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REVIEW ARTICLE

CNS Drugs 2010; 24 (6): 501-526 1172-7047/10/0006-0501/$49.95/0

2010 Adis Data Information BV. All rights reserved.

Ocular Adverse Effects of Common Psychotropic Agents


A Review
Sami Richa and Jean-Claude Yazbek
Department of Psychiatry, Psychiatric Hospital of the Cross, Beirut, Lebanon

Contents
Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Eyelid and Keratoconjunctival Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1 Phenothiazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4 Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Uveal Tract Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Tricyclic Antidepressants (TCAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Selective Serotonin Reuptake Inhibitors (SSRIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.1 Generalities about SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.2 Mechanisms of Action of SSRIs and Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4.3 Evidence for a Role of SSRIs in the Occurrence of Mydriasis . . . . . . . . . . . . . . . . . . . . . . . . . 3. Accommodation Interference. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 TCAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Phenothiazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Glaucoma (Specifically Angle-Closure Glaucoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 TCAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 SSRIs (and Serotonin Noradrenaline [Norepinephrine] Reuptake Inhibitors [SNRIs]?) . . . . . . . . . . 5. Cataract and Pigmentary Deposits in the Lens and Cornea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Phenothiazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Retinal Abnormalities/Retinopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Phenothiazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Carbamazepine and Valproate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Sertraline (SSRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Other Drug-Induced Ocular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Decreased Lacrimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Increased Palpebral Aperture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 Palinopsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 Dystonia of Ocular Musculature/Oculogyric Crisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1 Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2 Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502 504 504 504 505 505 505 505 506 506 506 506 507 507 508 508 508 508 510 510 510 510 511 512 513 513 514 514 514 515 515 515 515 515 515 516 516

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7.4.3 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.4 SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5 Impairment of Eye Movements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.1 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.2 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.3 Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.4 Lamotrigine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.5 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6 Exophthalmos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.7 Papilloedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8 Abnormal Colour Perception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9 Impaired Contrast Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9.1 Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9.2 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

All psychotropic medications have the potential to induce numerous and diverse unwanted ocular effects. Visual adverse effects can be divided into seven major categories: eyelid and keratoconjunctival disorders; uveal tract disorders; accommodation interference; angle-closure glaucoma; cataract/ pigmentary deposits in the lens and cornea; retinopathy; and other disorders. The disorders of the eyelid and of the keratoconjunctiva are mainly related to phenothiazines and lithium. Chlorpromazine, at high dosages, can commonly cause abnormal pigmentation of the eyelids, interpalpebral conjunctiva and cornea. It can also cause a more worrisome but rarer visual impairment, namely corneal oedema. Lithium can rarely lead to a bothersome eye irritation by affecting sodium transport. Uveal tract problems are mainly associated with tricyclic antidepressants (TCAs), typical antipsychotics, topiramate and selective serotonin reuptake inhibitors (SSRIs). TCAs, typical antipsychotics and SSRIs can all cause mydriasis that is often transient and with no major consequences, but that can promote closure of angles in susceptible patients. Topiramate has been frequently associated with a number of significant ocular symptoms including acquired myopia and angle-closure glaucoma. Problems with accommodation are related to TCAs and to low-potency antipsychotics. TCAs cause transient blurred vision in up to one-third of patients. Angle-closure glaucoma is a serious condition that has been mainly associated with TCAs, low-potency antipsychotics, topiramate and, to a lesser extent, SSRIs. When patients with narrow angles are given TCAs, they all appear to experience induction of glaucomatous attacks. Antipsychotics and SSRIs may lead to an added risk of developing angle-closure glaucoma, but only in predisposed eyes. Topiramate can lead to an allergic-type reaction whereby structures of the lens and ciliary body are displaced, which results in angle-closure glaucoma. Cataractous changes can result from antipsychotics, mainly from high dosages of chlorpromazine or thioridazine. These two drugs, when used at high dosages and for prolonged periods, frequently cause lenticular opacifications.

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Retinopathy has been shown to be related to high dosages of typical antipsychotics, mainly chlorpromazine and thioridazine. The frequency of occurrence of retinal effects seems to be proportional to the total amount of drug used over a long period of time. Other visual problems of special concern are the ocular dystonias, other eye movement disorders, and decreased ability to perceive colours and to discriminate contrast. Ocular dystonias can occur with antipsychotics (especially high-potency ones), carbamazepine (especially in polytherapy), topiramate and, rarely, with SSRIs. Disturbance in various eye movements is frequently seen with benzodiazepines, antiepileptic drugs and lithium. Impairment in the perception of colours and the discrimination of contrasts has been shown to occur not uncommonly with carbamazepine and lorazepam. Thus, typical antipsychotics, TCAs, lithium, benzodiazepines, carbamazepine, topiramate and SSRIs appear to produce most of the currently recognized ocular problems. Psychiatrists, ophthalmologists and patients need to be aware of and prepared for any medication-induced adverse effect. Early prevention and intervention can avoid most of the serious and potentially irreversible ocular toxicities.

Any psychotropic medication may potentially lead to harmful ocular adverse effects.[1-4] Depending upon the drugs individual idiosyncrasies, dosages and interactions with the specific biological milieu of individual patients, ocular adverse effects may range from nonexistent to overwhelming, from barely noticeable to severely handicapping, and from transient and reversible to irreversible despite eventual interventions. Scientists try to assess drug toxicity by first performing numerous experiments using animal models and then trying the drug in a healthy human population. Nonetheless, this approach does not guarantee that the tested drug will not exhibit adverse effects other than those already detected in preliminary trials.[4] The eye seems to be the second most frequent body organ to manifest drug toxicity, after the liver.[2] Many factors render the human eye sensitive to psychotropic treatments. Firstly, the visual apparatus consists of numerous tissues derived from different origins. The retina, for instance, is a direct extension of the human brain in the eyes. Secondly, the eye has a relatively small total mass and possesses an extensive and rich blood supply. Thirdly, tissues such as the retina and optic nerve exhibit a very high metabolic rate.
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On the other hand, a considerable proportion of psychiatric patients take medications on a long-term basis while frequently failing to report and describe their ocular symptoms promptly and thoroughly.[1,3] Moreover, research in the field of ophthalmological complications of psychoactive medications is relatively scarce or not very well structured; causality is rarely sought and confounding variables seem to influence some of the study results. As we will try to show, the vast majority of drug-induced ocular disorders could easily be prevented, monitored and even reversed, provided that clinicians and patients become aware of and watchful for ocular signs and symptoms. This article reviews ocular adverse effects of all the medications commonly used, to date, for the treatment of psychiatric conditions. It is based on papers published in English between the 1960s and July 2008 and indexed by PubMed. Searches included combinations of keywords such as eye, eye effect, ophthalmologic effects, ocular effects, ocular side-effects, antipsychotic, neuroleptics, mood stabilizers, antiepileptic, lithium, benzodiazepine, antidepressant, SSRI, TCA, psychotropic, psychiatry and psychiatric medication. These preliminary searches,
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along with other searches based on the reference lists of certain pertinent articles, led to hundreds of papers. Nonetheless, many articles were excluded for several reasons. A large proportion of papers was excluded because they involved medications that were not commonly used in the treatment of psychiatric conditions per se (e.g. antiepileptics with no indication in psychiatry such as vigabatrin, agents used for treating adverse effects of psychiatric medications such as pure anticholinergics, pure antihistaminergics and muscle relaxants, etc.). We also excluded studies listed as a PubMed result but not related to our subject matter (e.g. antidepressant and sleep cycle). Also, articles that were merely a repetition of previous papers and that provided no new discoveries, small case reports/studies in vitro or in animals not (yet) extrapolated to humans were generally not included. After having begun with a systematic literature search and then having applied critical judgement as to whether an article was relevant to our specific theme of investigation, around 100 articles were found to be pertinent and laid the ground for our investigation. One pharmacology book[5] was sometimes used to enrich the parts of our writing related to indication and mechanism of action of psychotropic agents, especially when the reference articles fell short of providing enough data in these areas. The book was not used to make statements about adverse effects. This article is structured by sections outlining the major drug-induced ocular disorders. Suspected causative medications are discussed in each section; their mechanism of action, degree of implication and extent of eye impact are reported as much as current evidence allows. Recommendations for appropriate ophthalmological monitoring and referrals are proposed whenever deemed necessary. 1. Eyelid and Keratoconjunctival Disorders The eyelids are made of a very thin skin along with specialized tissues that serve to protect and lubricate the eyes. Like the eyes, they can be involved in drug toxicity and related insults.[2] The
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cornea is the transparent anterior dome of the eye that covers the iris, pupil and anterior chamber. It is one of the most sensitive tissues of the body. The conjunctiva consists of a clear membrane that covers the visible part of the sclera and the inner surface of the eyelids. Keratopathy is a term referring to any pathological state of the cornea, which is the subject of discussion in the current section; corneal deposition of substances is presented in section 5.
1.1 Phenothiazines

