**2. Methodology**

We conducted an extensive literature search in the PubMed database from 1977 until 2021. The search was performed during March-May 2021 using the following terms: 'psychotropic medication', 'SSRI', 'citalopram', 'escitalopram', 'paroxetine', 'fluvoxamine', 'fluoxetine', 'sertraline', 'SNRI', 'duloxetine', 'venlafaxine', 'tricyclic antidepressants', 'clomipramine', 'amitriptyline', 'imipramine', 'doxepin', 'desipramine', 'nortriptyline' 'NDRI', 'bupropion', 'benzodiazepine', 'alprazolam', 'diazepam' 'antipsychotics', 'haloperidol', 'ziprasidone', 'risperidone', 'olanzapine', 'quetiapine', 'clozapine', 'topiramate' cross-referenced with 'glaucoma' and 'intraocular pressure'. We selected only articles written in English and based on clinical reports. After review of title, keywords and abstract, we retrieved 128 articles. Following removal of duplicates, full text assessment and then screening of the remaining articles for relevant studies that could be included in our paper, we finally included 90 articles divided as it follows: SSRI-7, citalopram-2, escitalopram-2, paroxetine-5, fluvoxamine-1, sertraline-1, SNRI-2, duloxetine-2, venlafaxine-5, tricyclic antidepressants-1, clomipramine-1, amitriptyline-1, imipramine-1, bupropion-4, benzodiazepine-2, diazepam-1, antipsychotics-8, haloperidol-3, risperidone-1, topiramate-40.

#### **3. Antidepressants**

#### *3.1. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)*

SSRIs and SNRIs are currently the first line drugs for the treatment of depression according to international guidelines [23,24]. SSRIs and SNRIs are the most prescribed drugs for depression and have the best overall tolerability and safety among all antidepressants. Also, these drugs are indicated as first choice for the treatment of anxiety, post-traumatic and obsessive compulsive disorders [25–27].

Since the discovery in 1974 of the first member of SSRI class, namely fluoxetine, continuing with sertraline, paroxetine, fluvoxamine, citalopram and escitalopram, these drugs have revolutionised the pharmacological therapy of depression. SSRIs mechanism of action implies a selective blockage of the reuptake of serotonin in the synaptic gap, therefore increasing the availability of the neurotransmitter and normalising the function of synapses. Until now seven families of serotonin receptors (5HT1-5HT7) have been

described as having a diffuse localisation, including eye structures. Experimental studies have determined that 5HT1A, 5HT2A/2C and 5HT7 are located in the iris-ciliary body complex. Stimulation of 5HT1A receptor reduces the IOP through the reduction of aqueous humour, while 5HT2A/2C receptors increase IOP by stimulation of the ciliary body blood flow, therefore they enhance the production of aqueous humour. 5HT7 receptors are responsible for mydriasis through the relaxation of the sphincter muscle and for rising IOP by increasing the production of aqueous humour [28,29]. In addition, mydriatic effects might appear due to their weak anticholinergic and noradrenergic actions [30]. These contrary possible effects of stimulating serotonin receptors have determined researchers to study the possible real relationship between glaucoma and SSRIs and SNRIs in order to shed some light on the field (Table 1, Figure 1).

The SNRI class has similar indications in psychiatry to SSRI, although they have been later on introduced, in the twentieth century. The SNRI class comprises venlafaxine (the first drug discovered from this class) and duloxetine. Their main mechanism is the inhibition of serotonin and norepinephrine reuptake, with weak dopamine transporter blockage. Noradrenaline is suggested to cause mydriasis and lid retraction through stimulation of α1 receptors; α2 inhibitory receptors from the ciliary epithelium can cause an increase in outflow facility of the aqueous humour while the blockage of these receptors by SNRI could reverse these effects leading to increased IOP [31]. The noradrenergic effect of SNRI is more dominant than the one of SSRI, suggesting a possible high risk of ACG. However, current data suggest that the systemic usage of SNRI could lead in long-term treatment to a decrease in the IOP. Another possible cause of mydriasis due to SNRI treatment would be the stimulation of serotoninergic receptors, mainly 5HT7, which in turn could lead to relaxation of the sphincter muscle [29,32].

