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Schizophrenia, psychotropic medication, and cataract
Letters to the Editor mance of the operation as was the case with many new procedures in ophthalmology, most notably the phacoemulsification of cataracts. We wish to reassure other investigators that, after hurdling the initial learning curve, success rates with ELA-DCR are comparable to, if not higher than, external DCR. JORGE G. CAMARA, MD MARIA DONNA D. SANTIAGO, MD Honolulu, Hawaii Reference 1. Camara JG, Santiago MD. Current surgical technique of endoscopic laser assisted dacryocystorhinostomy. In: Bosniak S, Cantisano-Zilkha M, eds. Operative Techniques in Oculoplastic, Orbital and Reconstructive Surgery. Philadelphia: W.B. Saunders, 1998;66 –72.
Schizophrenia, Psychotropic Medication, and Cataract Dear Editor: In the article “Schizophrenia, Psychotropic Medication, and Cataract” (Ophthalmology 1999;106:683–7) by McCarty et al, the authors have contributed significant findings regarding the incidence of cataract in the psychiatric population and identified an important need to clarify the relationship between cataract and schizophrenia. However, there are several issues associated with this study that I believe deserve further discussion. Phenothiazines represent a class of neuroleptic agents that have historically been associated with the development of lens opacities, particularly anterior stellate pigmentary changes. However, it is important to note that phenothiazines, as a drug class, are not equally associated with cataract formation. For example, chlorpromazine, a widely used aliphatic phenothiazine, appears to carry a higher incidence of anterior lenticular findings than thioridazine, which is considered to exert more toxicity within the retina.1,2 Moreover, the clinical appearance of characteristic granular anterior lens opacities associated with phenothiazines such as chlorpromazine is considered an idiosyncratic response.3 Various factors that may influence the development of phenothiazine-related lens opacities include the type of phenothiazine used, the total cumulative dose, compliance with drug use, concomitant medication, and, perhaps, environmental factors such as exposure to sunlight.2 Therefore, it is doubtful whether the severity of anterior lenticular opacities could be reliably used as a surrogate marker for estimating total dosage of psychotropic medication as the authors suggest. In addition, despite the characteristic appearance of phenothiazine-related lens toxicity, the presence of preexisting anterior axial punctuate lens opacities could complicate accurate prediction of phenothiazine exposure based on lens evaluation. Further, without correlative data regarding length of exposure, dose, and type of phenothiazine studied within the Melbourne Visual Impairment Project, the external validity of the negative association between phenothiazine use and anterior lens changes (Table 3) is questionable. The finding that phenothiazine users have a markedly lower rate of typical age-related cataract changes compared
to diazepam or tricyclic users is also notable. The results found in Table 3, which contradict intuitive conclusions regarding the appearance of cortical lens changes and nuclear sclerosis in patients with a mean age of 60 years, are particularly puzzling. The use of representative slit lamp photos to substantiate the findings of Table 3—the remarkable preservation of lens clarity in older adult phenothiazine users—would certainly have been of interest. The authors go on to conclude the need to “investigate whether newer agents, especially high-potency medications” cause anterior subcapsular cataracts (ASC) or whether a certain threshold of drug exposure must be attained before cataracts develop. However, there is little evidence to suggest that “high-potency” phenothiazines such as fluphenazine are any more likely to cause cataracts than chlorpromazine.3 Moreover, establishing a causal relationship between use of high-potency phenothiazines and cataract formation would be fraught with confounding factors. For example, management of individuals with severe psychotic disorders requiring fluphenazine often requires multiple drug therapy. In addition, as demonstrated by the findings displayed by McCarty et al, schizophrenia alone may influence cataract formation. The use however, of high-potency phenothiazines, which are associated with a significant risk of extrapyrimadal side effects, is likely to decrease with the recent introduction of drugs such as quetiapine. Quetiapine (Seroquel) is a dibenzothiazepine derivative marketed for use in various psychiatric disorders such as schizophrenia.4 Quetiapine appears to be a highly effective antipsychotic agent with a more favorable side-effect profile compared to high-potency phenothiazines.4 Interestingly, Seroquel is also associated with cataract formation. Preclinical dog studies with Seroquel demonstrated the association of abnormalities within the crystalline lens characterized by “focal triangular irregularities” in the posterior lens sutures (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). Dog lens abnormalities noted with quetiapine use occurred with long-term (1 year) administration at 4 times the maximum human dose.4 Animal studies suggested that quetiapine may interfere with cholesterol synthesis de novo; however, a relationship between quetiapine induced hypocholesteremia and human cataract formation has not been determined (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). Unlike phenothiazines, human cataract formation associated with the use of dibenzothiazepine derivatives such as Seroquel has not been firmly established or characterized. Phase III studies conducted prior to the introduction of Seroquel did not show any relationship between formation of lens opacities and quetiapine administration (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). However, Phase IV studies are being planned by the manufacturer of Seroquel to further explore the potential relationship between quetiapine and human cataract formation. BRUCE I. GAYNES, OD, PHARMD Chicago, IL