The phenothiazine family of typical antipsychotics is one of the most studied groups of psychotropic agents and causes numerous adverse effects such as ocular and dermatological complications. Chlorpromazine was marketed in the early 1950s and has been used very extensively, especially before the advent of atypical antipsychotics. This drug, when used in high dosages, commonly results in abnormal pigmentation of the eyelids, interpalpebral conjunctiva and cornea (and lens, as discussed in section 5.1).[2] It is noteworthy to report the epithelial keratopathy that has been described by many authors in the literature. This condition seems to be secondary to large dosages (>2 g/day) of the drug, and consists of swirling lines or fine streaks in the corneal epithelium.[6-8] It is not a serious condition because it does not cause visual impairment and tends to disappear, or at least diminish, after cessation of the drug. A more worrisome complication of phenothiazines is the potential secondary corneal oedema. It rarely occurs, but it causes severe visual impairment that can become irreversible if not promptly identified and if the drug (usually chlorpromazine) is not withdrawn. Indeed, the corneal endothelial cells can sustain irreversible phototoxic lysis secondary to chlorpromazine.[3,9]
1.2 Benzodiazepines

Benzodiazepines are commonly used in psychiatry for the management of anxiety, insomnia, agitation and many other states. Allergic conjunctivitis has been reported once with diazepam.[10] Since this reaction was only noted with
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diazepam, it is likely that other commonly used benzodiazepines (e.g. clonazepam, lorazepam) are not associated with ocular allergy.[1] A change from diazepam to another benzodiazepine should resolve the problem if it occurs.
1.3 Lithium

Lithium is one of the oldest mood stabilizers; its place in psychiatry is still prominent and it can also be particularly helpful for conditions other than bipolar disorders. Its mechanisms of action are still unclear, but they are believed to be complex: alteration of sodium transport across nerve and muscle cell membranes, actions on intracellular signalling, stabilization of nerve cell membranes, etc.[5] One bothersome potential adverse effect of lithium is eye irritation, usually noted during the first few weeks of treatment.[11] The explanation behind this uncommon finding could be the increased sodium content of the lacrimal fluid, a phenomenon probably related to the presence of sodium-chloride co-transport in human lens epithelial cells, as recently demonstrated by Lauf et al.[12] This problem is usually shortlived and can be resolved even faster if the patient uses over-the-counter artificial tears as needed.
1.4 Carbamazepine

myoepithelium, and is a continuation of the ciliary body. The sphincter pupillae is found around the pupil, within the iris stroma, and is made of smooth muscle.[2] These two kinds of muscles radial functional dilator and circular sphincter papillae control the size of the pupil. It is generally accepted that the former is innervated by the parasympathetic nervous system and the latter by the sympathetic nervous system.[14] Sympathetic stimulation of a1-adrenoceptors causes contraction of the radial muscle, and subsequent active mydriasis. It is important to note that the exact nature of the receptors involved in the control of pupillary diameter is still poorly understood. However, there is an acceptance for the role of a1-adrenoceptors and more specifically of a1A- and a1L-adrenoceptor subtypes in mediating neurally evoked mydriasis in humans.[15] Conversely, parasympathetic stimulation of muscarinic receptors causes contraction of the circular muscle and subsequent active miosis. Passive mydriasis occurs when the circular muscle relaxes. It is also believed that a2-adrenoceptors play a role in at least one of the mechanisms of mydriasis by inhibiting parasympathetic activation of the constrictor muscles in the iris; this would be the result of the activation of postsynaptic a2-adrenoceptors at the Edinger-Westphal nucleus.[16]
2.1 Tricyclic Antidepressants (TCAs)

Carbamazepine belongs to the widening class of antiepileptic medications that have a role in the management of psychiatric conditions. It is used for the treatment of affective disorders.[5] A single case report possibly implicating carbamazepine in the genesis of conjunctival squamous metaplasia was published in 2007.[13] The 22-year-old patient who was shown to exhibit this condition (thought to be reversible) did not report any substantial symptoms. Causality could not be proven, and carbamazepine is still to be considered very safe for the conjunctiva. 2. Uveal Tract Disorders The iris, ciliary body and choroid make up the uveal tract. The ciliary body is formed by smooth muscle fibres. On the posterior side of the iris, a functional dilator pupillae muscle is formed from
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Tricyclic antidepressants (TCAs) readily cause several ocular adverse effects, most of which present in the acute phase of treatment.[17,18] The two most common effects are mydriasis and cycloplegia. When mydriasis occurs in an individual who has not become tolerant to the effect of TCAs on the ocular smooth muscles, blurred vision and/or presbyopia (disturbance of near vision) can happen. TCA-induced mydriasis generally causes non-severe and transient visual disturbances. Cycloplegia (discussed in section 3) results from a paretic effect on the ciliary muscle. Both mydriasis and cycloplegia seem to be due mainly to the anticholinergic action of TCAs. Other mechanisms cannot be excluded: blockade of noradrenaline (norepinephrine) uptake and a-adrenergic receptors are of importance.[18] These
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two conditions improve with time. If they are too bothersome, pilocarpine 1% solution (1 drop four times daily), cholinergic agents such as bethanechol chloride (1030 mg/day) or even prescription lenses can be helpful.[1]
2.2 Antipsychotics

Antipsychotics with strong anticholinergic and/or antiadrenergic actions, e.g. chlorpromazine and fluphenazine, can also lead to mydriasis and cycloplegia.[8]
2.3 Topiramate

Initially designed for use as an antiepileptic, this sulpha-based drug seems to have several properties that make it useful in psychiatry. The off-label utilizations are mainly in the control of bipolar affective disorders, binge eating and drug-induced weight gain.[5] Mechanisms of action of this medication are believed to be multiple and they include, among others, blocking of voltage-sensitive sodium channels, inhibiting glutamate release, potentiating the activity of GABA, and weakly inhibiting carbonic anhydrase enzyme.[5] Topiramate interferes with ionic concentrations within various tissues (including the lens) by influencing the movement of sodium and chloride.[19,20] This action on ionic movements, along with a possible hypersensitivity effect on the uveal tract and lens (possibly mediated by prostaglandins[21]), are proposed mechanisms for the development of acute myopia (as well as acute angle-closure glaucoma).[19-21] Indeed, topiramate can lead to idiosyncratic swelling of the ciliary body, and even cilio-choroidal detachment.[2,4,19-22] These effects can result in refractive visual disturbance, namely myopia. The WHO has identified at least 13 ocular adverse effects of topiramate, and classified them into three categories: certain, probable/likely and possible.[22] A certain effect is defined as being a clinical event occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals y. A probable/ likely effect is defined by being a clinical event occurring with a reasonable time sequence to
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administration of the drug and unlikely to be attributed to concurrent disease or other drugs y.[22] Abnormal vision and acute myopia (up to 8.75 diopters) belonged to the certain category, whereas suprachoroidal effusions belonged to the probable/likely class of effects.[22] Both occur in a small but substantial proportion of patients, within a few weeks of initiation of treatment and even with usual therapeutic doses. In 2001, the US FDA reported 23 cases of ocular symptoms with topiramate, from postmarketing data from around 825 000 individuals taking the drug.[23] Myopia secondary to topiramate is considered transient; it reverses after discontinuation of the medication. Its mechanism is not fully understood, but could include uveal tract swelling, forward rotation of the lens and accommodation spasm.[4,19,20,22] Uveal tract swelling and displacement of the lens have been well documented by Rhee et al.[24] by means of slit-lamp photographs and ultrasound examinations. Other events possibly linked to topiramate are discussed in following sections (especially section 4).
2.4 Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) have been shown to be related to multiple, complex and probably interrelated phenomena affecting the eye, including mydriasis.[25]
2.4.1 Generalities about SSRIs

SSRIs are the most widely prescribed antidepressant and antianxiety treatments. Since their marketing authorization in the 1980s, they have been used by millions of people worldwide.[25] Fluoxetine, fluvoxamine, citalopram, escitalopram, paroxetine and sertraline are all SSRIs. They mainly act by enhancing serotonergic transmission in the CNS; this effect is thought to be secondary to the inhibition of serotonin reuptake at the synapse level. These medications generally have excellent safety and tolerability profiles; however, they are no longer considered to be purely and specifically serotonin reuptake inhibitors. Hence, other therapeutic as well as
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adverse effects are being discussed in the literature. Of particular interest are the possible adverse effects of SSRIs on the eyes; these include mydriasis, increased intraocular pressure (IOP), glaucoma and oculogyric crisis.[25-27]
2.4.2 Mechanisms of Action of SSRIs and Serotonin

