Psychosomatics 43:354-359, October 2002
© 2002 The Academy of Psychosomatic Medicine
Cataract Occurrence With Antipsychotic Drugs
Sajida Shahzad, M.D.,
Mohammad-Irfan Suleman, M.D.,
Hasan Shahab, M.D.,
Iourii Mazour, M.D.,
Amanpreet Kaur, M.D.,
Peter Rudzinskiy, M.D., and
Steven Lippmann, M.D.
Received Aug. 3, 2001; revision received Dec. 10, 2001; accepted Jan. 17, 2002. From the Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine. Address reprint requests to Dr. Lippmann, University of Louisville Hospital, 5 East, 530 South Jackson St., Louisville, KY 40202.
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ABSTRACT
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Chlorpromazine and several other phenothiazine neuroleptic drugs appear to induce cataract formation. However, the newer generation of antipsychotic agents has shown no evidence of an etiologic relationship with cataract occurrence. Research did reveal cataract occurrence in dogs who received quetiapine, which prompted concern despite there being no known causal link between quetiapine and lens opacities in humans. Nevertheless, quetiapine's manufacturer issued formal recommendations for ophthalmological follow-up examinations with the use of this drug. Infrequent occurrences of cataract development have been documented in people taking olanzapine but, again, without established causative association; a similar situation is seen with ziprasidone. Periodic ocular examinations of the lens are suggested for patients prescribed long-term treatment with phenothiazines or quetiapine.
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INTRODUCTION
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The lens is a transparent, biconvex body located behind the iris. Its function is the refraction of light rays to focus an image on the retina.1 Being elastic in nature, it can accommodate when focusing from distant to near images or vice versa.2 The lens has a protein concentration of 33% of its total weight;2 most of these proteins are transparent and water-soluble.1
A cataract is the clouding of the otherwise clear ocular lens, with disturbance in the passage of light.3 This can make vision hazy. This pathology is the world's most common cause of treatable blindness.4,5 Advanced cataracts, which impair vision, may require surgical intervention and a plastic, intraocular lens replacement to restore eyesight.
Congenital or infantile cataracts can cause visual impairment.6 Local dysgenesis or trauma may induce unilateral cataract development. In contrast, bilateral cataract formation is associated with systemic disorders, such as galactosemia, craniofacial abnormalities, Down's syndrome, or rubella.7
Cataract formation is a common cause of visual disturbance in diabetic patients.8 A diabetogenic influence by certain antipsychotic drugs makes this a potential iatrogenic complication. Cataract development is also a common finding in geriatric populations. Older people experience the additive risk factors of age, metabolic or other disorders, trauma, and exposures to a variety of medications or other agents. In addition, mechanical trauma, with or without perforation, can result in lens opacity. The same applies to electrical injury, radiation, and certain chemicals.9
Last, long-term use of corticosteroids, phenothiazines, certain other antipsychotic drugs, some antineoplastic agents, and amiodarone may increase cataract incidence.10 Cigarette smoking also escalates the risk.11 This is of special relevance, since smoking is so prevalent in people with psychiatric disorders.
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CATARACT OCCURRENCE WITH PSYCHOTROPIC MEDICATIONS
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In the mid-1960s, a decade after the marketing of phenothiazines, drug-related ocular changes were reported in patients who had been receiving years of high-dose antipsychotic medication; chlorpromazine was the primary offender.12–15 Research also associated cataract occurrence with other phenothiazines;16 thioridazine, thiothixene, trifluoperazine, levomepromazine, and perphenazine are frequently cited examples. Epidemiological reviews have suggested a possible link between cataract occurrence and other psychotropic medications, including benzodiazepines and certain antidepressants of the tricyclic and monoamine oxidase inhibitor classes.17–19 There is disagreement over the degree of visual impairment and whether or not the lesions are reversible.20,21 Concern about this side effect with these medications had been minimal. However, recent questions about quetiapine as a possible cataract inducer have increased the current interest in this issue across the antipsychotic pharmacotherapy spectrum. Since the newer generation antipsychotic drugs are now in such common use, understanding potential ophthalmological risk is especially important.
