How Does Usage of Serotonin Noradrenaline Reuptake Inhibitors Affect Intraocular Pressure in Depression Patients?

Abstract

Purpose:

To evaluate anterior segment parameters and intraocular pressure (IOP) modifications in patients using serotonin noradrenaline reuptake inhibitors (SNRIs) due to major depressive disorder.

Methods:

This cross-sectional study included 170 eyes of 85 subjects. All subjects were divided into three groups: group 1 included 44 healthy control subjects, group 2 included 22 patients receiving antidepressants for 1 week to 6 months, and group 3 included 19 patients receiving antidepressants for >6 months. All subjects underwent a detailed ophthalmologic examination, including gonioscopy. Anterior segments of all subjects were evaluated with the Scheimpflug system and pupil diameter (PD), central corneal thickness, anterior chamber depth (ACD), anterior chamber volume, and anterior chamber angle (ACA) measurements were enrolled.

Results:

The median IOP was significantly lower in patients using antidepressants [16.0 (11.0–21.0) mmHg] than the control group [17.5 (12.0–21.0) mmHg] (P = 0.041). The PD was significantly larger in patients using antidepressants [3.56 (2.29–5.60) mm] than the control group [2.95 (2.00–4.40) mm] (P = 0.000). In the study group, PD was also significantly larger in patients using SNRIs for ≥6 months [3.67 (2.38–5.08) mm] than <6 months [3.31 (2.29–5.60) mm] (P = 0.000). The median ACD was significantly lower in patients using antidepressants for ≥6 months [3.21 (2.52–4.06) mm] than the control group [3.44 (2.63–4.29) mm] (P = 0.000). ACAs were measured between 25° and 55° by Scheimpflug imaging.

Conclusions:

Treatment of SNRIs causes mydriasis and decrease in width of ACD. These changes may not increase IOP as long as the patient has an open angle. SNRIs lead to decrease in IOP particularly in long-term usage.

Introduction

Major depressive disorder (MDD) is the most frequent mood disorder in the world and it is predicted that it will become the second leading cause of disability worldwide by the year 2030.¹ Regarding this, antidepressants were reported as the most frequently prescribed drugs used by individuals aged 18–44 years in the United States.² Newer generation antidepressant drugs are often the first-line treatment for MDD because of their low side effect profile.^3,4 Serotonin noradrenaline reuptake inhibitors (SNRIs) are members of newer generation antidepressant drugs.³ Their therapeutic actions rely on presynaptic inhibition of serotonin, noradrenaline, and dopamine transporters, while selective serotonin reuptake inhibitors (SSRIs) inhibit only serotonin transporters.⁵

The long-term and widespread usage of SSRIs and SNRIs may cause a rise in the occurrence of rare adverse effects. Seven case reports were presented about ophthalmic adverse events related to intraocular pressure (IOP) during treatment with SNRIs between 1998 and 2016.^4–10 Among these patients, most of them had acute angle-closure glaucoma (AACG) and, moreover, some of them had permanent visual loss. For detecting the risk of AACG, it is important to evaluate the state of iridocorneal angle and anterior segment parameters.

The purpose of this study is to investigate the anterior segment and IOP modifications associated with the use of SNRIs in patients with MDD.

Methods

This cross-sectional study was carried out in the Department of Ophthalmology of University of Health Sciences, Bursa Yüksek Ihtisas Training and Research Hospital. It was approved by the Institutional Ethics Committee and all research protocols adhered to the tenets of the Declaration of Helsinki. Study subjects consisted of patients using SNRIs due to MDD. The control group consisted of healthy subjects not using any drugs. Signed informed consent was obtained from all patients and controls.

The patients using SNRIs (duloxetine or venlafaxine) for at least 1 week were referred to the ophthalmology department. The control subjects were patients who applied to the ophthalmology department for a routine examination and had never used SNRIs. Group 1 consisted of 44 control subjects. The patients receiving SNRIs were divided into two groups considering the duration of the treatment; group 2 consisted of 22 patients receiving SNRIs for 1 week to 6 months, and group 3 consisted of 19 patients receiving SNRIs for >6 months.