2.4.3 Evidence for a Role of SSRIs in the Occurrence of Mydriasis

SSRIs have multiple actions on the central and the peripheral nervous system, as well as on the smooth muscle fibres, including the dilator and constrictor muscles of the eye. Their therapeutic actions rely on the inhibition of the serotonin transporter and on the consequent increase in available serotonin in synapses. SSRIs also lead to an increase in serotonin in other areas of the body such as blood and eye tissues. Serotonin interacts with various types of serotonin receptors. There are seven families of serotonin receptors (5-HT1 to 5-HT7), and it is known that different subtypes exist within several of these families.[25,27] Some SSRIs are also capable of interfering with the cholinergic, noradrenergic and dopaminergic systems, either directly or indirectly.[5] For instance, fluoxetine has antagonistic properties at 5-HT2C receptors, which could indirectly increase noradrenaline and dopamine neurotransmission.[5] Paroxetine has direct anticholinergic actions, and it mildly blocks noradrenaline reuptake. Sertraline has some ability to block dopamine reuptake. The serotonin receptors that have been found to be involved in eye functioning are 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7.[25,27-32] All these receptors are implicated in the dynamics of IOP; their involvement in increased IOP and glaucoma are discussed in section 4. The effect of serotonin on 5-HT7 receptors located in the sphincter of the pupil leads to the activation of adenylate cyclase, an increase in cyclic adenosine monophosphate, and to subsequent relaxation of the muscle (passive mydriasis).[25,30] To sum up, SSRIs may cause mydriasis via at least two mechanisms:  noradrenergic or anticholinergic effects resulting in pupillary dilatation;  stimulation of the 5-HT7 receptors located within the iris musculature and the subsequent relaxation of the sphincter muscle of the pupil.
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Visual adverse effects of SSRIs have been, until lately, considered uncommon.[25] However, it is now believed that mydriasis and increased IOP are non-rare events. It is noteworthy that in several studies involving patients treated with SSRIs, one of the main reasons for patients to leave the study was the appearance of visual abnormalities.[33-36] In this section, we will try to focus on the evidence for a role of SSRIs in the induction of mydriasis; the evidence concerning glaucoma is tackled in section 4.5. However, it seems that mydriasis, increased IOP and glaucoma are strongly interrelated phenomena.[25,37-43] The problem that one encounters when trying to review the literature for specific kinds of visual effects (e.g. mydriasis, increased IOP and glaucoma) of psychotropic agents including SSRIs is that the studies seldom describe the visual effects in detail; they only mention vague terms such as visual disturbances or visual symptoms. For instance, in two clinical trials,[34,35] blurred vision was reported in 210% of participants taking SSRIs. Preskorn, in 1995,[33] reported visual disturbances in a significant proportion of SSRI-treated patients: 1.0% for patients taking fluoxetine, 2.2% for those taking paroxetine and 2.1% for those taking sertraline; on the other hand, 0% of patients taking fluvoxamine reported such symptoms. In addition, there is a general tendency for researchers to search for and report more serious symptoms (like attacks of glaucoma) rather than asymptomatic mydriasis.[2,25] As we will see in section 4.5, there is a limited number of papers[25,37-44] that strongly incriminate SSRIs in the possible induction or exacerbation of increased IOP, but what is extremely important to recognise is that it seems there is a central role for passive mydriasis in the pathogenesis of intraocular hypertension.[25,37-44] Few studies have specifically assessed the mydriatic effect of SSRIs, but the ones that have done so have usually reached a conclusion that SSRIs do have a mydriatic effect.[27,45-47] To our knowledge, the studies that have addressed and measured the mydriatic effect of SSRIs in humans have been performed by Saletu and
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Grunberger in 1988,[45] Deijen et al. in 1989,[46] Ramaekers et al. in 1995[47] and Schmitt et al. in 2002.[27] All these researchers have found that SSRIs such as sertraline, paroxetine, fluoxetine and citalopram induce significant pupillary dilatation. Saletu and Grunberger[45] were the first to study such an adverse effect of sertraline usage. Deijen et al.[46] studied the mydriatic effect of paroxetine in healthy volunteers. Ramaekers et al.[47] studied this effect in fluoxetine recipients compared with a placebo group. Schmitt et al.[27] found that both sertraline and citalopram, compared with placebo, led to a rapid and steady increase in pupil diameters; this increase reached a maximum 5 hours after the first administration of the drug, was around 1 mm in magnitude and remained stable all through the duration of treatment (15 days). The increase of pupil diameter brought about by sertraline was no different from that induced by citalopram. The authors of this study were the first to demonstrate a mydriatic effect for citalopram. They made suggestions for subsequent researchers who would eventually study any CNS effect of SSRIs to try to take into account the putative mydriatic effect of SSRIs. Indeed, they have shown that, after controlling for the mydriatic effect of sertraline and citalopram, the critical flicker fusion (CFF) threshold was decreased secondarily to these medications. CFF threshold denotes the frequency at which a flickering light is seen as steady. A decrease in this CFF value could be interpreted as a sedative action on the CNS. These findings would indicate that SSRIs, through complex serotonergic effects, could affect both pupil reaction and CNS activity in a way that has to be better understood.[27] However, these effects do not seem to cause any serious visual disturbance and are not considered dangerous. Therefore, it appears that SSRIs do induce mydriasis. This effect does not seem to cause major visual discomfort or problems, unless of course it becomes associated with a dramatic increase in IOP and with eventual glaucomatous attacks. The mydriatic effects of SSRIs are likely to be reversible after cessation of therapy, especially if they do not become complicated by angle-closure glaucoma. Formal ophthalmological
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examination for individuals at risk for angleclosure glaucoma and who are taking SSRIs is advisable; it does not seem to be necessary for the evaluation of mydriasis per se. 3. Accommodation Interference Accommodation refers to the process by which the eye increases optical power to maintain a clear image of the object on the retina.
3.1 TCAs

TCAs are known to cause blurred vision. This condition is mainly due to the anticholinergic effect of these medications and is usually a consequence of both cycloplegia and mydriasis.[1] Cycloplegia is an accommodation interference whereby the affected eyes cannot focus on near objects. Blurred vision occurs in roughly onethird of patients who are in the initial stages of treatment with TCAs. The patients usually develop tolerance to this effect, and vision spontaneously returns to normal after some time elapses. If the vision remains blurry, and if the TCA needs to be maintained, topical cholinergic agonists (such as pilocarpine) could be helpful.[3] Of course, the weaker the TCA at the anticholinergic level, the less likely and the less severe are the visual symptoms.
3.2 Phenothiazines

Antipsychotics with powerful anticholinergic and/or antiadrenergic properties (such as the phenothiazines) also have the propensity to decrease ocular accommodation.[9] The management is similar to that induced by TCAs (see section 3.1). 4. Glaucoma (Specifically Angle-Closure Glaucoma) Glaucoma is currently defined as a heterogeneous group of conditions that have in common a characteristic optic neuropathy and visual field defects, for which increased IOP is the major risk factor.[2,48] IOP results from a balance between aqueous humour production and drainage
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in the anterior chamber; its average normal value is 14.5 mmHg (range 921 mm Hg). The pressure can increase in a detrimental fashion mainly if an obstruction occurs at the level of fluid circulation. Many kinds of glaucoma exist, for example, open-angle versus angle-closure, and primary (with no identified precipitant) versus secondary (e.g. drug-induced). The term angle in glaucoma refers to the irido-corneal angle of the anterior eye chamber. Indeed, if this angle gets too narrow, fluid drainage from the chamber gets seriously impaired and an alarming rise in IOP usually ensues. As far as psychotropic medications are concerned, only drug-induced angleclosure glaucoma is of direct relevance, since psychotropic drugs seem not to affect other glaucomatous conditions.[1-4,9,22,23,25,28,48] Several psychotropic agents have been suspected to be involved, to varying degrees, in the precipitation of angle-closure glaucoma, but only in predisposed individuals (see table I). Risk factors for angle-closure glaucoma mainly consist of two kinds: anatomically narrow angle and use of drugs that interfere with IOP (table I).[48] Unfortunately, drug package inserts are oftentimes confusing to patients and clinicians; they tend to simply state glaucoma as a contraindication without further precision concerning the kind of glaucoma, mechanism of action on the eye and practical recommendations.[48] Drugs that produce significant anticholinergic effects (e.g. TCAs) are clearly implicated (via mydriasis) in the induction of angle closure or in the worsening of chronic angle-closure glaucoma. Other
Table I. Risk factors for acute angle-closure glaucoma Race (Inuit, Asian and Hispanic are at highest risk) Narrow angle (of anterior chamber) Shallow anterior chamber depth Hyperopia Small eye (nanophthalmos) Previous angle closure in fellow eye Family history positive for angle closure Increasing age (elderly) Female sex Use of any substance that causes papillary dilatation/excitatory situations

