## 5 SSRIs and AAC: Potential Mechanisms  
Previous studies have shown a higher incidence of acute angle closure in patients initiating SSRIs treatment [12, 13]. [PERSON] et al. showed a 5.8-fold greater risk of AAC in patients starting therapy with SSRIs [12]; while results obtained by [PERSON] et al. revealedthat among the study population, 5.6% of participants of which 1.3% were SSRIs users have received antidepressants in the year preceding the onset of AAC [13]. Drugs that cause mydiraiss may induce AAC in the pupillary block mechanism, especially in anatomically predisposed eyes with occludable angles [10, 15]. A positive correlation between the long-term use of SSRIs and the incidence of mydiraiss has been observed [38, 39]. To date, both animal and human studies have demonstrated that SSRIs can cause an increase in IOP. A single intravenous administration of fluoxetine increased IOP in rabbits [40]; while [PERSON] et al. revealed that the three-month use of serntraline at a dose of 25-100 mg by patients without eye disease is associated with a statistically significant increase in IOP and cup-to-disc ratio [41]. Furthermore, an increase in IOP 2 h after a single oral dose of 20 mg of fluoxetine in 20 healthy volunteers aged 33-47 years [42], as well asin 11 individuals aged 32-70 years using SSRIs from one week to five years was shown [43]. Additionally, fluoxetine and its active metabolite, norfluoxetine, exhibit antagonistic properties at the 5-HT\({}_{\text{2C}}\) receptor, which may lead to co-stimulation of the dopaminergic and adrenergic pathways, and predispose to both-an increase in IOP and mydiraiss [44]. Table 2 explains the potential mechanisms linking the use of SSRIs and the occurrence of AAC in the pupillary block mechanisms. Besides pupillary block, AAC in individuals using SSRIs may be associated with the occurrence of UE, which leads to AAC by the anterior chamber becoming more shallow as a result of ciliary body edema and secondary forward displacement of the iris-lens diaphragm [11]. This phenomenon causes iridocormeal angle closure in the non-pupillary block mechanism. So far, two cases of bilateral AAC associated with the use of SSRIs have been described, both in patients receiving citalopram [18, 27]. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multirow{2}{*}{**Drug Name**} & **CYP 450** & \multirow{2}{*}{**Inhibited CYP 450**} & \multirow{2}{*}{**Peak Plasma Concentration **} & \multirow{2}{*}{**Protein Binding (\%)**} \\  & **In-Volved in Metabolism** & & & **(Hours)** & \\ \hline \multirow{3}{*}{Fluoxetine} & 2D6, 3A4/5, 2C9, 2C19 & 2D6, 2C19, 2C9, 3A4/5, 1A2 & 4–8 & 90 & 94 \\  & 2D6, 2C19, 3A4/5, & & & & \\  & 2C9,2B6 & 2C19, 2D6 \({}^{\text{a}}\) & 5–9 & 28 \({}^{\text{c}}\) & 99 \\ \multirow{3}{*}{Paroxetine} & 2D6, 3A4,1A2 & 2D6 & 6–10 & 50 & 95 \\  & 2C19, 1A2, 2C9, & 4–8 & 53 & 77 \\ \cline{1-1} \cline{3-5} \cline{5-5}  
CYP2D6, CYP2C19, and CYP3A4 polymorphisms may condition poor metabolism of SSRIs and their higher serum concentrations [46]. Concomitant use of CYP2D6 (e.g., chinidin, lewomepromazine, methadone), as well as CYP2C19 (e.g., isoniazid, proton pump inhibitors) and CYP3A4 (e.g., clarithromycin, isoniazid, verapamil) inhibitors may increase the plasma concentration of SSRIs [7; 32; 33; 47; 48]. Moreover, a high degree of binding of sertaline, paroxetine, and fluoxetine to plasma proteins can cause interactions with other highly protein-bound drugs [7; 31; 35; 36; 49] (Table 1) and can contribute to the higher risk of side-effects through increased serum concentration of SSRIs. On the other hand, due to the extensive metabolism of SSRIs in the liver, as well as their elimination via the kidneys, impaired function of these organs may reduce the elimination of SSRIs and their metabolites from the organism, which may increase the serum concentration of the drug [30]. Interestingly, nearly half of the reported cases were associated with the use of paroxetine.