Pathophysiology
Lens opacities associated with psychotropic drugs are an accumulation of pigment usually located in the anterior subcapsular layers.14,15,21 Changes in the anterior surface of the lens and the posterior cornea imply alterations in aqueous humor.15,22 The lens and cornea are avascular and dependent upon diffusion for oxygen and nutrition.22 Alternatively, photosensitizing agents like chlorpromazine and its metabolites denature proteins, which become opacified when exposed to sunlight and are deposited in the lens, cornea, and skin.23 Melanin is also considered a probable cause of lens discoloration because it traps free radicals produced by chlorpromazine. Melanin and chlorpromazine have a strong bonding affinity.24 When chlorpromazine interacts with ultraviolet-B light, it produces purple or bluish colored free-radical metabolites.25 This phototoxic reaction creates the cataract cellular changes.26
Relation With Sunlight
There is an association between cataract occurrence and sunlight.27 High-intensity or long-duration sun exposure leads to greater opacification. Cataracts are most prevalent in areas where the amount of sunlight is high. 28 Pigmentation is increased in the late spring and summer months and fades slightly in winter when sunlight decreases.26 A 54-year-old man with lenticular opacifications had taken chlorpromazine 800 mg/day for 10 years.29 He presented an opportunity to compare the changes caused by this drug, since his left eye was exposed to sunlight while the right one was partially closed with ptosis. The ocular changes were more prominent on the left, supporting the idea that there is a toxic interaction between sunlight and chlorpromazine.
Reversibility
Whether or not these eye lesions are reversible remains controversial. When a person is not exposed to sunlight, there could be some clearing of pigmentation.30 Nevertheless, this pathology may be irreversible, with no improvement observed even when a patient is switched from chlorpromazine to thioridazine or a butyrophenone.31 Also, deposits in the lens did not increase in some patients taking chlorpromazine over many years;31 ocular pathology persisted 6 years after withdrawal of this drug.32
Visual Impairment
Although there is limited evidence for visual impairment due to phenothiazine-induced opacities, this issue is still unsettled.33–35 In a study of 50 subjects taking chlorpromazine, cataract formation and reduced visual acuity occurred in 14.
Lenticular Opacities
Anterior subcapsular opacities are graded from 1 to 5 by the degree of pigment accumulation, size, density, and prominence of a stellate pattern.14,15 Table 1 illustrates these grades. On occasion, one observes cataract cases with several potential coexisting causes (e.g., an elderly diabetic patient who smokes and takes a variety of pharmaceuticals, including antipsychotic drugs). People with schizophrenia are documented to be at a higher risk for ocular pathologies, since they often have many contributory factors, such as smoking, poor health, and concomitant illnesses or pharmaceutical exposures.36 A 1999 study compared cataract occurrence in schizophrenic patients and the general population;35 a much higher rate was observed in the schizophrenic subjects (26%) than in the comparison subjects (<1%).
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CATARACT OCCURRENCE WITH TYPICAL NEUROLEPTICS
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The introduction of chlorpromazine in 1954 was a milestone in the management and control of schizophrenia.37 After neuroleptics became commonly prescribed, investigators associated lens pigmentation with chlorpromazine use. Some other phenothiazine derivatives may also induce such opacification.16
Chlorpromazine
Research reports have documented that chlorpromazine can induce lenticular and corneal changes.38 These side effects most often occur in patients who have been given high doses of chlorpromazine for long periods. Chlorpromazine, at 800 mg/day for 2 years, can produce pigmentary deposition in the cornea and lens.13 Among 61 subjects treated with higher doses, 35 had these findings. Another study of 384 patients who received chlorpromazine over a long period reported deposits on the anterior lens capsule and the posterior surface of the cornea in 33% of cases.39 In a further investigation, eight subjects out of 125 had reduced visual acuity. Changes in the lens with chlorpromazine treatment may be dose-related; yet, persons receiving 400 mg/day of chlorpromazine for up to 10 years did not show lenticular alteration.12 Analysis revealed that there also is a relationship between even low-dose chlorpromazine and lens changes.40,41 Pigmentary inclusions have been observed in people prescribed chlorpromazine, 200 mg/day, over a period of 2 years.42
Thioridazine
Thioridazine has also been reported to induce lenticular changes unrelated to pigmentary retinopathy.39 However, contrary reports have indicated no evidence of lens opacity in patients taking this drug.32 Thioridazine is claimed to be safe if administered at less than 800 mg/day, without induction of retinopathy;43 the risk of cataract occurrence remains unclear.
Thiothixene
In one study, lens clouding occurred in 8% of patients treated with thiothixene.44 These individuals, however, were being treated with several neuroleptics, which makes specific statements on cataract etiology inconclusive.