drugs and other mechanisms also seem to play a role in this pathology: pupillary dilatation, forward displacement of the iris-lens structures, and swelling of the ciliary body are all mechanisms by which a substance can induce angle-closure glaucoma. Regardless of the mechanism of angleclosure glaucoma, this condition is an ophthalmological emergency that should be promptly recognized and treated. It is one of the most painful conditions of the body and, if left unattended, irreversible visual loss in the affected eye will follow.[2,3] Treatments include antiglaucoma medications (e.g. pilocarpine, topical b-adrenoceptor blockers and osmotic diuretics), laser iridectomy and more interventionist surgery.[2,48] Of course, the surest approach is preventive in nature and consists of: (i) considering risk factors; (ii) avoiding agents that are known to induce glaucomatous changes; and (iii) performing baseline and follow-up ophthalmological evaluations, especially in at-risk populations. Sometimes, preventive antiglaucoma therapies can be extremely valuable.[3] Visualization of the anterior eye chambers in order to exclude dangerously narrow angles could be performed by the eye specialist by means of very precise equipment (slit-lamp biomicroscope, gonioscopy, etc.), or by other clinicians by means of simple but less accurate methods such as the oblique penlight illumination test.[1,48] In the latter simple test, light is shed, aiming at the nose, perpendicularly to the visual axis. If the entire iris is illuminated, the chamber is probably wide. If, on the other hand, the nasal iris is covered by shadow, a narrow chamber cannot be excluded and further investigation is mandatory. In fact, people with narrow anterior chambers but who are adequately treated by antiglaucoma agents (or who have undergone laser iridectomy) and patients with safely wide anterior chambers can receive almost any psychotropic treatment without restriction, provided they are being followed up.[3] In addition, clinicians and patients should be aware of and alert for concerning signs and symptoms of angleclosure glaucoma: sudden onset of severe eye pain, lacrimation, eye redness, lid oedema, clouding of vision/decreased vision, brow pain, photophobia, headache, anxiety symptoms, nausea,
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vomiting, decreased heart rate and diaphoresis. Not all these events necessarily occur in all patients, but sudden eye pain, redness and visual disturbance are the most probable to occur during an angle-closure attack. The systemic symptoms may be so severe and so varied as to mislead the patients and their healthcare professionals.[1-3] The glaucomatous attack usually happens in one eye; however, bilateral ocular involvement can occur, and its impact is even more devastating and more visually hazardous than the monocular attack.[48]
4.1 TCAs

ties.[1] In practice, however, benzodiazepines are not seen to precipitate acute angle closure. Only diazepam, and only in one official case report, was suspected as having caused angle-closure glaucoma.[51] We can thus say that benzodiazepines (especially those other than diazepam) are safe drugs in relation to glaucoma. Patients who do not have chronic glaucoma and who do not have narrow angles need not worry about induction of angle closure while taking these drugs.
4.4 Topiramate

TCAs can induce glaucomatous attacks in predisposed individuals. This is mainly due to the anticholinergic action of these medications, and to the subsequent mydriasis and cycloplegia.[17,49,50] In 1994, Ritch et al.[49] administered oral imipramine to four patients with narrow angles; these routinely prescribed doses of TCA triggered acute angle-closure glaucoma. Thus, TCAs should be prescribed with great caution in patients with narrow angles, and these patients need to be monitored by an ophthalmologist.[49]
4.2 Antipsychotics

Theoretically, high doses of typical antipsychotics with significant anticholinergic and antiadrenergic action such as the phenothiazines can be a risk factor for angle-closure glaucoma. Mechanism, presentation of attacks and management would be similar to what we have described above.[9] Nonetheless, antipsychotics have a relatively weaker action on the ocular smooth muscle compared with TCAs, and the risk of them causing glaucoma is much lower than that of the TCAs.[3] In fact, we found no reports in the literature about antipsychotic-induced angleclosure glaucoma.
4.3 Benzodiazepines

In theory, benzodiazepines could be a risk factor for angle-closure glaucoma, since they can cause some relaxation of the sphincter pupillae and they can have mild anticholinergic proper 2010 Adis Data Information BV. All rights reserved.

Only a minority of patients using topiramate develop secondary glaucoma. There is still controversy as to the precise mechanism that explains the occurrence of such a complication.[2,52] It is thought that, in addition to the deleterious effect on ionic movements, this sulpha-based molecule can produce an allergic reaction. These effects on ocular tissues could cause swelling of the lens and the ciliary body. Significant displacement of the lens-iris complex with subsequent shallowing of the anterior chamber could ensue; this might culminate in acute angle-closure glaucoma.[2,4,24,48,53,54] More than 114 cases of topiramate-induced angle-closure glaucoma have been documented to date, including 86 cases of acute-onset glaucoma (83 bilateral and 3 unilateral), 17 cases of acute bilateral myopia (up to 8.75 diopters) and 9 cases of suprachoroidal effusions. Onset of glaucoma was acute, and occurred between days 1 and 49 (mean 7 days) after topiramate initiation; 85% of cases developed in the first 2 weeks.[2,4,22,48,53] Seven patients were reported to have gone blind secondary to this glaucomatous condition associated with topiramate. The WHO has identified this possible deleterious effect of topiramate on eye pressure and angle closure.[22] Many patients with topiramateinduced glaucoma had blurred vision as the initial symptom.[22,53-55] Fraunfelder and Fraunfelder[22] have proposed a series of recommendations to manage topiramate-induced glaucoma:  immediate consultation with the prescribing physician;  withdrawal of topiramate as soon as possible;
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 expect the occurrence of systemic adverse effects when the dosage of topiramate is decreased by more than 50 mg/day;  provide the patient with maximum medical therapies to treat raised IOP: oral agents (e.g. pressure-lowering treatments) and aqueous suppressants (e.g. topical b-blockers or prostaglandin analogues such as latanoprost drops);  avoid miotics (like pilocarpine), because they may lead to relative pupillary blockade. It is noteworthy that laser and peripheral iridectomies are of no use in these situations. Indeed, topiramate-induced glaucoma does not involve pupillary block; therefore, withdrawal of topiramate, with or without initiation of medical management (other than miotics) is required to help stop the glaucoma and save vision.[48] Visual acuity, IOP, anterior chamber and uveal tract anatomies all tend to normalize within hours to days of drug withdrawal.[22,53]
4.5 SSRIs (and Serotonin Noradrenaline [Norepinephrine] Reuptake Inhibitors [SNRIs]?)

SSRIs have been associated with mydriasis, increased IOP and angle-closure glaucoma.[25,28,48] The explanation for these adverse effects could be derived from the multiple actions of SSRIs, with interindividual variations, culminating in a pupillary dilatation and a relative blockade of the angle of the anterior chamber via anticholinergic or noradrenergic effects (albeit weak for the majority of SSRIs), and serotonergic effects. The action of serotonin at 5-HT2A and 5-HT2C receptors located in the iris-ciliary body complex leads to an increase in IOP; this happens because the activated receptors produce an increase in ciliary blood flow and thereafter an increase in aqueous humour production.[25] The effect of serotonin on 5-HT7 leads to the activation of adenylate cyclase and the production of two kinds of actions, depending on the location of the 5-HT7 receptor: (i) an effect on the sphincter of the pupil leads to relaxation of the muscle (passive mydriasis); and (ii) an effect on the irisciliary body complex leads to a direct increase in IOP by increasing the aqueous humour forma 2010 Adis Data Information BV. All rights reserved.