Inclusion criterion for patients was current use of duloxetine or venlafaxine for at least 1 week. Exclusion criteria were patient age <18 years or >55 years, receiving any systemic or topical medication, having narrow angles (<20°), glaucoma, refractive errors except ±3 diopters (D), previous ocular surgery or trauma, ocular inflammation, and corneal and retinal disease.

All of the participants underwent a complete ophthalmic examination, including refraction, best-corrected visual acuity, slit-lamp examination, IOP measurement, fundus examination, and gonioscopy. The Goldmann applanation tonometer was used for IOP measurements. IOP measurements were taken in the sitting position between 2 and 4 PM for eliminating the effect of circadian variation.

Anterior segment parameters, including pupil diameter (PD), central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber volume (ACV), and anterior chamber angle (ACA), were evaluated with a 3D rotating Scheimpflug camera Sirius (CSO, Costruzione Oftalmici, Florence, Italy). These measurements were performed with undilated pupils under scotopic conditions in the sitting position.

Statistical analysis

The statistical analysis was performed using the IBM SPSS 22.0 statistical program. The Shapiro–Wilk test was used to assess normal distribution of data. In normal distribution, single-direction variance analysis and unpaired t-test were used for comparing groups. Mann–Whitney U and Kruskal–Wallis tests were used in non-normally distributed variables. Normally distributed variables are stated as mean ± standard deviation; non-normally distributed variables are stated as median (min–max). Categorical variables were given as frequency and percent values and compared with Pearson's chi-squared and Fisher–Freeman–Halton tests. The association between variables was analyzed with Spearman's correlation coefficient. P value <0.05 was considered as statistically significant.

Results

The study included a total of 170 eyes of 85 subjects (70 women and 15 men) with a median age of 38 (min–max = 18–55) years. Group 1 was the control group, including 44 patients (88 eyes). Group 2 comprised 22 patients (44 eyes) taking SNRIs for 1 week to 6 months, group 3 comprised 19 patients (38 eyes) taking SNRIs for at least 6 months. The age and gender distributions of three groups were statistically similar (P = 0.463 and 0.930, respectively). The median duration of SNRI treatment was 28.5 (min–max = 7–90) days in group 2 and 360 (min–max = 180–1800) days in group 3 (P = 0.000).

In the study groups, patients were using either duloxetine or venlafaxine, two members of SNRIs. Twelve patients in group 2 and eight patients in group 3 were receiving duloxetine, while the others were using venlafaxine. There was no statistically significant difference in the number of patients using duloxetine or venlafaxine between the two study groups (P = 0.536). Table 1 shows the demographic data of all subjects and the duration and ratio of duloxetine or venlafaxine usage in groups 2 and 3.

Table 1.

Demographic and Clinical Data of Patients Using Serotonin Noradrenaline Reuptake Inhibitors and Controls

	Subjects not using SNRIs (n = 44)	Patients using SNRIs for <6 months (n = 22)	Patients using SNRIs for ≥6 months (n = 19)	P
Age (years) (min–max)	39 (18–50)	36.5 (20–52)	40 (25–50)	0.463
Sex (female/male)	37/7	18/4	15/4	0.930
Number of patients using Duloxetine/Venlafaxine	—	12/10	8/11	0.536
Duration of SNRI treatment (days) (min–max)	—	28.5 (7–90)	360 (180–1800)	0. 000

SNRI, serotonin noradrenaline reuptake inhibitor.

The statistically significant p values are shown with bold characters.

The median IOP was lower in patients using SNRIs than the control group and this difference was statistically significant (P = 0.041). In addition, this difference was more significant in patients receiving SNRIs for ≥6 months than <6 months, as seen in Table 2. The median IOP was also measured lower in patients receiving SNRIs for <6 months than the control group, but this difference was not statistically significant (P = 0.646).

Table 2.

