Anxiety and Depression in Glaucoma Patients and its Correlations with Vision-related Quality of Life and Objective Visual Function Indices

Background: To investigate anxiety and depression in glaucoma patients and its correlations with vision-related quality of life (VR-QoL) and objective visual function indices. Methods: In this cross-sectional study, the Hospital Anxiety and Depression Scale (HADS) and the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) questionnaires were administered to 446 Chinese glaucoma patients to assess their psychological disorders, namely anxiety and depression, and VR-QoL, respectively. Socio-demographic and clinical data were collected at the same time. Multivariate linear regression analysis was carried out to investigate the associations between VR-QoL, visual function indices and psychological disorders. Standardized partial regression analysis was used to identify the variable mostly indicative in evaluating psychological burdens. Results: The prevalence of anxiety and depression in Chinese glaucoma patients was 12.11% and 25.78%, respectively. Most of the subscales and the composite score of NEI VFQ-25 were negatively associated with each of anxiety and depression after adjusting for socio-demographic and clinical variables. For visual function indices, only the best corrected visual acuity of both eyes was correlated with anxiety after adjustment. Standardized partial regression analysis further showed VR-QoL but not the objective visual function indices mostly relevant to psychological disturbances. Conclusions: objective visual function indices provide signicantly subscores of HADS-A and HADS-D P < 0.05). (P and C/D of both eyes = 0.007) signicantly anxiety Statistically signicant correlations observed between marital status (P = 0.038), duration of glaucoma (P = 0.004), type of glaucoma (P < of anti-glaucoma (P < 0.0001), of anti-glaucoma surgeries (P higher IOP of both eyes (P < 0.0001) and depression For visual function indices, BCVA eyes MD statistically signicantly with the subscores of HADS-A and HADS-D P 0.05).