tion.[25,30] On the other hand, the agonist action of serotonin on 5-HT1A receptors leads to a decrease in IOP; this occurs through inhibition of adenylate cyclase in the ciliary body and a subsequent decreased production of aqueous humour.[25,31] Paroxetine, which possesses a relatively strong potency for inhibiting noradrenaline reuptake, has been the most incriminated among the SSRIs in angle-closure glaucoma.[25] The noradrenergic action of SSRIs such as paroxetine and of serotonin noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine[48] could lead, by a sympathomimetic action, to active mydriasis. This active mydriasis, together with the passive mydriasis brought about by serotonergic activity, would lead to heavy crowding at the eye angle. A consequent blocking of aqueous humour outflow could occur, and an increase in IOP with or without a glaucoma attack could follow.[25,28] In fact, it is important to stress that more and more evidence for a possible increase of IOP produced by SSRIs is accumulating; however, most of these cases are largely under-reported and asymptomatic and do not necessarily lead to a full-blown, angle-closure glaucoma attack.[25,28] Our PubMed search identified eleven papers reporting cases of SSRI-associated glaucoma: six were related to paroxetine,[25] two to citalopram,[56,57] one to escitalopram,[58] one to fluoxetine,[37] one to fluvoxamine[43] and none to sertraline. Therefore, most of the glaucoma cases involved paroxetine.[25] Three out of the six reported attacks associated with paroxetine occurred in elderly patients, whose ages ranged from 70 to 91 years. Two other cases were seen in younger individuals who were hyperopic.[25] The last case occurred in a patient with plateau iris configuration.[59] Two attacks of glaucoma have been recently documented secondary to the usage of citalopram. One was a case report of a woman who overdosed on citalopram and was also an alcohol abuser.[56] She completely recovered after medical and surgical interventions. The other case was associated with a regular dose of citalopram.[57] Only one case of escitalopram-related angleclosure glaucoma was found in the literature. It happened in a 41-year-old woman in whom
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escitalopram use is believed to have resulted in uveal effusions, angle rotation, and acute, bilateral angle-closure glaucoma. Cessation of escitalopram and treatment with corticosteroids led to complete resolution of the patients condition.[58] Fluoxetine was the first SSRI to be associated with angle-closure glaucoma, in the case of a young man who had been receiving oral fluoxetine for 5 weeks.[37] His predisposing risk factors for glaucoma were not provided. Although no other cases of symptomatic glaucoma have been reported since that date, experimental studies have shown that fluoxetine can cause significant elevation in IOP in animals[28] as well as in humans.[60] Finally, a 66-year-old woman had aggravation of her angle-closure glaucoma following initiation of fluvoxamine given for headache. These symptoms resolved following cessation of the medication.[43] In addition to these papers, the Australian Adverse Drug Reaction Bulletin of February 2001 reported another 11 cases of glaucoma attacks associated with SSRIs: three with fluoxetine, three with paroxetine, four with sertraline and one with citalopram. The patients ages ranged from 32 to 70 years and most of them had asymptomatic increased IOP on routine testing before occurrence of blurred vision and eye pain.[44] What we can say at this time is that precautions must be taken before prescribing SSRIs to patients at risk for increased IOP (e.g. the elderly), and that ophthalmological consultation before and periodically after initiation of antidepressant treatment is to be considered, especially in the presence of glaucoma-predisposing factors. If any sign of glaucoma appears, stopping the medication and seeking medical treatment by a specialist is recommended.[48] 5. Cataract and Pigmentary Deposits in the Lens and Cornea The lens is a transparent biconvex structure located behind the iris. It is subdivided into three layers: the capsule (the outermost layer), the cortex and the nucleus (the innermost layer). It functions as a delicate light refractor that focuses an
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image of the outside world on the retina. When the passage of light through the lens is significantly impaired secondary to a clouding of the lens, the eye is considered to have a cataract. This condition can be either unilateral or bilateral; when it is secondary to medications, it is not unusual for the cataractous changes to involve both eyes.[61] Cataracts represent the most common cause of treatable blindness worldwide. Risk factors for cataract are numerous, including galactosaemia, diabetes mellitus, increasing age, trauma, radiation, certain chemicals including certain medications, and cigarette smoking.[61] Hyperglycaemic states, for instance, can lead to cataractous changes. This is true in chronic diabetic patients, but also in patients receiving medications that produce a state of diabetes (e.g. certain antipsychotics as discussed in section 5.2).[61] Since a substantial proportion of psychiatric patients tend to have several of these risk factors, it is not surprising that cataracts are of special concern in this population. We have included in this section the terms cataract, lens and cornea because when lenticular opacities including cataracts do occur, they are rather frequently associated with corneal opacities, especially if the disease state is due to a strongly predisposing agent (e.g. a phenothiazine).[61] However, not every lenticular opacity or pigmentary deposit necessarily forms a true cataract.[3] Furthermore, alterations in the aqueous humour produced by certain drugs can lead to the accumulation of pigments both in the anterior subcapsular layers of the lens and in the posterior part of the cornea. At least two mechanisms are involved in the formation of these opacities: (i) photosensitizing drugs (such as chlorpromazine) seem to denature proteins and render them vulnerable to sunlight in a way that they form opacities, which become accumulated in the lens, cornea and skin; and (ii) endogenous melanin could trap free radicals produced by certain psychotropic agents (e.g. chlorpromazine), and the resulting compounds show as lens discolouration.[3,6,61,62] Reversibility of these eye lesions is not always possible; it depends on the causative agent and on the degree of structural changes.[63-65] Visual disturbance varies, depending on the severity of the
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ocular changes.[61] No medical treatment has shown significant benefit for pigmentary deposits and for cataracts. Preventive measures are to be taken, especially in at-risk patients. These include:[3,66]  trying to avoid medications strongly associated with cataract (e.g. chlorpromazine);  using the lowest possible dose of medication, and for the shortest possible period;  avoiding direct exposure to sunlight, and wearing sunglasses when UV light is of concern;  installing UV-blocking panes on windows. It is particularly important to periodically check the eyes of patients who are receiving medications known to be associated with these pathologies (see sections 5.1 and 5.2) because the changes that happen in the eyes are often subtle in presentation and do not show on gross inspection (without ophthalmological devices). Severe cataract can be managed by surgical intervention that replaces the diseased lens with an artificial lens.
5.1 Phenothiazines

opacities caused by these antipsychotics, it is believed that there is progressive accumulation of fine whitish (to yellowish) granules in the anterior cortex just beneath the capsule and around the pupillary aperture. Gradually, a stellate pattern of opacities develops, which then leads to a true anterior polar cataract.[2] Note that trifluoperazine, fluphenazine and perphenazine are also, albeit less frequently, associated with eye changes.[3] Butyrophenones (such as haloperidol), even with prolonged usage, are not documented to cause cataract.
5.2 Atypical Antipsychotics

Almost all the antipsychotics belonging to this group have been implicated in some form of eye opacities, but chlorpromazine and thioridazine are the most common culprits.[2,9,67,68] This adverse event appears to be drug and dose dependent: for chlorpromazine, use of high doses for long periods (e.g. 35 of 61 patients exposed to chlorpromazine 800 mg/day for 2 years exhibited such findings[69]) is very much associated with eye opacities. However, there are still no clearcut values that define the exact dose/duration of phenothiazines leading to high risk of opacity formation.[61] A study showed that 33% of 384 patients who had been receiving long-term treatment with chlorpromazine had deposits in the lens and the cornea.[70] Of course, some patients may develop eye opacities with even small doses of phenothiazines, while others may not experience such findings even at higher drug dosages.[71] This kind of adverse event is also probably dose dependent for thioridazine; this is why the maximum recommended dosage of this antipsychotic is much less than 800 mg/day.[72] Concerning the evolution of
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There is much debate as to whether the atypical antipsychotics can cause cataract. The main studies of quetiapine and its relation to cataract deserve mention.[73] The prescribing information for quetiapine mentions that studies in dogs receiving four times the recommended human dose revealed cataract occurrence; however, it also reports trials in monkeys (at 5.5 times the recommended human dose) that did not increase cataract formation.[73] On PubMed, there is no clearcut case of quetiapine-induced cataract in humans. However, the manufacturer mentions: reports, in a small number of patients, of changes to the lens, although it is not known whether or not these changes are caused by quetiapine.[73] Indeed, cataract can happen as a result of many different factors (aging, etc.), and the fact that a medication has been associated with it does not necessarily imply causality. Nevertheless, a routine eye examination in patients receiving the drug is recommended by the manufacturer.[61,74] Clozapine (a very useful treatment, especially for resistant schizophrenia) and risperidone are not known to produce cataract. The prescribing information for ziprasidone and olanzapine do mention infrequent occurrence of lenticular changes.[61] Nevertheless, for all the atypical antipsychotic agents, rates of cataract occurrence (in presence of the drug) are lower than that of the general population.[61] A possible link might exist between the diabetogenic properties that sometimes occur with certain antipsychotics (e.g. olanzapine and clozapine) and an increased
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risk for cataractous changes (probably due to the effect of hyperglycaemia on the eye). Aripiprazole has not been associated with secondary cataract. To be on the safe side, although no universal recommendation exists for newer antipsychotics, a formal eye examination at initiation of treatment and at 6-month intervals (for long-term therapies) should be considered by clinicians. 6. Retinal Abnormalities/Retinopathy Being ontogenically part of the brain, the retinal functions are very much mediated by neurotransmitters and ion movements that are directly or indirectly affected by psychotropic agents.[23] Furthermore, this thin nervous tissue can be rather easily affected by systemic substances that reach the eye through the vascular supply. Two main parts of the retina can sustain noninflammatory abnormalities (including pigmentation and degeneration): the pigment epithelium and the sensory retina (rods and cones).[2]
6.1 Phenothiazines

The most commonly documented retinal lesion secondary to phenothiazines is pigmentary retinopathy. Phototoxic processes are believed to be involved in both pigmentary retinopathy and retinal degeneration. Pigments are gradually deposited starting from the periphery to the central retina, producing loss of peripheral vision, decreased night vision, central scotomata and eventually total blindness.[75-77] It is important to be aware of the early symptoms of this retinal disease, since patients may report blurred vision or decreased night-time visual acuity even before pigmentary retinopathy becomes evident. Also, the earlier the detection of symptomatology and discontinuation of the offending drug, the higher the probability of stopping the disease process and of improving vision (although the pigments tend to remain present).[77] A study in dogs revealed that pigmentary retinopathy tends to be irreversible and, especially, that considerable histological lesions become evident.[78]
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Most cases are associated with thioridazine; a lesser percentage of cases are related to chlorpromazine (and rarely to other phenothiazines).[8,75-77] The disorder follows long-term treatment with large dosages of phenothiazines. For thioridazine, dosages >800 mg/day (especially >1000 mg/day) are considered very hazardous to retinal safety. For chlorpromazine, the adverse effects are also related to dose and duration. The deleterious effects of thioridazine appear much sooner than those of other phenothiazines; toxic events are seen within weeks of high-dose treatment. After a few months of progressive phenothiazine-induced retinopathy, atrophy of the pigment epithelium ensues and severe visual losses can occur.[2,8,75-77] Investigations performed on rat retinal cultures pinpoint the fact (the significance of which deserves more studies and further interpretation) that dopamine acts as a neuroprotective factor via action on dopamine D1 receptors, whereas glutamate tends to be neurotoxic.[79] By the same token, it would be interesting to postulate that antipsychotics, by their antidopaminergic actions, tend to prevent the beneficial effect of dopaminergic mechanisms on the life-regulatory functions of retinal tissues. Periodic formal eye examinations are recommended from the start of phenothiazine therapy up to the period following the eventual cessation of these antipsychotics.
6.2 Carbamazepine and Valproate