Comparison of Intraocular Pressure and Anterior Segment Parameters of Patients Using Serotonin Noradrenaline Reuptake Inhibitors and Controls

	Subjects not using SNRIs (n = 88)	Patients using SNRIs for <6 months (n = 44)	Patients using SNRIs for ≥6 months (n = 38)	P
IOP (mmHg)^*	17.5 (12.0–21.0)	17.0 (13.0–21.0)	16.0 (11.0–21.0)	0. 010
PD (mm)^*	2.95 (2.00–4.40)	3.31 (2.29–5.60)	3.67 (2.38–5.08)	0.000
CCT (microns)^*	540.5 (450.0–621.0)	538.50 (483.0–593.0)	542.5 (446.0–630.0)	0.746
ACD (mm)^*	3.44 (2.63–4.29)	3.46 (2.73–3.88)	3.21 (2.52–4.06)	0.000
ACV (mm3)^**	140.932 ± 27.08	143.25 ± 23.65	133.95 ± 28.43	0.269
ACA (°)^**	39.01 ± 6.36	40.07 ± 4.89	37.18 ± 5.84	0.087

Median (min–max) values are given.

Mean ± standard deviation values are given.

The statistically significant p values are shown with bold characters.

ACA, anterior chamber angle; ACD, anterior chamber depth; ACV, anterior chamber volume; CCT, central corneal thickness; IOP, intraocular pressure; PD, pupil diameter.

The median ACD was shallower in patients using SNRIs for ≥6 months than the control group (P = 0.000). However, there was no statistically significant difference in ACD between patients using SNRIs for <6 months and the control group (P = 0.802).

PD was the only parameter that was different in all three groups (P = 0.000). The measurement of PD was the largest in patients using SNRIs for ≥6 months and the smallest in the control group.

There was no statistically significant difference in CCT, ACV, and ACA values between the three groups (P = 0.746, P = 0.269, and P = 0.087). ACAs were classified as grades 3–4 according to the Shaffer system with gonioscopy. ACA measurements obtained by Scheimpflug imaging were between 25° and 55° and they were well correlated with gonioscopy.

In correlation analysis, it was determined that ACA, ACD, and ACV values were decreasing, while the duration of SNRI use was getting longer (P = 0.001, r = −0.355; P = 0.000, r = −0.429; and P = 0.012, r = −0.275). There was no correlation between IOP and duration of SNRI use (P = 0.097 and P = 0.531).

When patients using duloxetine and venlafaxine were evaluated independently of the groups, there were no statistically significant differences in IOP, PD, CCT, ACD, ACV, and ACA values (P = 0.501, P = 0.807, P = 0.625, P = 0.212, P = 0.072, and P = 0.069).

Discussion

SNRIs are widely used for the treatment of MDD because of their favorable efficacy, safety profile, and tolerability. The most known members of SNRIs are venlafaxine and duloxetine. These molecules facilitate neurotransmission by blocking presynaptic reuptake of serotonin, noradrenaline, and to a lesser extent dopamine in the central and peripheral nervous systems.⁵ By this way, the amounts and effects of serotonin, noradrenaline, and dopamine are increasing in the synaptic cleft.^11,12 The receptors that belong to these neurotransmitters were also found in ocular tissues. Therefore, the ever-increasing use of SNRIs may cause a rise of the rate of different ocular side effects.

In this study, mydriasis was determined as the most remarkable effect of SNRIs on the anterior segment of the eye. The PD was found to be significantly larger in patients using SNRIs than the controls. The measurement of PD was the largest in patients using SNRIs for ≥6 months and the smallest in the control group.

The size of the pupil is regulated by the autonomic nervous system, so this outcome has not been surprising as SNRIs show their therapeutic actions through serotonin and noradrenaline. While the iris sphincter muscle is innervated by the parasympathetic nervous system, the iris dilator muscle is controlled by the sympathetic nervous system.¹³ Noradrenaline causes mydriasis through α-1 adrenergic receptors that are present on the iris dilator muscle. In addition, 5-HT7 receptors of serotonin have been identified at the sphincter of the pupil.¹¹ Stimulation of 5-HT7 receptors by serotonin leads to relaxation of the sphincter muscle and causes mydriasis.^12,14,15