Background
Glaucoma is the leading cause of irreversible blindness globally. It was estimated that China would account for one quarter in number with glaucoma worldwide [1]. Due to fear of blindness, increased nancial burdens [2] and long-term usage of anti-glaucoma medications, patients with glaucoma are more likely to suffer from psychological disturbances compared to the reference subjects [3]. Among them, anxiety and depression are the two most common forms [3]. Glaucoma patients with depressive symptoms have a greater likelihood of developing poorer medication compliance [4].
Glaucoma, as a chronic disease, has long-standing negative effects on patients' vision-related quality of life (VR-QoL) [5]. Decreased QoL is related to increased economic burden on community and healthcare system [5]. QoL has been increasingly considered as an important measure in glaucoma management [6]. Anxiety and depression affect the VR-QoL of glaucoma patients signi cantly [7].
Although a higher prevalence of anxiety and depression in glaucoma patients, these disturbances have not raised enough clinical research interest. Only a few studies focused on anxiety, depression and their risk factors in glaucoma patients. In this cross-sectional study, we investigated the variables affecting anxiety and depression in Chinese glaucoma patients. Importantly, we found that self-reported VR-QoL rather than objective visual function indices, such as visual eld (VF) and visual acuity (VA), played the The HADS was composed of 2 subscales, representing HADS-anxiety (HADS-A) and HADS-depression (HADS-D). It was developed by Zigmond and Snaith to identify and quantify anxiety and depression symptoms in populations with physical illnesses [8]. Each subscale includes 7 questions graded on a 4point Likert scale from 0 to 3. Thus, the minimum sum score for each subscale is 0 and the maximum is 21. Higher scores indicate higher degrees of anxiety and depression. As previously described [3,9], the scores of HADS-A and HADS-D above than 10 were de ned as anxiety and depression, respectively. The translated Chinese version from the original HADS has been con rmed reliability and validity [2,10].
The NEI VFQ-25 consists of 25 items related to vision-targeted QoL. These items are grouped into 12 subscales: general health, general vision, ocular pain, near activity, distance activity, social function, mental health, role di culties, dependency, driving, color vision and peripheral vision. Each subscale has a minimum value of 0 and a maximum value of 100 indicating extreme disability and no disability, respectively. The composite score of the NEI VFQ-25 was the mean score of all the subscales except for general health domain.
All participants were underwent comprehensive ophthalmologic examinations including the slit-lamp biomicroscopy. Best-corrected visual acuity (BCVA) was measured using the Snellen chart and was transformed to the logarithm of the minimum angle of resolution (logMAR). Intraocular pressure (IOP) was measured by a Goldmann applanation tonometer. Cup-to-disc(C/D) ratio was evaluated according to the fundus photographs by an experienced ophthalmologist. A central 30°VF test was examined using the automated static perimetry (Humphrey Visual Field Analyzer 30 − 2, Humphrey Instruments, San Leandro, California, USA). VF tests taken within 3 months before the enrollment and with a reliability factor less than 15% were eligible for the study.
Pearson or Spearman tests were used to assess the correlations between the variables and the psychological disorders. Student's t test, nonparametric test or analysis of variance using Bonferroni post hoc test was carried out for comparisons of subgroups among variables. Multiple linear regression analysis was used to identify the predictive factors for psychological disturbances. Results were summarized as standardized partial regression coe cients. P value < 0.05 was considered to be statistically signi cant.
Results 446 glaucoma patients, including 247 POAG, 168 PACG and 31 SG patients, participated in the study. Among them, POAG was the most common glaucoma type. The socio-demographic and clinical information of the participants were shown in Table 1. The subjects consisted of 232 male and 214 female. The average age of the patients was 57.40 ± 15.99 (mean ± SD) years, ranging from 18 to 91 years. The mean BCVA of the better-seeing eyes was 0.20 ± 0.29 and 0.65 ± 0.76 for the worse-seeing eyes. The mean MD of the less-damaged eye was − 7.54 ± 6.07 dB, whereas that of the more-damaged eye was − 13.93 ± 8.26 dB.   , respectively. As previously described, scores above 10 on the HADS-A and HADS-D were de ned as anxiety and depression, respectively [3,9]. In this study, the prevalence of anxiety and depression in patients with glaucoma was 12.11% and 25.78%, respectively. The mean composite score of NEI VFQ-25 was 71.52 ± 15.72 (range: 14.79 to 97.17, Fig. 1B). Because of the high missing rate (308/446, 69.1%), driving had the lowest score among the 12 subscales (20.97 ± 34.9), while color vision had the highest score (88.62 ± 21.74). As previously reported [11], the subscale of driving was not included to calculate the composite score of NEI VQF-25.
The univariate associations between socio-demographic, clinical factors and psychological disorders were shown in Table 2. Age and educational level were both statistically signi cantly correlated with the subscores of HADS-A and HADS-D (all P < 0.05). Living status (P < 0.0001) and smaller C/D of both eyes (P = 0.007) were signi cantly correlated with anxiety disorders. Statistically signi cant correlations were observed between marital status (P = 0.038), duration of glaucoma (P = 0.004), type of glaucoma (P < 0.0001), numbers of anti-glaucoma medications (P < 0.0001), history of anti-glaucoma surgeries (P < 0.0001), higher IOP of both eyes (P < 0.0001) and depression disorders. For visual function indices, BCVA of the better-/worse-seeing eyes and MD of the less-/more-damaged eyes were all statistically signi cantly associated with the subscores of HADS-A and HADS-D (all P < 0.05).  Multivariate linear regression analysis was carried out to evaluate the relationships between VR-QoL, objective visual function indices and the psychological disturbances without or with adjustment for socio-demographic and clinical factors. The correlations between the 12 subscales, the composite score of NEI VFQ-25 and the psychological disorders were shown in Fig. 2. After adjustment for variables, the 12 dimensions and the overall score of NEI VFQ-25 were all negatively associated with HADS-A ( Fig. 2A). Except dependency (P = 0.187) and peripheral vision (P = 0.564), the other dimensions and the composite score of NEI VFQ-25 showed negative correlations with HADS-D after adjustment (Fig. 2B). The effects of visual function components on anxiety and depression were shown in Fig. 3. Only BCVA of the better-/worse-seeing eyes was signi cantly correlated with anxiety after adjustment. There were no statistical relationships between BCVA of the better-/worse-seeing eyes and depression. MD of the less-/more-damaged eyes had no statistically signi cant associations with each of HADS-A and HADS-D after adjustment.
Standardized partial regression analysis was further employed to identify which ones of the visual function indices and VR-QoL played the most important roles in deciding the psychological disturbances. As shown in Table 3, the absolute coe cient value of the composite score of NEI VFQ-25 in HADS-A and HADS-D was 0.65 and 0.39, respectively (both P < 0.0001), which was the highest and was the only statistically signi cant deciding factor when compared to objective visual function indices.