In a prospective study examining 45 epilepsy patients treated long term with either carbamazepine or valproate, no modification of retinal nerve fibre layer and macular thickness was found.[80] In fact, valproate (a widely used mood stabilizer and antiepileptic drug) has not been shown to cause any significant or irreversible ocular disturbance.[9,80] Carbamazepine use has been possibly associated with only two case reports of retinopathy;[81] this association has not been described as causative. These reports were of two epileptic, middleaged women treated with carbamazepine for >7 years. Symptoms and objective retinal findings
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did improve upon withdrawal of the drug.[81] However, there are no additional literature reports of retinopathy related to carbamazepine. A study done by Verrotti et al. in 2006[82] in 45 epileptic patients demonstrated that after 1 year of therapy with valproate or carbamazepine, nyctometry evaluation continued to be normal; this allowed exclusion of impairment in macular function. For all these reasons, it seems that carbamazepine and valproate do not cause retinopathy. Ophthalmological assessment on a routine basis, especially for long-term carbamazepine recipients, can be performed, though it is not necessarily recommended for all patients. Certain antiepileptic drugs with no acknowledged use in psychiatry do have significant and diverse ocular effects, including serious retinopathy,[83] but they fall outside the scope of this article.
6.3 Sertraline (SSRI)

events resolved after stopping the drug.[85] In practice, artificial tears can be of great relief.
7.2 Increased Palpebral Aperture

The TCA amitriptyline was shown in one case report to lead to an increase in the palpebral aperture. This state resembled exophthalmos, and its mechanism and significance are still unclear.[86]
7.3 Palinopsia

The visual phenomenon whereby images of recently viewed objects tend to persist or reappear is termed palinopsia. Hughes and Lessell[87] reported three cases of trazodone-induced palinopsia. This odd effect was dose related; its mechanism of appearance is still unknown. However, it did subside with a decrease in dose or cessation of the antidepressant.
7.4 Dystonia of Ocular Musculature/Oculogyric Crisis

A unique case of a presumed sertralineinduced maculopathy with a decrease in visual acuity was reported in 2001.[84] After discontinuation of the antidepressant, the maculopathy resolved, but visual acuity remained suboptimal during the 20 months of follow-up.[84] No causality was inferred, and other than that case report, no other studies have mentioned a possible association between this generally safe SSRI and retinal problems. Therefore, although the authors advised regular funduscopic examination to check for possible retinal damage in all patients receiving sertraline, the cost effectiveness of this procedure is questionable. Sertraline is still to be considered safe for the retina. 7. Other Drug-Induced Ocular Disorders
7.1 Decreased Lacrimation

Rarely clinically significant, decreased lacrimation can be caused by the anticholinergic effects of the TCAs.[1] In a case implicating amitriptyline, blurred vision and ocular irritation occurred in a contact lens user; these bothersome
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Dystonia is an involuntary contraction that can involve various muscular groups, including the extraocular muscles (in such cases, it is referred to as oculogyric crisis). It often has a dramatic presentation: severe dystonia can be very painful and can even be life-threatening if laryngeal muscles become involved.[9] Oculogyric crisis is one of the possible presentations of dystonic reactions; we focus on this reaction throughout this section. Any variant of gaze paralysis can appear. The dystonic effects of certain psychotropic medications (antipsychotics, carbamazepine, topiramate and possibly escitalopram) are of common concern in psychiatry. More often than not, they are of acute onset, but cases of tardive dystonia are also well documented in the literature.[9] Acute dystonias have a complex aetiology; they can be secondary to dopamine receptor blockade, but other mechanisms are likely to play a role as well.[4,9,22,26] Treatment of acute dystonias is rapidly efficacious,[88] including anticholinergic drugs (e.g. intramuscular benzatropine 12 mg), antihistaminergic drugs (with anticholinergic properties,
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such as diphenhydramine 50 mg) and other agents (such as intramuscular lorazepam 12 mg). Prophylactic treatment with oral forms of these medications should be considered in atrisk patients (e.g. young males receiving high doses or rapidly increasing doses of typical antipsychotics), and is often necessary in patients who have already experienced dystonic attacks and who are still receiving the incriminated psychotropic agent. This latter approach is recommended at least in the initial stages of psychiatric treatment; its necessity can be re-evaluated once the patient has been on a stable dose of long-term treatment with no more dystonic effects.[1,9]
7.4.1 Antipsychotics

no reports of ocular dystonia with sertindole, quetiapine or ziprasidone. Lastly, the first case of acute oculogyric dystonia with the use of aripiprazole was reported in 2006. It concerned a patient on low-dosage aripiprazole given for Tourettes disorder.[94] Clinicians prescribing medications that predispose to the emergence of dystonias should be aware of the disturbing and bizarre nature of these reactions. They should try to avoid the occurrence of any severe dystonia because of the seriousness of this adverse event and also because of the eventual problem of the patients future compliance.[9]
7.4.2 Carbamazepine

Typical antipsychotics (butyrophenones, as well as phenothiazines) especially those with powerful antidopaminergic action (high-potency antipsychotics) combined with weak anticholinergic effects (e.g. the butyrophenone haloperidol) have a high potential for producing dystonias.[5] Phenothiazines possess relatively weak antidopaminergic actions combined with significant anticholinergic effects. Chlorpromazine, for instance, at low-to-moderate doses, has only a slight risk of precipitating dystonia.[5,9] A very large investigation in 1995 by Tan et al.[89] searched for oculogyric spasm among 2035 Asian psychiatric inpatients over a 2-month period. It was found that 1.7% of these patients developed oculogyric reactions; all of them had been receiving chlorpromazine (or another typical antipsychotic) maintenance treatment for >5 months, and those with recurrent oculogyric crises were taking a mean chlorpromazine equivalent dosage of 511 mg/day.[89] Certain atypical antipsychotics have been reported to produce oculogyric dystonias; this is especially true for risperidone.[90] Olanzapine has been associated more than once with oculogyric dystonia.[91,92] Clozapine has not been significantly associated with this kind of extrapyramidal symptom.[9] In 2007, Uzun and Doruk[93] reported three cases of tardive oculogyric crisis during treatment with clozapine; however, no causality could be inferred, especially as confounders were not well defined. There have been
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Carbamazepine has been reported, more than once, to cause ocular dystonia.[95-98] When used in polytherapy[4,97] with other antiepileptic drugs, it increases the likelihood of several eye movement disorders, including muscular palsies. This antiepileptic drug may cause dystonia at usual doses or at toxic doses;[96-98] it may also be associated with a rare idiosyncratic kind of dystonia.[95]
7.4.3 Topiramate

The WHO has warned of the likely association between topiramate and oculogyric crisis.[22] This effect, like most of the other adverse events of this medication, is considered reversible, provided the agent is stopped.
7.4.4 SSRIs

SSRI administration may lead to extrapyramidal symptoms. In two review articles the first by Leo in 1996[99] and the other by Gerber and Lynd in 1998[100] akathisia, followed by dystonia, were reported to be the most common extrapyramidal adverse effects associated with SSRIs. Gerber and Lynd[100] identified 127 reports of SSRI-induced extrapyramidal symptoms, among which 19 were reports of dystonia. Dystonia usually affects muscles unrelated to the eye, as described in the literature.[99,100] It can also affect ocular muscles and lead to visual symptoms, but this phenomenon is relatively rare.
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Escitalopram has been reported in a single case to produce a unique dose-dependent ocular dystonia with anaphylactic symptoms.[26] This was the only report that appeared on a PubMed search with the terms ocular dystonia and SSRI. The patient, who had been at first misdiagnosed as having a panic attack, seemed to benefit from intramuscular adrenaline (epinephrine) injections. These features led the corresponding authors to hypothesize about a common mechanism leading to both dystonia and allergy, and possibly involving histamine as a common key player.[26]
7.5 Impairment of Eye Movements

7.5.2 Lithium

Even at therapeutic doses, lithium can bring about several ocular effects, including a sometimes distressing downbeat nystagmus.[107-110] The latter phenomenon can be reversed by either decreasing the lithium dose or stopping the medication altogether. Rarely, the nystagmus persists even after the discontinuation of lithium.[109] A subclinical impairment in smoothpursuit eye movement may be found in certain situations.[107]
7.5.3 Carbamazepine

As a general term, impairment of ocular movements encompasses numerous and varied disturbances, some of which were discussed in relation to dystonic reactions in section 7.4. In this section, we try to shed light on other frequent movement problems that are secondary to benzodiazepines, lithium and antiepileptic drugs.
7.5.1 Benzodiazepines