5
Ophthalmology Volume 107, Number 1, January 2000 References 1. Grant WM. Toxicology of the Eye: Drugs, Chemicals, Plants, Venoms. 2nd ed. Springfield, IL: Thomas, 1974:1008. 2. Deluise VP, Flynn JT. Asymmetric anterior segment changes induced by chlorpromazine. Ann Ophthalmol 1981;13: 953–5. 3. Gualtieri CT, Lefler WH, Guimond M, Staye JI. Corneal and lenticular opacities in mentally retarded young adults with thioridazine and chlorpromazine. Am J Psychiatry 1982;139: 1178 – 80. 4. Goren JL, Levin GM. Quetiapine, an atypical antipsychotic. Pharmacotherapy 1998;18:1183–94.
Author’s reply Dear Editor: Dr. Gaynes has provided some very useful additional information concerning new psychotropic medications in use and their potential for causing cataract. We would like to address a few of the issues he raised in his letter. We agree with Dr. Gaynes that it would be useful to separate the potential effect of the separate phenothiazines in relation to cataract. However, we have insufficient statistical power in our study to evaluate the drugs separately. We also acknowledge the potential limitation of the self-reported data in the Melbourne Visual Impairment Project. With any epidemiologic study such as ours, we are reliant on the self-reported information about some exposures. As we stated in our methods section, slit-lamp examination and/or photography was used to document the lens opacities of all study participants. Photographs were available for more than 90% of the study populations. Subjects who were categorized as not having cataract according to our definition did not necessarily have clear lenses. Their level of opacity was just not severe enough to be categorized as having a cataract. Finally, we agree that it would be difficult to separate the potential effect of schizophrenia versus the medication on the development of cataract. This would require prospective data collection on a large number of patients. However, we do feel that it would be worthwhile. CATHY MCCARTY, PHD East Melbourne, VIC, Australia
Excimer Laser Photorefractive Keratectomy The following two letters address an article that appeared in the February 1999 issue of the Journal: Ophthalmic Procedure Preliminary Assessment: Excimer Laser Photorefractive Keratectomy (PRK) for Myopia and Astigmatism (Ophthalmology 1999;106:422–37) Dear Editor: I would like to congratulate those who write ophthalmic procedures preliminary assessments because they are of great interest and, in my opinion, have a great impact on ophthalmologists all over the world. I would like to comment on the article’s section concerning complications of such surgery, in particular endothelial cell loss. The authors state that “Four studies examined a
6
total of 149 eyes pre- and post-PRK to evaluate changes in endothelial cell densities and morphology . . . ,” and cite references 58 to 61. In reviewing these references, I found that reference 60 did not deal with the corneal endothelium. I would also recommend that the sentence be changed to read, “Among the articles we chose four . . . ,” because the reader could mistakenly believe that four (or maybe three) papers have been published on that topic, when at least six other studies1– 6 have been published in peer reviewed literature. How could the author forget the first historical study published by Amano and Shimizu?1 In the author’s opinion if these articles do not deserve to be cited, this change in wording could be supported by the exact criteria used for the choice, and not just a generic statement in the beginning of the article. Again, in my opinion, these kinds of articles have a great impact on the ophthalmological field all over the world, including areas that are not fluent in English. Every effort should be made to be very precise and thus avoid confusion. NICOLA ROSA, MD Naples, Italy References 1. Amano S, Shimizu K. Corneal endothelial changes after excimer laser photorefractive keratectomy. Am J Ophthalomol 1993;116:692– 4. 2. Cennamo G, Rosa N, Guida E, et al. Evaluation of corneal thickness and endothelial cells before and after excimer laser photorefractive keratectomy. Refract Corneal Surg 1994;10: 137– 41. 3. Perez-Santonja JJ, Meza J, Moreno E, et al. Short-term corneal endothelial changes after photorefractive keratectomy. Refract Corneal Surg 1994;10(2 suppl):S194 – 8. 4. Rosa N, Cennamo G, Del Prete A, et al. Effects on the corneal endothelium six months following photorefractive keratectomy. Ophthalmologica 1995;209:17–20. 5. Cennamo G, Rosa N, Del Prete A, et al. The corneal endothelium 12 months after photorefractive keratectomy in high myopia. Acta Ophthalmol Scand 1997;75:128 –30. 6. Rosa N, Cennamo G, Del Prete A, et al. Endothelial cells evaluation two years after photorefractive keratectomy. Ophthalmologica 1997;211:32–9.