**Table 1.** Mechanisms of ction of psychopharmacological drugs and their possible effect on intraocular pressure, pupil size and glaucoma risk.



#### **Table 1.** *Cont.*

↑, increased; ↓, decreased; IOP, intraocular pressure; 5HT, 5-hydroxytryptamine (serotonin); DA, dopamine; TNF, tumour necrosis factor; R, receptor.

**Figure 1.** Schematic representation of the relationship between antidepressant and antipsychotic drugs and the various ocular side effects related to glaucoma pathogenic mechanisms. AAP, atypical antipsychotics; IOP, intraocular pressure; AH, aqueous humour; TCA, tricyclic antidepressants; ↑, increased; ↓, decreased.

#### 3.1.1. OAG

Zheng et al. (2018) documented a potential negative association between SSRIs with primary open angle glaucoma (POAG). More precisely, Zheng et al. (2018) showed that POAG patients treated with systemic medication and under SSRI therapy have a significant lower risk of developing POAG that would require a procedure (patients undergoing treatment with SSRI were at an averagely 30% lower risk for the development of OAG than non-SSRIs users). An approximately 30% reduced risk was also associated with the SNRI class, although less significantly. Also, it has been suggested that there is a dose-response relationship with lower odds of POAG with greater days of treatment [41].

These findings are similar to another cross-sectional study in which three groups of patients with open angle eyes were compared (patients receiving SSRI for 1 week to 6 months, longer than 6 months, or patients under no treatment). IOP was lower in patients under SSRI treatment for less 6 month or more than 6 months in comparison with controls, but the pupil diameter was higher in the abovementioned groups [30].

In contrast, a rise in IOP was documented in the case of a patient with chronic OAG during the initiation of treatment with venlafaxine (a SNRI). After the patient complained of headaches, the starting dose of 225 mg was reduced to 75 mg. No symptoms were reported after the dosage was lowered. Although asymptomatic at 3 months, the IOP increased and the retinal nerve suffered damages [42].

#### 3.1.2. ACG

Regarding ACG, in a large population-based study it was associated with a recent exposure to antidepressants in older adults [43], whereas long exposure to SSRIs did not influence the risk of ACG [44]. Another study conducted by Chen et al. (2017) concluded that individuals under SSRIs therapy had a greater risk of glaucoma (OAG, PACG, glaucoma state, glaucoma suspicion, other forms of glaucoma) incidence. Also, long-term use (>365 days) and/or high dosage were associated with a greater risk of developing glaucoma with an additive effect when both variables were included [37]. In a case-control study that

included 1456 ACG patients, immediate SSRI users had 5.80 higher chances to develop ACG as compared to nonusers [45].

Conversely, a recent meta-analysis outlined that treatment with SSRIs was not associated with a higher risk of POAG or PACG and that IOP seemed to be lower in patients exposed to SSRIs. Also, Wang et al. (2018) concluded that pupillary diameter was higher in subjects under this type of antidepressant treatment [46].

Regarding the individual risk of each drug from the SSRIs class to cause glaucoma, current research is scarce and only a few case reports are available in the literature.

Citalopram-induced glaucoma (unilateral ACG) was reported in the literature in a case of drug overdose where the patient presented with blurred vision, pain and corneal oedema, in association with a high IOP. This patient was noted to have shallow anterior chambers in both eyes. After initial ophthalmologic treatment her IOP maintained normal without anti-glaucoma maintenance treatment [47]. Another case of citalopram induced bilateral symptomatic acute angle closure was reported in a patient with a history of 5 months of treatment with a normal dosage (the patient presented with blurred vision and headache) [48].

