This meta-analysis of seven eligible studies involving 447,672 cases and 1,510,391 controls supports a significant positive association of SSRIs, SNRIs and TCAs use with risk of cataract. To the best of our knowledge, this is the first systematic review and meta-analysis aimed to evaluate the relationship between antidepressants use and risk of cataract development.

Heterogeneity is often a concern in a meta-analysis. In the present study, obvious heterogeneity was observed among most analyses, which was partially explained by the following factors: study design was different. Although most included studies were performed in Western countries, population characteristics still varied in genetic and environmental background, antidepressants use, and matched or adjusted confounders.

Several mechanisms may be involved in the positive association of antidepressants use with cataract risk. In animal models, serotonin has been reported to play a crucial role in lens transparency [19]. Elevated serotonin levels have been shown to lead to lens opacity in rats [20]. Similarly, cataract and glaucoma patients also had increased levels of serotonin in the aqueous humor [21]. In addition, serotonin 5-HT1A, 5-HT2A/2C, and 5-HT7 receptors have been identified in the crystalline lens, which participate in regulation of intraocular pressure (IOP) homeostasis [22]. Increased IOP is able to contribute to glaucoma, which is a risk factor for cataract formation [23]. TCAs use is reported to be related with photosensitivity to ultraviolet or sunlight. This latter exposure has been suggested to be associated with cortical cataract in Beaver Dam Eye Study [24]. On the other hand, TCAs is able to inhibit norepinephrine uptake, which may also have cataractogenic properties [25].

Our study had some important strengths. Considering individual studies had limited statistical power, this meta-analysis of seven studies involving a large number of cases and controls improved the power to detect a potential association and provided more robust estimates. Most of the original studies matched or adjusted a series of variables, which greatly reduced the likelihood of confounding bias.

Potential limitations of our study should be considered. First, the number of eligible studies was limited, especially in some subgroup analyses, which might influence the reliability of the results. Second, significant heterogeneity was observed among included studies, which might distort the conclusion of our study. Third, a certain degree of publication bias was observed. Gray literature (e.g., conference abstract) was difficult to find and studies with null results were less likely to be published. Finally, random misclassification of antidepressants might influence the results.