There have been limited studies about SNRI-associated mydriasis. Howell et al.¹⁶ reported the rate of mydriasis as 36.6% in 260 cases of venlafaxine poisoning. In a recent study, including 325 eyes of 166 subjects, we reported that PD was significantly larger in patients receiving SSRIs for <6 months and ≥6 months than subjects not using any drugs. This mydriasis effect was independent of the duration of the treatment.¹⁷ However, in the present study, PD of patients using SNRIs for ≥6 months was larger than in patients using SNRIs for <6 months. Mydriatic effects of SNRIs might be more significant than SSRIs as noradrenergic action is more dominant with SNRIs. To sum up, it has been suggested that SNRIs and SSRIs could cause mydriasis because of their adrenergic effects, increased levels of serotonin, or weak anticholinergic activities.¹⁸ Fortunately, the subjects on drug treatments did not complain of any issues with vision due to the mydriatic effects of SNRIs.

Our PubMed search identified seven articles presenting cases of glaucoma associated with SNRI use; five were related to venlafaxine and two to duloxetine.^4–10 Generally, glaucoma could be divided into two broad categories; open-angle and angle-closure glaucoma. The difference between them depends on the status of the ACA, located near the junction of the iris and cornea.¹⁹ Within these seven SNRI-associated glaucoma cases, six of them (85.7%) were AACG. The patients who were predisposed to develop AACG usually had narrow ACAs,^19,20 so it is important to evaluate the width and anatomic variations of ACAs in patients using SNRIs to assess the risk for developing angle-closure glaucoma. If the angle had already been narrow, additional mydriasis could make the angle crowded and trigger a glaucomatous attack. In our study, ACAs and the other anterior segment parameters were evaluated by Scheimpflug imaging. According to Scheimpflug measurements, ACAs were between 25° and 55° and classified as wide or moderately open angles. We did not observe any AACG among 41 patients using SNRIs despite significant mydriasis. It was thought that mydriasis did not cause increase of IOP and secondary AACG because all patients in the study had wide or moderately open angles.

ACD was detected to be shallower in patients using SNRIs for ≥6 months than the control group, and in the correlation analysis, it was determined that ACA, ACD, and ACV values were decreasing, while the duration of SNRI treatment was getting longer. Mydriasis associated with SNRIs could cause an insignificant narrowing in the angles and accordingly ACD might decrease in long-term SNRI treatment. However, as the eyes had already wide or moderately open angles in this study, this insignificant decrease of the width of ACA and ACD did not cause angle closure or increase of IOP.

On the contrary, we determined that the median IOP was lower in patients using SNRIs than the control group. However, while this decrease was statistically significant between patients using SNRIs for ≥6 months and controls, it was not statistically significant between patients using SNRIs for <6 months and controls. Therefore, it was suggested that systemic use of SNRIs leads to decrease in IOP in depression patients especially during long-term treatment. Comparably, in a recent SSRI study, including 325 open-angle eyes of 166 subjects, it was reported that systemic use of SSRIs provided a decrease in IOP in short- and long-term use.¹⁷ Similar to these results, in 2015, Chen et al.²¹ reported that long-term use (>1 year) of SSRIs did not increase the risk of primary open-angle glaucoma or primary angle-closure glaucoma in depression patients. On the other hand, in 2017, Chen et al.²² stated that at higher doses and with long-term use, SSRIs might elevate the risk for glaucoma. However, comorbid systemic diseases and systemic medication were not excluded from the study and these factors might play a role in increasing IOP.²² These two studies, presented by Chen et al.,^21,22 were performed using data derived from the Taiwan National Health Insurance database. To our best knowledge, this is the first study evaluating the anterior segment parameters and IOP modifications based on a complete ophthalmologic examination in depression patients receiving SNRIs.

Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine that has been found mainly in the central and peripheral nervous systems and in several non-neuronal parts of the human body, including the eye. To date, seven different families of 5-HT receptors (5-HT1 to 5-HT7) and several subtypes of them have been identified.¹¹ Within these receptors, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT7, 5-HT5, and 5-HT4 are located in the human iris–ciliary body complex.^11,12,23,24 The existence of serotonin in aqueous humor, along with 5-HT receptors in the iris–ciliary body complex, suggests that serotonin may have a role in IOP regulation. Direct activation of 5-HT7 receptors has been shown to increase aqueous production, and stimulation of 5-HT2C receptors in the ciliary body indirectly enhances ciliary body blood flow, thus increasing the production of aqueous by ciliary processes.¹² The effect of 5-HT2 receptor agonist has not yet been fully investigated in humans; however, it was presented that 5-HT2A agonists had the ability to lower IOP in cynomolgus monkeys.^25–28 Moreover, aqueous humor dynamic studies performed by Sharif et al.²⁹ revealed that the 5-HT2 agonistic effect of a single topical ocular dose (300 μg) of cabergoline caused IOP reduction probably due to increase in uveoscleral outflow. Besides that, 5-HT1A agonists decreased IOP in rabbits, but had no effect in eyes of cynomolgus monkeys.³⁰ Although there are major species differences in the ocular hypotensive effects of 5-HT agonists,²³ these outcomes imply that SSRIs and SNRIs could cause a decrease in IOP.

Noradrenaline is the transmitter secreted from adrenergic neurons to sympathetic postganglionic nerve endings.³¹ Four main types of adrenergic receptors (α-1, α-2, β-1, and β-2) are identified. Noradrenaline is primarily an α-adrenergic agonist.³² α-1 receptors are located in the arterioles, dilator pupillae, and Müller muscle. Stimulation of α-1 receptors causes hypertension, mydriasis, and lid retraction. α-2 inhibitory receptors are located in the ciliary epithelium and stimulation results in increase in the outflow facility of aqueous humour.^31,32

Dopamine is an organic chemical in the catecholamine family released from postganglionic nerve fibers of the superior cervical dopaminergic ganglion in the aqueous humor and showed its effect by binding to five different types of DA receptors (DA1-5). DA1 and DA2 receptors have been identified in human eyes. DA1 receptors seem to be more expressed by the ciliary body, uveoscleral tissue, and trabecular meshwork. Stimulation of DA1 receptors increases production of aqueous humor and could cause an elevation in IOP. The expression of DA2 receptors in the anterior segment was confirmed, but the exact tissue has not yet been identified. DA2 and DA3 receptors are mainly located on postganglionic sympathetic nerve endings such as α-2 adrenergic receptors. DA2 agonists are responsible for a decrease in IOP by suppressing the production of aqueous humor.³³

As already mentioned, molecular events responsible for glaucoma are still not definitely known. Various molecules are able to regulate IOP: adrenergic, cholinergic, serotonergic, and dopaminergic systems are all involved.³³ Interestingly, SSRIs and SNRIs show their mechanisms of action through all the above-mentioned molecules (serotonin, noradrenaline, and dopamine) and their receptors. The probable ocular effects of receptors of serotonin, noradrenaline, and dopamine are summarized in Table 3. Moreover, a molecule makes its effect through more than one receptor as well receptor families and subtypes. Therefore, a molecule could have different effects on IOP through different receptors. The effect of the same molecule could even change in humans and different species. Because of that the studies investigating the association between SSRIs and IOP and also the current study, including SNRIs, have conflicted results.

Table 3.

Receptors of Serotonin, Noradrenaline, and Dopamine-Related to Intraocular Pressure and Pupil Size

Receptors	Localization of receptors in the human eye	Probable ocular effects
5-HT1A	Iris–ciliary body	Decreasing IOP^*^,23,29
5-HT2A	Iris–ciliary body	Decreasing IOP^**^,23,29
5-HT2C	Iris–ciliary body	Increasing IOP¹¹
5-HT7	Iris–ciliary body	Increasing IOP¹¹
	Sphincter pupillae	Mydriasis¹¹
5-HT5	Iris–ciliary body/ciliary epithelium	Unknown²³
5-HT4	Iris–ciliary body/ciliary epithelium	Unknown²³
α-1	Dilator pupillae	Mydriasis³⁰
α-2	Ciliary epithelium	Decreasing IOP³⁰
DA1	Ciliary body, UT, TM	Increasing IOP³²
DA2	Unknown	Decreasing IOP³²

Superscripted numbers indicate the reference numbers.

In rabbits, not in monkeys.

