study could derive additional information about the incidence of depression. As noted in Table 1, during the 11-year follow-up period, the cumulative incidence of depression was 5.9% among glaucoma patients, which was significantly higher than the 3.2% in the control group.

According to the definition made by the World Health Organization, happiness/health is a dynamic state of complete physical, medical, social, and spiritual well-being. Therefore, systemic diseases, substance abuse, lack of social network such as family support or religion, all may have effects on depression risk. These variables are confounders and have to be adjusted when we investigate the relationship between glaucoma and depression. Table 1 compares these confounders between glaucoma and control groups. It is compatible with previous studies that the glaucoma group has a significantly higher severity of systemic diseases [5, 19]. Table 1 also shows the glaucoma group and the control group are matched well on age and gender, thus the two groups have the same distributions of age and gender. It is noteworthy that the mean glaucoma diagnostic age in our glaucoma group is 59.4 years, which is younger than the average glaucoma presenting age of 71.1 years in other country [20]. Besides, the diagnostic prevalence of glaucoma in the younger age categories was almost the same as that in the older age categories. One reason is that the prevalence of open-angle glaucoma (including normal tension glaucoma) has been higher than that of angle-closure glaucoma since 2005 [21], and patients with normal tension glaucoma generally have a younger age than those with angle-closure glaucoma [22], thus lowering the average age of glaucoma patients. Another reason is the high accessibility of healthcare achieved by the Taiwan NHI system [23], thus glaucoma can be diagnosed at an earlier age.

In addition, Table 1 shows that glaucoma subjects have a significantly higher insurance amount (income) as well as a significantly higher urbanization level of residence. The phenomenon can imply a higher chance of glaucoma to be identified in people with higher socioeconomic status (SES). The possible reason was that people with higher SES might have higher glaucoma awareness, and have more eye care seeking behavior because of increased prevalence myopia [24, 25]. Therefore they have more chances to be incidentally found to have glaucoma.

As shown in Table 2, the glaucoma group exhibited a significantly higher risk for developing depression than the control group (adjusted HR = 1.71). Similarly, a study conducted in the US by Wang et al., using the database of the National Health and Nutrition Examination Survey found glaucoma was significantly associated with depression after adjusting for the impact of demographic factors and systemic comorbidities (OR = 1.59; 95% CI: 1.01–1.52) [8]. Our cohort study design allowed an assessment of HR, providing more information than OR about subsequent risk of depression. We also found that lower income, living alone, and substance abuse were significant risk factors of depression, which were compatible with previous studies [26‐29]. The possible explanation is the lack of financial or emotional support may predispose people to depression.

Among glaucoma patients in our study, older patients and female patients were at a greater risk of developing depression (Table 3). These results are consistent with previous studies [6, 10‐12]. In addition, a lower income significantly increased the risk for depression, which implies that economic burden may predispose glaucoma patients to depression. Furthermore, living alone and substance abuse were associated with depression. Therefore, familial and social support were important for the psychological health among glaucoma patients. Our study revealed a consistent finding with previous studies that neither the number nor the types of glaucoma medications was a significant risk factor for depression among glaucoma patients [8, 30]. Also, we found the use of β-blocker eye drops was not an independent risk factors for depression. While systemic β-blockers are addressed to have side effects such as asthma, bradyarrhythmia, and depression [3, 31‐33], the association between topical β-blocker eye drops and depression is still controversial. Topical β-blocker eye drops might be absorbed through nasal and pharyngeal mucosa and could cause depression in some studies [2, 34, 35] While drug manufactures label β-blockers with a possible risk of depression, the current study along with many prior studies [6, 8, 13, 36, 37] do not support this claim. The inconsistencies may be resulted from discrepancies in study design and case definition. Most of the studies supporting an association between β-blocker eye drops and depression used case series and case reports, whereas findings from cross-sectional or case-control studies were equivocal. Differences in case definition may also explain the inconsistencies. Studies using a diagnosis of depression mostly did not support the relationship. However, studies using depressive symptoms were about evenly split. Still another explanation of inconsistencies might be ethnicity. Most of previous literature revealed significant association were studies among Caucasians. Our study, with a cohort study design among an Asian population and used depression diagnosis as case definition, revealed no significant association between β-blocker eye drops and depression. Future studies will be needed to further investigate the issue using a comparable study design and case definition among different ethnicities.

The strengths of our study are a large sample size, a lengthy study period, disease confirmation through well-accepted ICD9-CM codes, and a statistical analysis that adjusted for confounders. However, studies based on claimed database may have the limitation that the diagnostic codes in the database are not as accurate as those in the clinical charts. Fortunately, in our health care system, the National health Administration (NHA) frequently checks the consistencies between the claimed data and the charts. NHA also checks whether the patient received a standard protocol of examinations to confirm the diagnoses. Therefore, the diagnoses in our database had high accuracies.

It is another limitation that NHIRD does not have the information regarding the detailed clinical characteristics of depression (e.g., Hamilton rating scale), or about visual quality. Besides, the NHIRD did not supply data about religion, which may have a protective effect on depression in previous studies [12, 38, 39]. Future studies combining the chart review will be conducted to consider and adjust these confounding effects. At present stage, we have adjusted many possible confounders, such as age, gender, CCI, income, urbanization level of residency, living alone, substance use, and number/types of glaucoma medications. Based on the significant risk factors of depression that were found in our study, early intervention to prevent or treat psychological problems could be considered among glaucoma patients with high risks.

In our study, glaucoma patients are at significantly greater risk of developing depression. Among glaucoma patients, age, female, and low income were significant risk factors for depression. The findings from our study have clinical and public health implications. Clinically, when treating glaucoma patients, ophthalmologists need to focus not only on the medical aspects of glaucoma, but must also provide psychological support to their patients. Glaucoma patients at a high risk for depression, such as older patients, female patients, and patients with a low income, should be referred to a psychiatrist if early signs of depression become apparent. From a public health perspective, policy makers are encouraged to enforce screening for depression risk in patients with glaucoma, and to provide more substantial and integrated care.