It is well known that benzodiazepines, especially in drug-na ve patients or/and in combination with ethanol, pose a serious safety problem when it comes to the operation of machinery such as automobiles.[101] This is due not only to the sedating and depressogenic actions of benzodiazepines on the nervous system, but also to disturbances in the saccadic and smooth-pursuit eye movements. The latter disturbances can alter the formation, on the retina, of a clear image of moving objects. Thus, tracking can be seriously impaired, especially after high doses of benzodiazepines. Patients should be warned about these kinds of adverse events and they should avoid combining benzodiazepines with other depressogenic substances (e.g. ethanol).[102,103] Nystagmus is an involuntary and rhythmic eye movement. Clonazepam has been reported to improve acquired nystagmus.[23,104,105] In 2001, Young and Huang[106] showed that clonazepam was 100% effective in the treatment of five cases of idiopathic downbeat nystagmus. These properties of clonazepam could be used clinically by neurologists.
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Many psychotropic drugs have the potential to induce disturbance of various functional classes of eye movements: vergence and gaze-holding, fixation, vestibulo-ocular reflexes, smooth pursuit and saccades.[4,23] This is especially true for antiepileptic drugs, particularly carbamazepine (and topiramate). Carbamazepine works by inhibiting voltage-dependent sodium channels.[5] It commonly induces diplopia and gaze-evoked nystagmus, but it rarely leads to gaze palsies, downbeat or periodic alternating nystagmus.[4,111] Of course, psychotropic polytherapy involving carbamazepine would greatly increase the chance of eye movement symptoms.[4] Downbeat nystagmus and ophthalmoplegia were shown to resolve upon discontinuation of carbamazepine.[112] Lateral-gaze nystagmus, though not usually clinically significant, can affect 25% of patients receiving carbamazepine.[1] Thus, this specific adverse effect does not necessitate cessation of the antiepileptic drug. An illusionary movement of objects (called oscillopsia) has been described in some patients taking carbamazepine.[111] It would be wise to provide routine eye examinations for patients receiving this drug.
7.5.4 Lamotrigine

Lamotrigine has received US FDA approval for the maintenance treatment of bipolar disorders. It also seems to be of some help in neuropathic pain.[5] It acts as a use-dependent blocker of voltage-sensitive sodium channels, as an inhibitor of the release of the excitatory neurotransmitter
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glutamate and possibly as a blocker of voltagedependent calcium channels.[23] Lamotrigine can lead, albeit very rarely, to nystagmus.[4,83] In 2005, Alkawi et al.[83] reported two cases of downbeat nystagmus as a result of lamotrigine toxicity; such occurrences have not been reported with low-to-regular doses. The authors warn about such ocular adverse effects of lamotrigine at high doses or when it is given with valproate, since the latter tremendously increases the half-life of lamotrigine. Diplopia and possible interference with eye movements have been rarely reported with lamotrigine monotherapy, especially at low or moderate doses.[23,83] However, bizarre eye movements have been of concern when lamotrigine was taken in overdoses or when it was combined with carbamazepine.[113,114]
7.5.5 Topiramate

7.8 Abnormal Colour Perception

Carbamazepine may cause a mild and specific disturbance in colour. In patients treated with a 1-year carbamazepine regimen, central and paracentral colour vision clearly decreased.[117] This effect is not universally accepted, since many trials in humans have not detected such findings.[23] In a cross-sectional study involving 18 patients who had been taking valproate monotherapy for 220 years, only minor abnormalities in colour vision were discovered in two patients.[118] Short wavelength-sensitive cones seemed to be affected by the antiepileptic drug. This uncommon effect is mostly subclinical and does not require monitoring. Visual acuity, both subjective and objective, was preserved.[118]
7.9 Impaired Contrast Sensitivity
7.9.1 Carbamazepine

Topiramate can induce nystagmus, especially at high doses.[4,22] The mechanisms behind this eye effect are still unclear; idiosyncratic reactions cannot be excluded.[4] If the effect on ocular movement is too pronounced, a decrease in dose or cessation of the drug should be considered.
7.6 Exophthalmos

Lithium has been reported as causing a rare abnormal protrusion of the eyeball (exophthalmos) that resembled the cases seen in certain endocrinopathies. This effect was first observed a long time ago: in 1973, Segal et al.[115] showed that 9 of 100 patients receiving a 6- to 20-month maintenance lithium treatment exhibited objective (unilateral and bilateral) exophthalmos. There is no recommendation to necessarily stop lithium in such situations; however, if such a measure is implemented, the eye protrusions resolve.[3]
7.7 Papilloedema

The capacity of detecting low-contrast visual information is termed contrast sensitivity. An effect at this level of visual processing can have a significant effect on visual perception in general, even if gross visual acuity is preserved. The possible impairment of contrast sensitivity secondary to carbamazepine therapy is still a matter of controversy.[119] Some researchers have found the presence of such an association,[120-122] while others found no association whatsoever.[123] Steinhoff et al.[123] did not find any disturbance in colour perception when they delivered a single oral dose of carbamazepine to healthy individuals.
7.9.2 Benzodiazepines

To date, at least five cases of optic disc swelling (papilloedema) associated with therapeutic doses of lithium have been reported. Blurred vision and papilloedema did resolve in patients who discontinued the drug, but they tended to persist in the other patients.[116]
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In a recent study published in 2006, Giersch et al.[124] reviewed the literature concerning the effects of benzodiazepines (both in acute or longterm usage) on visual acuity and especially on contrast sensitivity. In addition, the researchers ophthalmologically tested 15 long-term lorazepam recipients and 15 matched untreated healthy subjects. It was found that several reviewed studies had shown a global loss of contrast sensitivity with benzodiazepines.[124,125] Furthermore, this trials specific findings were that long-term lorazepam recipients exhibited impaired contrast
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Ocular Adverse Effects of Common Psychotropic Agents

Table II. Ocular adverse effects of common psychotropic agents Medication Effect Mechanism Incidence Degree of visual disturbance References

Antipsychotics Phenothiazines/butyrophenones Oculogyric crisis Mydriasis Cycloplegia Chlorpromazine (others?) Pigmentary deposits in lens and cornea Epithelial keratopathy Corneal oedema Pigmentary and granular retinopathy Fluphenazine Thioridazine (others?) Antidepressants TCAs (e.g. imipramine, amitriptyline, protriptyline) Lacrimation Accommodation interference Palpebral aperture Angle-closure glaucoma Trazodone SSRIs (e.g. citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) Palinopsia Mydriasis Anticholinergic Anticholinergic (anti-a-adrenergic?) Unknown Anticholinergic (anti-a-adrenergic?) Unknown Serotonergic (via 5-HT7 receptors), noradrenergic, anticholinergic Serotonergic, noradrenergic, anticholinergic Idiosyncratic Idiosyncratic (and others?) Rare Common Extremely rare Rare to commonb Extremely rare Common? None to mild Mild and transient Mild Severe Mild None (unless leading to glaucoma) Severe Mild Moderate 1,85 1,3 86 17,49,50 87 27,45-47 Maculopathy Pigmentary retinopathy Antidopaminergic (and others?) Anticholinergic (anti-a-adrenergic?) Anticholinergic (anti-a-adrenergic?) Photosensitization Rare to common Rare to common Rare Common Moderate; transient None to mild; transient Mild; transient None to mild 89 8 8 2,9,67-70, 72,126 6-8 3,9 75-77 8 75-77

Unknown Phototoxic (and others?) Unknown Unknown (phototoxic?) Unknown

Rare Rare Rare Rare Commona

None Severe Mild to moderate Moderate Moderate to severe

Angle-closure glaucoma Maculopathy Oculogyric crisis

Rareb Single case report Very rare

25,28,37,43, 44,48,56-59 84 26 Continued next page

519

Table II. Contd Medication Effect Mechanism Incidence Degree of visual disturbance None to milda References

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520

Benzodiazepines

Eye movements/tracking Angle-closure glaucoma Allergic conjunctivitis Impaired contrast sensitivity

GABA agonist (and others?)

Rare to common (doserelated) Single case report; extremely rare Single case report

101-103

Diazepam (others?)

Pupil sphincter relaxation/anticholinergic

Severe

51

Diazepam

Unknown

Moderate

10

Lorazepam (others?)

GABA agonist (and others?)

Common?

None to mild

124,125

AEDs AEDs used as mood stabilizers Miscellaneous eye movement disturbances Lateral and/or downbeat nystagmus Oculogyric crisis Ophthalmoplegia Lamotrigine Nystagmus Multiple; drug-dependent Varies depending on the AED and on the patients susceptibility Rare to common Variable; dosage dependent Mild 22,83,111,112

Carbamazepine

Inhibition of voltage-dependent sodium channels Idiosyncratic (and others?) Inhibition of sodium channels (?) Inhibition of voltage-sensitive sodium channels, glutamate release, and voltage-dependent calcium channels Interference with sodium and chloride ion movements causing displacement of ciliary body and lens Displacement of lens and angle obstruction Unknown Inhibition of voltage-sensitive sodium channels and glutamate release; GABAergic Inhibition of voltage-sensitive sodium channels, GABA

111,112

Rare Rare Rare

Moderate Mild; transient Mild

96-98 112 83

Topiramate

Myopia

Rare to common

Mild to moderate; transient Severe Moderate Mild to moderate None (to mild)

19,20,22

Angle-closure glaucoma Oculogyric crisisa Nystagmus

Rare to common Rare Rare to common

2,4,22,48, 53-55 22 4,22

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Valproate

Colour vision abnormalities

Rare

117,118

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521

Degree of visual disturbance

Mild to moderate; transient

Mild to moderate

Mild to moderate

sensitivity (and exophoria), and this was independent of the sedative effects of the benzodiazepine. This was seen to be concomitant with a normal visual acuity. The authors finally warned that visual acuity testing alone does not seem to be sufficient for detecting all visual impairments.[124]
AED = antiepileptic drug; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants; indicates increase; indicates decrease.

