Evaluation of the effects of duloxetine treatment on anterior segment parameters by optical coherence tomography

To evaluate the effects of Duloxetine on anterior segment parameters and intraocular pressure (IOP) in open angle eyes. 38 eyes of 38 patients with fibromyalgia who had open or wide open angles according to the Shaffer classification. Anterior segment optic coherence tomography was performed before and after (month 3) Duloxetine treatment. IOP, central corneal thickness (CCT), corneal endothelial cell density (CECD) and anterior chamber depth (ACD) were also recorded and evaluated. No statistically significant difference was determined in IOP, CCT and CECD (p > 0.05). However, a statistically significant decrease was determined in both the temporal and nasal anterior chamber angle, angle opening distance, nasal trabecular-iris space area and ACD values between the baseline and month 3 (p < 0.001). We think that the short term use of Duloxetine does not lead to clinically significant changes despite their statistically significant effects on the anterior chamber parameters.


Introduction
Duloxetine is a strong serotonin (5-HT) and norepinephrine reuptake inhibitor (SNRI) and is commonly used in the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder, and fibromyalgia. [1]. Some studies in the literature have reported that duloxetine [2,3] and Selective Serotonin Reuptake Inhibitors (SSRI) [4][5][6] may lead to angle-closure glaucoma. However, these have been in the form of case reports or case series. Before starting the use of these and similar drugs in our clinical practice for patients referred to us from various clinics, cases with a risk of angle closure or with a narrow-angle are first determined. Patients whose treatment plan continues unaltered despite such findings are informed about angle-closure glaucoma and followed up closely. However, the effects of these drugs on parameters related to the anterior chamber and angle have not been fully clarified, especially in open-angle eyes. We aimed to reveal how the use of duloxetine in openangle eyes affects the intraocular pressure (IOP), iridocorneal angle parameters such as anterior chamber angle (ACA), angle opening distance (AOD), nasal trabecular-iris space area (TISA) and other anterior segment parameters such as central corneal thickness (CCT), anterior chamber depth (ACD) and corneal endothelial cell density (CECD) in this study.

Study population
The study was started after permission was obtained from the local ethics committee. The 38 eyes of 38 patients over the age of 18 years who had not undergone intraocular surgery previously, had an intraocular pressure below 20 mmHg, did not use anti-glaucoma treatment, had grade 3 (20-34 degrees) or 4 (35-45 degrees) angles according to the Shaffer classification; did not suffer from hypertension, diabetes, or other diseases or use any systemic medication; volunteered to participate in the study, and could read and understand the informed consent form were included in the study. The right eye was used when both eyes were suitable for inclusion as the measurements generally showed a positive correlation between the two eyes [7].

Duloxetine treatment
The IOP was measured with Goldmann applanation tonometry and the anterior chamber and angle parameters of CECD, ACD, and CCT were determined with anterior segment optical coherence tomography (AS-OCT) at the beginning and at the end of the 3rd month of treatment in patients who were started Duloxetine capsule 30 mg once a day for the diagnosis of fibromyalgia at the physical treatment and rehabilitation clinic.

AS-OCT
The baseline and 3rd-month AS-OCT (NIDEK RS-3000, NIDEK Co. Ltd, Japan) measurements were performed by the same AS-OCT operator, nasal and temporal quadrant (180° and 0° meridians) images were obtained with the patient in a darkened room. Adequate centration and quality for the analysis were ensured by using the ACA while the CCT was measured using the corneal radial scan pattern.
The angle between the posterior corneal angle and the tangential iris line was measured to calculate the ACA width. The apex of the iris recess and the scleral spur were first identified manually, followed by the use of standard parameters for ACA width analysis. The perpendicular distances to the iris anterior surface from the trabecular meshwork at positions 750 and 500 µm anterior to the scleral spur were accepted as the angle opening distances (AOD 750 and AOD 500, respectively). The trapezoid-shaped area with boundaries constituted by the AOD 750 or AOD 500, the anterior iris surface, the inner corneoscleral wall, and the perpendicular distance from the scleral spur to the opposing iris was accepted as the trabecular iris space area (TISA 750 and TISA 500, respectively) ( Fig. 1).
ACD at baseline and the 3rd month of treatment was determined using biometry with the Monitor A&B Scan. A topical corneal anesthetic was administered and the biometry probe placed vertically at the central cornea. The mean value of five consecutive measurements was calculated to determine the ACD.
The IOP was measured with Goldmann applanation tonometry at baseline and the 3rd month of Duloxetine treatment. The Kolmogorov-Smirnov test was used for confirmation of the normal distribution of study data. The t-test was used for statistical calculations between two dependent groups and p values < 0.05 and < 0.001 were accepted as statistically significant. The analysis software was SPSS, version 20.0 (SPSS Inc., Chicago, IL, USA).

