Fluoxetine for Anterior Ischemic Optic Neuropathy (AION); a Double Blind Randomized Clinical Trial

Background: Fluoxetine enhances the levels of brain-derived neurotrophic factor (BDNF); considering its known improving effects on neurogenesis and plasticity, it seems to improve the Anterior Ischemic Optic Neuropathy (AION). This study aimed to evaluate the effect of Fluoxetine on clinical prognosis of patients with AION. Methods: In this double-blind placebo-controlled randomized clinical trial, subjects with AION who were referred to Rasool Akram Hospital were divided into two study groups; the uoxetine group that received 20 mg Fluoxetine daily(n=50) and the control group (n=50) that received placebo for a period of six months. Patients underwent clinical and paraclinical evaluations before and after the trial. This study was a registered trial with IRCT code IRCT20181109041596N1. Results: One hundred patients were enrolled from August 2019 to December 2020 and assessed in this study. Subjects in Fluoxetine group showed signicant improvement in visual acuity in comparison to the placebo group with less score in LogMAR scale (P: 0.008 and 0.002, respectively), improvement in MD parameters of perimetry (P: 0.003 and 0.002, respectively), and decrease in VEP latencies (P (in 1 st minute): <0.001 and <0.001, P (in 15 st minute): 0.038 and 0.011, respectively). There were no differences in color vision, Rn in all dimensions, PSD parameter of perimetry or VEP amplitudes following the trial of Fluoxetine therapy (Ps> 0.05). Conclusion: Fluoxetine showed promising therapeutic value for patients with AION besides its safety as an additive treatment option to corticosteroids.

e cacy in amblyopia [22] . Fluoxetine has also been e cient in improving cognitive performance in patients with vascular dementia [23] .
Although, Fluoxetine has the potential to increase serum levels of BDNF, it seems to be effective in neurogenesis in the optic nerve and potentiation of plasticity in the visual cortex; hence, the therapeutic effect of Fluoxetine in Anterior Ischemic Optic Neuropathy (AION) by induction of neuronal repair gives us the idea to perform this study in order to assess the effect of Fluoxetine in the clinical prognosis of patients with AION.

Methods And Materials:
This double-blinded randomized clinical trial was aimed to assess the effects of Fluoxetine on the clinical prognosis of patients with non-arteritic Anterior Ischemic Optic Neuropathy (AION).The study population consisted of patients with non-arteritic AION who were referred to Rasool Akram Hospital, Ophthalmology Clinic. Eligible participants were asked to sign the consent form to participate in the study. Inclusion criteria were patients diagnosed with AION with an age of 18 years old and above while the exclusion criteria were over 3 weeks of latency from the beginning of symptoms, visual impairment correlated to other diseases but not due to AION, pregnancy and or being pregnant during the clinical trial, history of using psychiatric drugs with the inclusion of Fluoxetine, and any history of eye trauma or any surgical interventions. Subjects that met the inclusion criteria were randomly selected into 2 groups; the Fluoxetine group were given Fluoxetine capsule 20mg daily for six months and the control group who received placebo. Subjects were evaluated in the initial phase of the clinical study and on the 6th month of the clinical trial, demographic data were obtained through a questionnaire and baseline physical examination was done to assess visual acuity (examed by Snellen chart), IOP (measured by Goldmann tonometer), biomicroscopy with the use of a slit lamp in order to assess for any evidence of cataracts, VEP (Visual evoked potential) assessed by EvokeDx NextGen icVEP to measure both latencies and amplitudes in 1st and 15th minutes, perimetry test which was performed using Carl Zeiss Meditec device, and Rn in all dimensions using OCT (optic coherence tomography) which was assessed by Optovu-heidelberg.
Both patients and investigators were unaware of the type of medication received by patients to provide double blinding of the trial. Block randomization using 25 quaternary blocks was used. Concealment was preserved by placing patients in the study groups according to the order of the randomization list.

Analysis
Statistics of quantitative data are presented by means and standard deviations or medium and interquartile ranges and qualitative data are presented by frequencies. For comparison of quantitative variables between study groups, student independent samples T-test or its non-parametric equivalent, Mann-Whitney U test was used while compared T-test or its non-parametric equivalent, Wilcoxon test was used in order to compare the results before and after treatment in each group. For comparison of parameters between study groups, possible confounding biases by baseline characteristics were addressed by covariance analysis (Bootstrapping for non-parametric data). Sample size was determined 45 cases in each group using G power by consideration of the effect size d : 0.6, alpha error equal to 5 % and power equal to 80%. 10 percent lost to follow up was predicted and 50 patients in each of the two study groups was considered. P-value equal or less than 0.05 was considered statistically signi cant. IBM statistics SPSS version 22 was used for obtaining statistical analysis.