Other Neuroleptics
Trifluoperazine and levomepromazine are also suspected to cause eye changes,45,46 but there is limited documentation. A relation between such pathology and perphenazine use is considered as well.47 Despite biological effects that resemble those of phenothiazines, butyrophenones have not been associated with ocular opacification. Haloperidol, despite years of high utilization, is not thought to cause cataract occurrence,17,48 even though it has been observed in persons taking the drug.49
Lenticular pathology was noted also in two patients who had never received chlorpromazine.15 One took methotrimeprazine for 3 months and fluphenazine for 4 years, and the other received trifluoperazine for 7 months. Although chlorpromazine may be the main drug responsible for cataract occurrence, other phenothiazine derivatives are also capable of producing such findings.15
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CATARACT OCCURRENCE WITH NEWER GENERATION ANTIPSYCHOTIC DRUGS
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There have been questions about whether quetiapine causes cataract occurence. This concern has important clinical, investigational, and legal ramifications. Among the new generation agents, quetiapine is the only one for which the manufacturer recommends routine eye examinations for detection of lens opacities; clozapine and risperidone are not known to be associated with this problem. Prescribing information for olanzapine and ziprasidone mentions cataract occurrence as having been infrequently observed in patients during pharmacotherapy evaluations, but no causal relationship has been established. There is very little information about any of these agents' potential for inducing lenticular change. None of the new generation antipsychotic drugs has a proven etiologic relationship to cataract occurrence, and rates are lower than those for cataract occurrence in the general population.
New generation atypical antipsychotic drugs may have an adverse effect on glucose metabolism, with hyperglycemia and a tendency toward development or exacerbation of diabetes.50–54 Clozapine and olanzapine may be diabetogenic, but for risperidone and quetiapine such associations are less clear. It remains controversial as to whether ziprasidone can influence glycemic control. There are findings that suggest the possibility of such alterations and reports that indicate no change in blood sugar assays.55 Alteration of glucose homeostasis from medicinal exposures may be due to pharmaceutical influences on various receptors, which change insulin and growth hormone physiology.50,51 If diabetic induction or diminished glucose tolerance were to occur in patients taking such medicines, it would be an additive risk factor for cataract development.
Quetiapine
This medicine was approved for marketing in the United States in 1997. There is concern that quetiapine might cause cataract formation.56 At four times the recommended human dose, studies with beagle puppies revealed cataract development. Even if this occurs in dogs, such effects in humans are not proven. Research on monkeys, at 5.5 times the recommended human dose, did not increase cataract development.56
Cataract occurrence has been observed in humans during long-term quetiapine treatment, but an etiological relationship between quetiapine and lens abnormalities has not been established. The presence of cataracts, even unrelated to any pharmaceutical use, increases with advancing patient age. Nevertheless, the possibility of lenticular pathology caused by quetiapine in humans cannot be excluded. Therefore, examination of the lens is formally recommended at initiation of treatment, or shortly thereafter, and at 6-month intervals during long-term therapy.56,57 This precaution is, however, not uniformly acknowledged.
A survey based on approximately 620,000 subjects was done to assess the risk of lens opacities in persons who had taken quetiapine in daily doses between 25 and 900 mg. Cataract formation occurred at a rate of about 0.005%, which is lower than the 0.2% incidence in the general population.58,59 A very low rate of lenticular opacities with quetiapine may be due to a limitation in the survey or insufficient data. This suggests that cataract occurrence associated with quetiapine treatment is probably not very common; however, the recommendation for regular eye examinations leaves a question about the risk involved. There is one case report of lenticular change developing while receiving quetiapine treatment; however, this individual was a smoker and received several medications that might have induced cataract occurrence.60 Coincidental occurrence could not be ruled out. A documented causal relationship is not evident in current literature. Ocular assessments may be based more on patient care and malpractice concerns than on objectified, proven pharmacological science. People with schizophrenia do have other risk factors, such as smoking, that contribute to cataract development. Any pharmaceutically induced tendency toward diabetes would be an additional concern.
Olanzapine
The manufacturer of this drug reports infrequent cataract formation observed in humans during treatment with olanzapine.61 The cause is unknown. Olanzapine is not implicated, but whether there could be any etiologic association between this medication and lens pathology has yet to be clarified. There are no formal recommendations to provide ophthalmologic examinations in patients prescribed olanzapine, but monitoring blood sugar levels has relevance as a diabetic precaution.61 There are concerns about glucose intolerance being associated with this medicine, but there is also evidence that documents no glycemic dysregulation with olanzapine.62
Clozapine and Risperidone
There is no evidence for clozapine being etiologically associated with cataract occurrence,63 nor is there such evidence for risperidone.64 Neither of these drugs mentions cataract occurrences in their prescribing information.
Ziprasidone
Cataract occurrence was observed as an infrequent finding during screening for adverse events before ziprasidone was approved for clinical use.65 However, there is no known causal connection between this drug and lenticular opacities.
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ABSTRACT
INTRODUCTION