In rats and cynomolgus monkeys, not in cats and rabbits. It was reported that several 5-HT2A receptor agonists could affect human ciliary muscle and human trabecular meshwork and lower IOP.

5-HT, 5-hydroxytryptamine; IOP, intraocular pressure; TM, trabecular meshwork; UT, uveoscleral tissue.

It is a fact that SNRIs and SSRIs could cause AACG in eyes with narrow angles and peripheral iris abnormalities. Mydriasis associated with the use of these drugs tends to precipitate AACG in patients having predisposing factors such as anatomically narrow angle, shallow anterior chamber, hyperopia, large anteroposterior lenticular thickness, plateau iris, female gender, and older age.¹⁸ Mydriasis could cause angle closure either as a result of crowding of the angle by folds of the dilated iris or a result of a mid-dilated pupil causing pupillary block. Besides that, another mechanism of SNRI-induced acute angle closure could be the formation of supraciliary effusion as shown with ultrasound biomicroscopy in a patient using venlafaxine.⁷ Supraciliary effusion could cause AACG as a result of anterior displacement of the lens–iris diaphragm and cause myopic shift as a result of relaxation of zonules and thickening of the lens.^7,34 Therefore, patients at risk of angle closure should be advised ophthalmological screening, particularly gonioscopy, before starting antidepressant drug therapy.⁷

Footnotes

Acknowledgments

The authors are grateful to Emre Güler, MD, for his helpful comments and advice.

Author Disclosure Statement

No competing financial interests exist.

References

Mathers

C.D.

, and Loncar

Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 3:e442, 2006.

Pratt

L.A.

, Brody

D.J.

, and Gu

Antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief. 76:1–8, 2011.

Carvalho

A.F.

, Sharma

M.S.

, Brunoni

A.R.

, Vieta

, and Fava

G.A.

The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother. Psychosom., 85:270–288, 2016.

Shifera

A.S.

, Leoncavallo

, and Sherwood

Probable association of an attack of bilateral acute angle-closure glaucoma with duloxetine. Ann. Pharmacother., 48:936–993, 2014.

Botha

V.E.

, Bhikoo

, and Merriman

Venlafaxine-induced intraocular pressure rise in a patient with open angle glaucoma. Clin. Exp. Ophthalmol., 44:734–735, 2016.

Duarte

A.D.L.

, Silva

S.E.

, Melo

Acute angle closure glaucoma induced by duloxetine [abstract P3.14]. Paper presented at 10th European Glaucoma Society Congress, Copenhagen, Denmark, June 17–22, 2012.

de Guzman

M.H.

, Thiagalingam

, Ong

P.Y.

, and Goldberg

Bilateral acute angle closure caused by supraciliary effusions associated with venlafaxine intake. Med. J. Aust., 182:121–123, 2005.

Ezra

D.G.

, Storoni

, and Whitefield

L.A.

Simultaneous bilateral acute angle closure glaucoma following venlafaxine treatment. Eye (Lond). 20:128–129, 2006.

, Sanbrook

G.M.

, Malouf

A.J.

, and Agarwal

S.A.

Venlafaxine and bilateral acute angle closure glaucoma. Med. J. Aust., 176:241, 2002.

10.

Aragona

, and Inghilleri

Increased ocular pressure in two patients with narrow angle glaucoma treated with venlafaxine. Clin. Neuropharmacol., 21:130–131, 1998.

11.

Costagliola

, Parmeggiani

, Semeraro

, and Sebastiani

Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure. Curr. Neuropharmacol., 6:293–310, 2008.

12.

Richa

, and Yazbek

J.C.

Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 24:501–526, 2010.

13.

Raczak-Gutknecht

, Frąckowiak

, Nasal

, and Kaliszan

Mydriasis model in rats as a simple system to evaluate a2-adrenergic activity of the imidazol(in)e compounds. Pharmacol. Rep., 65:305–312, 2013.

14.

Costagliola

, Parmeggiani

, and Sebastiani

SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms. CNS Drugs. 18:475–484, 2004.

15.

Saletu

, and Grünberger

Drug profiling by computed electroencephalography and brain maps, with special consideration of sertraline and its psychometric effects. J. Clin. Psychiatry., 49:59–71, 1988.