References

107-110

11,12

115

Mild

116

8. Conclusions As an increasing number of patients are receiving prolonged biological therapies, and since the number and variety of marketed psychotropic compounds are expected to grow continuously,[3] understanding potentially harmful adverse effects of neuropsychotropic agents can be of great value. Tables II and III summarize the ocular adverse effects of psychotropic agents discussed in this article. Mechanisms of action and monitoring guidelines are also provided. Unfortunately, these non-rare ocular disorders do have miscellaneous impacts on both the physical and psychological states of already vulnerable psychiatric patients. An anxious, psychotic, depressed or agitated patient is likely to feel much worse if an unexpected, cumbersome ocular disturbance were to occur. In addition, psychiatrists tend to ignore the eye when prescribing medications.[1,3] Typical antipsychotics, TCAs, lithium, benzodiazepines, carbamazepine and topiramate induce most of the currently recognized ocular problems. The phenothiazine thioridazine, especially at high doses, can commonly lead to pigmentary retinopathy and thus to significant disturbances in vision. Chlorpromazine, another phenothiazine antipsychotic, can rarely induce pigmentary and granular retinopathies; it can commonly photosensitize the lens and the cornea and lead to the formation of relatively benign pigmentary deposits in these structures. A serious and severe visual disturbance brought about by chlorpromazine would be the rare corneal oedema. Butyrophenones carry a significant risk of causing oculogyric crises, and these dystonic reactions, though reversible, can be very disturbing
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Rare to common

Incidence

Very rare

Rare

Alteration of sodium transport across nerve cell membrane? Papilloedema a At high dosages and/or with prolonged therapy.

Unclear and complex (alteration of sodium transport across nerve cell membrane?)

Rare

Table II. Contd

Medication

Lithium

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Angle-closure glaucoma occurs only in susceptible eyes having narrow anterior chambers.

Mechanism

Exophthalmos

Unknown

Eye irritation

Nystagmus (downbeat)

Effect

Sodium in lacrimal fluid

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Table III. Summary of the main ocular complications of psychotropic medications Ocular complication Refractive error Raised IOP Eye movement disturbance Oculogyric crisis Medication Topiramate Topiramate, TCAs (e.g. amitriptyline), SSRIs AEDs (including topiramate), benzodiazepines, lithium Typical antipsychotics with high potency > typical antipsychotics with low potency, atypical antipsychotics (e.g. risperidone) at high doses, topiramate, SSRIs (very rare), carbamazepine (very rare) Typical antipsychotics (mainly chlorpromazine) other antipsychotics (rare and controversial) Typical antipsychotics

Lens opacity/cataract Retinopathy

AEDs = antiepileptic drugs; IOP = intraocular pressure; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic antidepressants.

to patients. They can also cause mydriasis, which is usually transient. TCAs commonly promote interference in the accommodation process; this event is mild and transient in contrast to the serious angle-closure glaucoma that can be frequently provoked in narrow-angled eyes. SSRIs are increasingly being shown to lead to mydriatic events. The consequence of such a phenomenon, when it occurs in eyes that are very susceptible to angle closure, can be the induction of a glaucomatous attack. Benzodiazepines, on the other hand, have a potential to induce a dose-related disturbance in various eye movements; they should be avoided as much as possible during such activities as driving an automobile, especially when taken in combination with alcohol or other nervous system depressants. Mood stabilizers of the antiepileptic type also rather frequently induce various eye movement problems. Carbamazepine has the propensity to provoke nystagmus and sometimes oculogyric crises, both of which create a moderate visual disturbance. Lamotrigine, especially if combined with valproate, can produce significant ocular movement troubles. Valproate has rarely been reported to produce subclinical problems with colour dis 2010 Adis Data Information BV. All rights reserved.

crimination. Topiramate has been more and more directly incriminated, not only in the production of nystagmus and other movement disorders, but also in the creation of a myopic state in a large number of eyes. A kind of idiosyncratic reaction induced by topiramate in vulnerable individuals transforms (usually reversibly if the agent is stopped) the whole structure of the lens and ciliary body complexes and can produce not only refractive errors but also eventual angle obstruction and a severe decrease in vision. Last but not least, lithium can induce rather commonly, and especially at high doses, downbeat nystagmus with consequent moderate subjective anomalies in visual function. Taking all these facts into consideration, one could state that, even though ocular adverse effects of psychotropic agents are not very common, great precautions need to be taken when it comes to the prescription of some of these molecules. One should keep in mind the association between phenothiazines and retinopathy; chlorpromazine and cataractous changes; butyrophenones and ocular dystonias; TCAs and angleclosure glaucoma in at-risk subjects; SSRIs and increased IOP in narrow-anterior chambered eyes; benzodiazepines, antiepileptic drugs and lithium (each alone or in combination) and ocular movement disturbances; and finally topiramate and very significant refractive problems, and even secondary glaucomas. When psychiatrists, ophthalmologists and patients are aware of and attentive to medicationinduced adverse effects, early prevention and intervention can then easily circumvent the occurrence of the vast majority of cases of serious and potentially irreversible ocular damage. Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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24. Rhee DJ, Goldberg MJ, Parrish RK. Bilateral angleclosure glaucoma and ciliary body swelling from topiramate. Arch Ophthalmol 2001; 119 (11): 1721-3 25. Costagliola C, Parmeggiani F, Sebastiani A. SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms. CNS Drugs 2004; 18 (8): 475-84 26. Patel OP, Simon MR. Oculogyric dystonic reaction to escitalopram with features of anaphylaxis including response to epinephrine. Int Arch Allergy Immunol 2006; 140 (1): 27-9 27. Schmitt JA, Riedel WJ, Vuurman EF, et al. Modulation of the critical flicker fusion effects of serotonin reuptake inhibitors by concomitant pupillary changes. Psychopharmacology (Berl) 2002 Apr; 160 (4): 381-6 28. Costagliola C, Mastropasqua L, Capone D, et al. Effect of fluoxetine on intraocular pressure in the rabbit. Exp Eye Res 2000 May; 70 (5): 551-5 29. Tobin AB, Unger W, Osborne NN. Evidence for the presence of serotonergic neurons and receptors in the irisciliary body complex of the rabbit. J Neurosci 1988; 8: 3713-21 30. Chidlow G, Le Corre S, Osborne SS. Localization of 5-hydroxytryptamine1A and 5-hydroxytryptamine7 receptors in rabbit ocular and brain tissues. Neuroscience 1998; 87: 675-89 31. Osborne NN, Chidlow G. Do beta-adrenoceptors and serotonin 5-HT1A receptors have similar functions in the control of intraocular pressure in the rabbit? Ophthalmologica 1996; 210: 308-14 32. Tobin AB, Osborne NN. Evidence for the presence of serotonin receptors negatively coupled to adenylate cyclase in the rabbit iris-ciliary body. J Neurochem 1989; 53: 686-91 33. Preskorn SH. Comparison of the tolerability of bupropion, fluoxetine, imipramine, nefazodone, paroxetine, sertraline and venlafaxine. J Clin Psychiatry 1995; 56 Suppl. 6: 12-21 34. Trindade E, Menon D, Topfer LA, et al. Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis. CMAJ 1998; 159: 1245-52 35. Beasley Jr CM, Koke SC, Nilsson ME, et al. Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated metaanalysis. Clin Ther 2000; 22: 1319-30 36. Thompson C, Peveler RC, Stephenson D, et al. Compliance with antidepressant medication in the treatment of major depressive disorder in primary care: a randomized comparison of fluoxetine and a tricyclic antidepressant. Am J Psychiatry 2000; 157: 338-43 37. Ahmad S. Fluoxetine and glaucoma [letter]. DICP 1991; 25: 436 38. Kirwan JF, Subak-Sharpe I, Teimory M. Bilateral acute angle closure glaucoma after administration of paroxetine [letter]. Br J Ophthalmol 1997; 81: 252 39. Lewis CF, DeQuardo JR, DuBose C, et al. Acute angleclosure glaucoma and paroxetine. J Clin Psychiatry 1997; 58: 123-4

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Correspondence: Dr Sami Richa, MD, PhD, Department of Psychiatry, Psychiatric Hospital of the Cross, Main Street, PO Box 60096, Jall-Eddib, Beirut, Lebanon. E-mail: samiric@idm.net.lb

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CNS Drugs 2010; 24 (6)

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