Results
The mean age of the patients included in the study was 48.5 ± 13.9 years (range: 33-65 years). The 38 eyes (34 right eyes and 4 left eyes) of 38 patients (18 females, 20 males) were included in the study.
No statistically significant difference was found in comparing the IOP, CECD, and CCT measurements before and after the treatment (p; 0.214, 0.311, and 0.117, respectively). The demographic data and the IOP, CECD, and CCT values are summarized in Table 1. Table 2 shows that the mean ACD value was 3.71 ± 0.57 mm (3.2-4.2 mm) before treatment and 3.13 ± 0.46 mm (3-3.8 mm) after treatment (p < 0.001). The ACA, AOD 500 and 750, and TISA 500 and 750 measurements were statistically significantly higher at baseline than after treatment (p < 0.001).

Discussion
SNRIs are commonly used in the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder, and fibromyalgia, due to their strong effect, favorable safety profile, and good tolerability. Venlafaxine and Duloxetine are the best-known drugs in this group. They act by blocking the reuptake of presynaptic serotonin and noradrenaline, and also dopamine to a smaller extent, in the central and peripheral nervous system. In this way, they increase the amount and effect of serotonin, noradrenaline, and dopamine in the synaptic gap. Considering that receptors for these neurotransmitters can be found in the ciliary body, iris, and various other parts of the eye [1], we believe that frequent and long-term use of SRNIs could lead to various ocular effects.
Review of the baseline and 3rd-month results of the patients with open and wide open iridocorneal angles referred to us in our study revealed no significant difference between the IOP, CECD, and CCT measurements. However, the anterior chamber depth was lower at the end of the study with a narrowing/ decrease of angle parameters. There was no significant finding requiring discontinuation of Duloxetine treatment in any patient when the intraocular pressure and angle status were taken into account.
There are few clinical studies on the ocular side effects of the commonly used medication groups of SNRIs (Duloxetine, Venlafaxine, etc.) and SSRIs (Fluoxetine, Sertraline). Seitz et al. have evaluated the use of antidepressants in the last year in angle-closure glaucoma patients and found a positive correlation between such use and angle-closure in a populationbased study [8]. SSRI agents have been reported to increase the intraocular pressure in another review, but this did not require discontinuation of the drugs and only required follow-up by the Ophthalmology team [9]. However, some case reports have indicated that SNRIs such as Duloxetine [2,3] and Venlafaxine [10,11], and SSRIs such as sertraline [5], paroxetine [12], and citalopram [13] can cause angle-closure glaucoma. The reason is reported in these studies as the serotonin receptors in the iris, cornea, and ciliary body. In other words, the increased adrenergic effects, weak anticholinergic activity, or ciliary congestion due to increased serotonin levels and mydriasis are thought to be the cause. We could not measure the pupillary diameter to evaluate the mydriatic effects of this agent. Gündüz et al. evaluated the ACA, ACD, ACV, CCT, IOP, and pupil diameter in patients using Duloxetine/Venlafaxine in their comprehensive study on patients using SSRIs. A significant increase in PD was found when compared to the control group in patients diagnosed with depression who had used Duloxetine/Venlafaxine for shorter and longer than 6 months, indicating the presence of mydriasis. Besides, a significant decrease in ACD was detected in the case of using the medication for more than 6 months. Another finding was a significant decrease in the IOP after long-term use [14]. Chen et al. [15] similarly revealed that long-term use of SSRIs does not increase the risk for IOP, and open or closedangle glaucoma. However, another study published in 2017 reported in contrast that long-term and highdose SSRI use increased the IOP and glaucoma risk. The same study also indicated that excluding severe systemic diseases and the relevant systemic medications was a weakness of the study design. [16]. Botha et al. [17] have reported increased IOP with Venlafaxine that was started later in a patient diagnosed with open angle glaucoma in a case report. Some other studies on the effects of SSRI agents on the IOP have also reported that the IOP may increase with the use of these drugs [9,17]. We found no statistically significant difference in the IOP compared to the baseline after a usage period of 3 months in our study. We believe that the exclusion of patients with other systemic diseases and/or systemic medications in the current study makes our results more reliable.