16.

Howell

, Wilson

A.D.

, and Waring

W.S.

Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutivecases. Br. J. Clin. Pharmacol., 64:192–197, 2007.

17.

Gündüz

G.U.

, Parmak Yener

, Kılınçel

, and Gündüz

Effects of selective serotonin reuptake inhibitors on intraocular pressure and anterior segment parameters in open angle eyes. Cutan. Ocul. Toxicol., 37:36–40, 2018.

18.

Lachkar

, and Bouassida

Drug-induced acute angle closure glaucoma. Curr. Opin. Ophthalmol., 18:129–133, 2007.

19.

Martin

M.E.

, Patrianakos

, and Giovingo

Medication induced glaucoma. Dis. Mon., 63:54–57, 2017.

20.

Rüfer

, Schröder

, Klettner

, et al. Anterior chamber depth and iridocorneal angle in healthy white subjects: effects of age, gender and refraction. Acta. Ophthalmol., 88:885–890, 2010.

21.

Chen

H.Y.

, Lin

C.L.

, and Kao

C.H.

Long-term use of selective serotonin reuptake inhibitors and risk of glaucoma in depression patients. Medicine. 94:e2041, 2015.

22.

Chen

V.C.H.

, Ng

M.H.

, Chiu

W.C.

, et al. Effects of selective serotonin reuptake inhibitors on glaucoma: A nationwide population-based study. PLoS One. 12:e0173005, 2017.

23.

Sharif

N.A.

, and Senchyna

Serotonin receptor subtype mRNA expression in human ocular tissues, determined by RT-PCR. Mol. Vis., 12:1040–1047, 2006.

24.

Chidlow

, Hiscott

P.S.

, and Osborne

N.N.

Expression of serotonin receptor mRNAs in human ciliary body: a polymerase chain reaction study. Graefes. Arch. Clin. Exp. Ophthalmol., 242:259–264, 2004.

25.

May

J.A.

, McLaughlin

M.A.

, Sharif

N.A.

, Hellberg

M.R.

, and Dean

T.R.

Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys. J. Pharmacol. Exp. Ther., 306:301–309, 2003.

26.

Gabelt

B.T.

, Okka

, Dean

T.R.

, and Kaufman

P.L.

Aqueous humor dynamics in monkeys after topical R-DOI. Invest. Ophthalmol. Vis. Sci., 46:4691–4696, 2005.

27.

Sharif

N.A.

, McLaughlin

M.A.

, and Kelly

C.R.

AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist. J. Ocul. Pharmacol. Ther., 23:1–13, 2007.

28.

May

J.A.

, Dantanarayana

A.P.

, Zinke

P.W.

, McLaughlin

M.A.

, and Sharif

N.A.

1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity. J. Med. Chem., 49:318–328, 2006.

29.

Sharif

N.A.

, McLaughlin

M.A.

, Kelly

C.R.

, Katoli

, Drace

, Husain

, Crosson

, Toris

, Zhan

G.L.

, and Camras

Cabergoline: pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes. Exp. Eye Res., 88:386–397, 2009.

30.

Sharif

N.A.

Serotonin-2 receptor agonists as novel ocular hypotensive agents and their cellular and molecular mechanisms of action. Curr. Drug Targets., 11:978–993, 2010.

31.

Kanski

J.K.

, Bowling

, eds. Clinical Ophthalmology: A Systematic Approach. 7th ed. Edinburgh, NY: Elsevier Saunders; 2011.

32.

Langham

M.E.

Role of adrenergic mechanisms in development and therapy of open-angled glaucoma. Proc. Roy. Soc. Med., 64:622–628, 1971.

33.

Pescosolido

, Parisi

, Russo

, Buomprisco

, and Nebbioso

Role of dopaminergic receptors in glaucomatous disease modulation. Biomed. Res. Int., 2013:193048, 2013.

34.

Murphy

R.M.

, Bakir

, O'Brien

, Wiggs

J.L.

, and Pasquale

L.R.

Drug-induced bilateral secondary angle-closure glaucoma: a literature synthesis. J. Glaucoma., 25:e99–e105, 2016.