Discussion
The present study examined anxiety and depression in Chinese glaucoma patients and investigated the factors in uencing these two psychological disorders. The most important nding of the study was that patients' self-reported VR-QoL other than objective visual function indices, such as MD and BCVA, played the most important deciding role in psychiatric illnesses.
The prevalence of anxiety and depression in glaucoma patients in our study was 12.11% and 25.78%, respectively, which was signi cantly higher than that of the general normal Chinese population (2.4% and 1.4% for anxiety and depression, respectively). It was consistent with previous studies [9,12,13], indicating that glaucoma is a predictor of psychological disturbances. The prevalence of anxiety in glaucoma patients in our study was signi cantly lower than that in Singapore (64%) [14] and was similar to that in Turkey (13.5%) [7] and Japan (13%) [9]. The prevalence of depression in our study was lower than that in Turkey (57%) [7] and Singapore (30%) [14], but was higher than that in Australia (19.09%) [15], Hungary (12.1%) [16] and America (10.9%) [13].
Univariate analysis showed that age had a positive correlation with each of the anxiety and depression in glaucoma patients. The relationships between age and anxiety were controversial. Zhang et al reported that the likelihood of having anxiety along with glaucoma did not change with age [17]. However, other studies revealed that age negatively correlated with anxiety [2,3]. The reasons of the inconsistency could be due to the differences in races, age ranges and numbers of glaucoma patients. In terms of depression, our ndings was consistent with previous studies [3,15], which showed that older age was a risk factor for depression. Our results con rmed this nding in a larger range of ages (ranging from 18 to 91 years) in glaucoma patients.
Educational level was another demographic factor that reached statistical signi cance with both of anxiety and depression. The results implied that increased educational level was along with decreased anxiety and depression symptoms. Living with family related to a decreased anxiety status. In addition, smaller C/D of both eyes was positively associated with anxiety, indicating that worse situation of the better eye signi ed a more serious anxiety status. A single marital status, long glaucoma course, POAG type, less numbers of glaucoma medications and no history of surgery treatment were related to a low degree of depression. Besides, higher IOP of both eyes was positively correlated with depression.
Multivariate linear regression analysis revealed that the composite score of NEI VFQ-25 and most of the 12 subscales were signi cantly negatively correlated with each of anxiety and depression disorders after adjusting for socio-demographic and clinical variables. However, for visual function indices, only BCVA of the better-and worse-seeing eyes was signi cantly related to anxiety after adjustment for other variables and the composite score of VR-QoL. Standardized partial regression analysis further showed that the composite score of NEI VFQ-25 accounted the most important part in each of the HADS-A and HADS-D with statistical signi cance.
Glaucoma is characterized by progressive optic neuropathy that could lead to visual function damage including VF defects and VA decrease [18]. Ophthalmologists paid close attention to these objective visual function indices in clinical practice. However, our results indicated that patients' self-reported QoL but not visual function components played the most important role in psychological distresses.
Reports about the associations between self-reported measures, objective visual function indices and anxiety in eye diseases were very little. Zhou et al found that worse self-reported visual function assessed by Glaucoma Quality of Life-15 questionnaire (GQL-15) was consistently correlated with decreased anxiety and depression in glaucoma patients [2]. In retinitis pigmentosa patients, the degree of anxiety was signi cantly correlated with the general health and role di culties of the NEI VFQ-25 dimensions but not with any objective visual functions, such as BCVA of better-and worse-seeing eyes [19]. With regard to depression, our results were consistent with several previous studies. Skalicky et al reported that the total score of GQL-15 was an independent predictor of depression [15]. Jampel et al studied depression and mood indicators in newly diagnosed POAG patients. In compliance with our results, they found that poorer visual function, such as worse VA and more damaged VF, were not correlated with depression symptoms and altered mood. However, patients' perception of their vision in daily-life activities was associated with depression signi cantly [20]. This study has several limitations. First, selection bias may be caused because the participants were recruited from a single tertiary institution. Second, even though the HADS questionnaire is common used for study purpose, it could not represent a formal psychological diagnosis of anxiety and depression. In addition, the cross-sectional design of the study made it unable to establish causality. Prospective studies will be needed to further con rm the conclusions.

Conclusions
Our study showed that self-reported VR-QoL played the most important role in anxiety and depression disorders in glaucoma patients. NEI VFQ-25 is a useful tool to screen glaucoma patients with high risk to suffer from psychological disturbances. This nding help ophthalmologists and psychologists to nd patients with psychological disorders early and offer interventions and assistances timely.
All data generated or analysed during this study are included in this published article and its supplementary information les.

Competing interests
The authors declare that they have no competing interests.  Figure 1 The average scores of the HADS (A) and the NEI VFQ-25 (B). Black squares and thin error bars represent means and maximum/minimum values, respectively. HADS-A: Hospital Anxiety and Depression Scale-