A case report of escitalopram-induced bilateral ACG described ciliochoroidal effusions after 4 weeks of treatment with a daily dose of 20 mg in a patient that presented with blurred vision. Ophthalmic examination revealed: high IOP, bilateral shallow anterior chamber, best corrected visual acuity was 20/40 bilaterally and a myopic shift of 4 dioptres over the current spectacle prescription. The condition was resistant to medical and surgical treatment but the patient recovered completely after escitalopram was discontinued [49]. Another article reported headache, blurred vision, vomiting, and photophobia (typical symptoms of AACG) in a patient that suddenly stopped escitalopram 1 month before the debut of symptoms. The risk factors identified in this case included hypertension (under control with beta-blockers) and escitalopram use for 1 year [50].

Patients under paroxetine therapy have reported ACG specific symptoms (i.e., loss of visual acuity or blurred vision) between 1 day and 4 months of treatment [51–55]. Interestingly, Sierra-Rodriguez et al. (2013) presented a case report of a unilateral visual loss due to chronic ACG under paroxetine treatment for 4 months. After discontinuation of paroxetine and laser iridotomy, the IOP normalised. Unfortunately, the patient resumed treatment on her own with consequent IOP rise despite patent iridotomies [53].

Regarding fluvoxamine, a patient with a previous history of narrow angle glaucoma (with no iridectomy) presented with daily headaches for 3 months and depressive symptoms (for anxiety the patient was taking lorazepam 2mg/day) and was prescribed fluvoxamine. After two months treatment the patient reported severe orbital pain and blurred vision (increased IOP and mydriasis). Despite specific therapy, IOP decreased only after the withdraw of the antidepressant [56].

Similar ACG symptoms were reported after three days of sertraline treatment, in a 64 year old Chinese woman with hypermetropia. It is worth to mention that Chinese ethnicity, old age, female gender and hypermetropia are risk factors for AACG [57].

Concerning SNRIs, the current literature describes only two and four ACG case reports involving duloxetine and venlafaxine, respectively.

The possible association of duloxetine with the appearance of ACG symptoms was reported in two female patients (46 and 81 years old, respectively). It is important to mention that the 81 years old patient was suffering from other comorbidities, hypermetropia and cataract [33,58].

Regarding venlafaxine, literature reports 4 possible cases of AACG after recent administration of this antidepressant, with the onset of symptoms ranging between 4 h and 10 days. In all reported cases, the patients were females of different age (between 35 and 70 years old) and had blurred vision as a common symptom [59–62].

Taking into account all the described current literature data, SSRIs and SNRIs have in general no association with either types of glaucoma or increased IOP. Moreover, it is worth emphasizing that long term treatment with SSRIs or SNRIs is associated with a decrease in the IOP, which suggests a possible protective effect of these drugs that needs further investigation. Of course, studies that assess the relationship between specific SSRIs or SNRIs and the risk of raised IOP and glaucoma are necessary in order to better characterise each drug regarding this possible side effect. The current case reports that describe a possible relationship between a specific SSRI or SNRI and ACG should warn the prescribers to closely monitor patients during treatment, especially the individuals with associated risk factors.

#### *3.2. Bupropion*

Bupropion is a noradrenaline and dopamine reuptake inhibitor (NDRI) and has been used since 1985 mainly as an antidepressant and more recently as adjuvant for smoking cessation. Bupropion is known to have anti-tumour necrosis factor (TNF) effects and a decreased activity on acetylcholine receptors that result in less anticholinergic side effects [63]. Studies hypothesised that IOP might be raised by TNF through increased caspase activity or mitochondrial dysfunction in the aqueous humour outflow channels. TNF synthesis is decreased by noradrenaline (β2 receptor) and dopamine (D1 receptor) activation [39,64]. All these effects led to the possible conclusion that bupropion could have some protective proprieties regarding IOP and glaucoma (Table 1).

A cross-sectional study that included patients over 40 years old investigated the relationship between self-reported glaucoma and self-reported bupropion use for at least 1 year. Masis et al. (2017) concluded that the usage of bupropion for longer than one year may be associated with a lower risk of self-reported glaucoma. Other covariates associated with high risk included Hispanic/Black ethnicity, increased age, cataract extraction, and diabetic neuropathy. One important limitation of this study is the lack of specificity in glaucoma type (ACG or OAG) [64].
