Fluoxetine exposure associated with reduced risk of geographic atrophy

Abstract

Purpose : Previously we found fluoxetine (FLX) was associated with a reduced risk of dry age-related macular degeneration (AMD) and inhibited Alu RNA-induced retinal pigmented epithelium (RPE) degeneration. We sought to determine whether (1) FLX exposure reduces progression from dry AMD to geographic atrophy (GA); (2) FLX inhibits complement-induced RPE degeneration.

Methods : Retrospective longitudinal and cross-sectional health insurance claims analyses of Veterans Administration (VA), Truven, and PearlDiver databases were performed from Oct. 2015-2021. ICD-10 diagnostic codes and National Drug Codes were used. The key predictor was exposure to FLX and models were adjusted for sociodemographic factors. The rate of development of GA was analyzed in patients with depression and dry AMD using Kaplan Meier time-to-event analyses. Prevalence odds ratios (OR) were computed for each database and random-effects models used to compute a pooled OR. Statistical significance was assessed using log-rank and z tests. RPE degeneration was induced in C57BL/6J mice by subretinal injection of complement C3a or C5a. FLX or DMSO was injected into the vitreous humor. RPE degeneration was assessed by fundus imaging and ZO-1-stained RPE flat mounts. Statistical significance was assessed using two-tailed Student t test.

Results : Kaplan Meier analyses revealed FLX-exposed patients progressed from dry AMD to GA at a slower rate in the VA (N=109,321; p<0.001), Truven (N=203,890; P=0.023) and PearlDiver (N=134,722; p=0.046) databases. FLX-exposed patients had a reduced prevalence of GA in the VA (OR=0.74), Truven (OR=0.96) and PearlDiver databases (OR=0.84). A pooled analysis showed a protective association of FLX (OR=0.85; 95% CI=0.77-0.94; p=0.002). FLX reduced the area of RPE degeneration induced by C3a (64%±13%; N=9; p=0.008) and by C5a (51%±11%; N=9; p=0.019).

Conclusions : FLX use was associated with a reduced incidence of progression from dry AMD to GA in people. Complement-induced RPE degeneration in mice was partially inhibited by FLX administration. If confirmed by prospective clinical trials, these findings suggest that FLX use might be beneficial for GA.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1: Kaplan Meier plots of dry AMD to GA progression in VA (A), Truven (B), and PearlDiver databases (C).

 

Figure 2: Representative fundus photos (A,C) and ZO-1-stained RPE flat mounts (B,D) of mice injected with subretinal C3a (A,B) or C5a (C,D) and intravitreous DMSO (left) or FLX (right).