Gündüz et al. [17] have also investigated the anterior chamber and angle parameters in their study published in 2017 on open-angle eyes in patients using SSRIs. A decrease in the IOP was observed in depressed patients using SSRIs. A statistically significant increase was found in the pupil diameter but there was no significant change in the CCT, ACD, ACV, and ACA measurements. We also found no increase in IOP with SSRI use in the current study but there was a significant decrease in the angle parameter values and ACD. The reason could be some differences in the study design. For example, the Gündüz et al. [17] study included the 325 eyes of 166 patients using 6 different SSRI agents, while only one agent (Duloxetine, SNRI) was included in our study. Besides, we included only one eye of each patient in our study as we thought that it would show a statistically similar trend. However, our results may have been affected by our patient population not having other comorbid systemic diseases and not using any systemic drugs. The difference could also be explained by Duloxetine also blocking noradrenaline reuptake, unlike SSRI agents. The eye contains nerves originating from the central and peripheral nervous system. All neurotransmitters/neuromediators of the brain and the relevant receptors are found in the neurons of the iris, ciliary body, cornea, choroid, and also the retina, which is a part of the central nervous system. Serotonin (5-hydroxytryptamine or 5-HT) is found in the aqueous humor, and receptor subtypes such as 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, 5-HT5, and 5-HT4 have been detected in the iris-ciliary body complex. This suggests that serotonin may have effects on aqueous production, IOP regulation, iris configuration, and pupil diameter [18,19]. We believe that the somewhat contradictory results from studies on SSRIs and SNRIs in the literature are due to the different effects of different receptors. For example, it has been revealed that 5-HT1A and 2A decrease the IOP [20], while 5-HT2C and 7 increase the IOP and cause mydriasis with their effect on the pupil sphincter [9]. Among the noradrenaline receptors, α-1 and α-2 have also been shown to decrease the IOP and cause mydriasis with their effect on the pupil dilator muscle [21]. Besides, Dopamine DA1 and DA2 receptors have been proven to act in regulating the IOP in various ways [22]. Considering all the above-mentioned mechanisms, these drugs could act on the IOP, ACD, and other anterior chamber parameters through various receptors and in various ways.
In conclusion, we found the use of Duloxetine in patients with no additional systemic disease except fibromyalgia or medication and with an open and wide anterior chamber angle decreased the anterior chamber depth and angle parameters although it did not lead to intolerable side effects or major changes in the IOP and anterior chamber parameters. We think that the use of this drug for 3 months does not lead to clinically significant changes despite their statistically significant effects on the anterior chamber parameters. We also think that further studies with a longer duration and on a larger patient population are required to validate and develop these data.
Acknowledgements Part of this work will present at the 18 th Turkish Ophthalmological Association National March Symposium of Ophthalmology 11-13 March 2022.
Funding No funding was received for this research.

Declarations
Conflicts of interest All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest, or non-financial interest in the subject matter or materials discussed in this manuscript.
Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the (Giresun University Clinical Research Ethics Committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.