Results:
One hundred patients with Anterior Ischemic Optic Neuropathy (AION) were enrolled 50 in each of the two study groups from August 2019 to December 2020 (64 males and 36 females) with a mean age of 58.62 ± 12.13 years old. Demographic data are represented in Table 1. Visual acuity score, color vision score, perimetry parameters (MD and PSD), Rn s in all six dimensions (Nasal, superonasal, superotemporal, temporal, inferotemporal, and inferonasal), VEP amplitudes and latencies on 1st and 15th minutes, and intraocular pressure (IOP) were equal in the baseline measurements between study groups (P-value > 0.05).
Visual acuity score in the LogMAR scale was signi cantly lower among the Fluoxetine group in the nal evaluation in comparison to the baseline result (P-value: 0.008) and in comparison to the nal evaluation result of the placebo group (p-value: 0.002). There was no signi cant difference noted on the visual acuity score of the placebo group before and after the trial (P-value: 0.132) [ Table 2]. Also, no signi cant difference was noted on the color vision on the two groups before and after the trial (P-values > 0.05) [ Table 2]. MD parameter in perimetry was statistically signi cant which is near zero among the Fluoxetine  Table 2]. Latencies in 1st and 15th minutes in the assessment of VEP were both statistically signi cantly, lower among Flouxetine group in the nal assessment compared to their preliminary results (P-values: <0.001 and 0.038, respectively) and in comparison to the placebo group's nal result (P-values: < 0.001 and 0.011, respectively). Results indicated that no signi cant difference was noted in optic nerve latencies on the placebo group before and after the trial (P-values: 0.121 and 0.160, respectively). Also, no signi cant difference was noted of the Amplitudes in 1st and 15th minutes visual disability assessment by VEP in the Fluoxetin group before and after the clinical trial (P-values: 0.409 and 0.907, respectively) nor to the placebo group's nal result (P-values: 0.292 and 0.749, respectively) [ Table 2].
Results of Rn assessment in all six dimensions using OCT (optic coherence tomography) indicated no signi cant difference between the preliminary and nal evaluation results on both groups (P-values > 0.05)[ Table 2].No signi cant changes were noted in the IOP on both Flouxetine and placebo groups in the baseline and nal assessments (P-value > 0.05)[ Table 2].
Adverse effects such as glaucoma or cataracts were not reported by any of the Flouxetine group, but some participants reported mild drowsiness or insomnia and there was no lost to follow up.

Discussions:
This study has found Fluoxetine as a safe complement therapeutic option in Anterior Ischemic Optic Neuropathy (AION) with promising improvements in their clinical prognosis.
Since there were no noted serious side effects of Fluoxetine, it seems to be a safe treatment strategy to complement with corticosteroids. However, Fluoxetine has shown improvements in visual acuity, perimetry, and VEP latencies, there were no statistically signi cant changes in VEP amplitudes, color vision, or Rn s. Overall, the improvements observed especially in visual acuity are enough evidence to support the desirable effect of Fluoxetine in the prognosis of patients with AION.
The equality of the baseline characteristics such as demographic parameters were ensured and confounding biases were addressed by covariance analysis.
Serum levels of BDNF as a neuroprotective factor increases in case of pathologies involving the optic nerve [1] . Fluoxetine is a BDNF inducer involved in neuronal plasticity and neuroregeneration besides its high penetration into the retina [2][5] [7] . Previous studies have showed improvements in visual cortex plasticity and re-establishment of axonal interactions by Fluoxetine leading to desired clinical e cacy in Amblyopia and improvement in vision [3][4] [21] .
Since AION is an ischemic disease that involves neural tissue of the retina, therefore, AION is comparable to ischemic stroke in its pathophysiology. Fluoxetine has been reported as an effective treatment option for improving the post-stroke motor function by the acceleration of the neurogenesis and neuroplasticity [11][14-16] [24] . Cognitive performance has improved and three-year recurrence in stroke patients has decreased by Fluoxetine [10] [12] . However, some studies have disagreed to the e cacy of Fluoxetine in stroke patients [17][18][19] . It should be considered that the therapeutic effectiveness of Fluoxetine widely depends on the early initiation of treatment upon the manifestation of symptoms [16] . Fluoxetine has also been effective in improving the clinical prognosis in patients with vascular dementia and multiple sclerosis as examples of other neurodegenerative disorders [20] [23] . Futher studies should be considered regarding the effectiveness of Fluoxetine in AION on the early iniation of treatment upon the initial manifestation of symptoms.

Conclusion:
Fluoxetine is a safe complement therapeutic option in Anterior Ischemic Optic Neuropathy (AION) with promising effects on clinical prognosis.

Declarations:
Ethics approval and consent to participate This study is approved by Ethics Committee of Vice Chancellor for Research & Technology, IUMS (code: IR.IUMS.FMD.REC.1397.093). This study was a registered Trial in 07/01/2019 with IRCT code IRCT20181109041596N1. All patients and control subjects signed the informed consent. This study was performed in accordance with the ethical standards of the Declaration of Helsinki (2013) and its subsequent amendments.

Consent for publication
Informed consent was obtained from all patients whom clinical data were reported in this article to participate in the study and assessments.
Availability of data and materials The datasets generated during and analyzed during the current study are not available publicly because it is collected on the data repository of the eye research center of Rasool Akram hospital which are intended to be reused in another study too but are available from the corresponding author on reasonable request Con icting interest/Competing interests