**5. Antipsychotics**

Antipsychotic drugs are the cornerstone in the management of schizophrenia. Other indications for this category include schizoaffective disorder, bipolar disorder, delusional disorder, severe agitation, delirium, or psychotic features of major depressive disorder. They can be divided in two categories: typical or first generation (Haloperidol and Chlorpromazine as most known) and atypical or second generation (clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine, and aripiprazole). Typical antipsychotics manage the symptoms of psychosis through the blockage of the dopaminergic postsynaptic receptors, with additional histaminergic, α1 adrenergic and cholinergic blockade. Atypical antipsychotics are serotonin and dopamine antagonists with affinities for serotonin (5HT1A, 5HT2C, 5HT6, 5HT7), dopamine (D1, D3, D4) receptors, but also histamine (H1), muscarinic (M1, M2, M3, M4, M5) and adrenergic (α1, α2) receptors [78]. Most AAPs have in common a more potent 5HT2A action than dopamine (D2) antagonism. They are also partial agonists of 5HT1A. All these features contribute to the low extrapyramidal effects. Some other actions include the inhibition of muscarinic receptors (anticholinergic activity). A possible explanation for the association between antipsychotic drugs and glaucoma might be the cholinergic receptor blockade (muscarinic) [34,79] (Table 1, Figure 1).

Unfortunately, current research reports only the possible effects of antipsychotics on IOP and does not scrutinise the relationship between these drugs and OAG or ACG.

A cross-sectional study including 28 patients with schizophrenia showed that individuals under typical antipsychotics treatment had normal IOP [79]. This result is similar to the one reported by Reid et al. (1976). Moreover, Reid et al. (1976) study concluded that there was no IOP raise despite high dosage of typical antipsychotics [80]. Actually, not only haloperidol was found to lower IOP in glaucomatous eyes, but also it was proposed as a possible treatment for glaucoma [81–83].

Atypical antipsychotics (AAP) have cardiovascular side effects through the vasoconstriction determined by α1 adrenoreceptors blockage. Risperidone, clozapine, iloperidone and quetiapine may lead to hypotension via this mechanism [34]. Animal studies showed instilled APP into the eye determined a significant reduction of IOP observed after 1 h. Also, reduction of blood pressure occurred within 10 min after administration [84].

Reactive oxygen species (ROS) production is involved in the pathogenic mechanism of glaucoma. Risperidone was demonstrated to have the ability to decrease oxidative stress (OS) in schizophrenic patients by controlling the inflammatory response [85]. Other AAP that have been shown to decrease OS are clozapine and olanzapine [86]. However, the relationship between AAP, OS and glaucoma has been incompletely investigated. Therefore, future studies are necessary to elucidate this possible mechanism.

Several studies described that IOP elevation may lead to the inhibition of brainderived-neurotrophic factor (BDNF) which could have in turn a contributing effect to the visual loss. Risperidone and clozapine have been found to increase levels of BDNF [87–89].

There is some evidence that AAPs could enhance glaucoma through anti-muscarinic action. For example, clozapine and olanzapine have high affinity for muscarinic receptors (inhibition) and anticholinergic activity, which could possibly exacerbate glaucoma [90]). Thus, the actions of AAP by downregulating OS and neurotrophins may be unbalanced because of their anti- muscarinic receptor action. This observation could explain that, in general, AAPs are not associated with a glaucoma risk [66].

A cross-sectional analysis of 28 patients with schizophrenia and under antipsychotic therapy (4 on typical antipsychotics, 16 on AAP, and 8 on both types) provided interesting conclusions. More precisely, a raise of IOP has been found only in patients under AAP therapy, particularly all on ziprasidone. Ziprasidone is known to exert a potent serotoninergic (5HT2A) and dopaminergic (D2) affinity [79].

In conclusion, clinicians should be aware that second generation antipsychotics could have some implication in the variations of IOP, therefore a special attention should be paid to patients at risk and also when prescribing ziprasidone. Increased IOP could have no clinical significance in certain situations (e.g., minor increase or lower basal IOP) or could lead to the development or progression of glaucoma (OAG or ACG) depending on the characteristics of the patient. Typical antipsychotics are suggested to be safer in relation to a possible rise of IOP.

#### **6. Topiramate**

Topiramate is a sulpha-derivative monosaccharide and it is commonly prescribed for treatment of epilepsy and migraine prevention. Off label indications include eating disorders, obesity and tobacco dependence. Regarding psychiatric recommendations, the current literature describes the benefits of topiramate in weight gain prevention and metabolic dysfunction in schizophrenic patients as a result of treatment with certain antipsychotics (i.e., olanzapine, clozapine) [91].

Topiramate's mechanism of action involves inhibition of carbonic anhydrase, calcium channels, and glutamate receptors, as well as blockage of the sodium channels and stimulation of gamma-aminobutyric acid receptors. Topiramate is suggested to cause or worsen glaucoma due to an acute hypersensitivity reaction and alteration of osmotic status. The mechanism is suggested to involve ciliochoroidal effusion which leads to anterior rotation of the swelled ciliary body with anterior shifting of lens-iris diaphragm and consequently shallowing of the anterior chamber and narrowing of the angle [92,93]. All these changes may also occur in normal eyes. Given this fact, clinicians should be more vigilant and it is advisable to adopt a watchful waiting approach for all patients treated with topiramate.

In a retrospective study, Ho JD et al. (2013) reported a greater risk of developing ACG after topiramate therapy in the first month of treatment (hazard ratio 7.41 times higher than control subjects) [93]. Other data showed an increased risk of ACG, myopia, suprachoroidal effusion, and abnormal vision, all reversible with the discontinuation of treatment [94,95].

Numerous case reports found in the current literature described the association of topiramate treatment with the development of ACG. In 38 reported cases [96–130], patients under topiramate treatment developed ACG after a short time from the treatment initiation (the majority between 1 day and 14 days), most of them being adult women (27 women/ 38 patients) with an age ranging from 23 to 59 years. Table 2 presents a summary of current topiramate induced acute angle closure or AACG case reports (Table 2).


**Table 2.** A summary of currently reported topiramate-induced acute (primary) angle-closure or acute (primary) angleclosure glaucoma cases (in adult patients).


**Table 2.** *Cont.*

yo, years old.