Dear Editor: In the ophthalmic procedures preliminary assessment there is, as would be expected, a lengthy discussion of the complication of elevated intraocular pressure caused by the postoperative use of steroids, either topical prednisolone acetate or fluorometholone. However, another important known complication, cataract formation—also commonly attributed to the postoperative use of topical steroids—is barely mentioned on page 426 and only vaguely suggested on page 429. Steroidinduced cataract is usually given more attention in discussions of complications of photorefractive keratectomy (PRK); indeed, it has been documented in case reports. For example, in a 24-year-old woman a posterior subcapsular cataract after PRK was associated with 4 months of intensive postoperative treatment with fluorometholone.1 To underscore the reality of cataract formation subsequent to excimer laser corneal ablation, Figures 1 and 2 reveal the bilateral postoperative cataracts in one of my
Schizophrenia, Psychotropic Medication, and Cataract Dear Editor: In the article “Schizophrenia, Psychotropic Medication, and Cataract” (Ophthalmology 1999;106:683–7) by McCarty et al, the authors have contributed significant findings regarding the incidence of cataract in the psychiatric population and identified an important need to clarify the relationship between cataract and schizophrenia. However, there are several issues associated with this study that I believe deserve further discussion. Phenothiazines represent a class of neuroleptic agents that have historically been associated with the development of lens opacities, particularly anterior stellate pigmentary changes. However, it is important to note that phenothiazines, as a drug class, are not equally associated with cataract formation. For example, chlorpromazine, a widely used aliphatic phenothiazine, appears to carry a higher incidence of anterior lenticular findings than thioridazine, which is considered to exert more toxicity within the retina.1,2 Moreover, the clinical appearance of characteristic granular anterior lens opacities associated with phenothiazines such as chlorpromazine is considered an idiosyncratic response.3 Various factors that may influence the development of phenothiazine-related lens opacities include the type of phenothiazine used, the total cumulative dose, compliance with drug use, concomitant medication, and, perhaps, environmental factors such as exposure to sunlight.2 Therefore, it is doubtful whether the severity of anterior lenticular opacities could be reliably used as a surrogate marker for estimating total dosage of psychotropic medication as the authors suggest. In addition, despite the characteristic appearance of phenothiazine-related lens toxicity, the presence of preexisting anterior axial punctuate lens opacities could complicate accurate prediction of phenothiazine exposure based on lens evaluation. Further, without correlative data regarding length of exposure, dose, and type of phenothiazine studied within the Melbourne Visual Impairment Project, the external validity of the negative association between phenothiazine use and anterior lens changes (Table 3) is questionable. The finding that phenothiazine users have a markedly lower rate of typical age-related cataract changes compared
to diazepam or tricyclic users is also notable. The results found in Table 3, which contradict intuitive conclusions regarding the appearance of cortical lens changes and nuclear sclerosis in patients with a mean age of 60 years, are particularly puzzling. The use of representative slit lamp photos to substantiate the findings of Table 3—the remarkable preservation of lens clarity in older adult phenothiazine users—would certainly have been of interest. The authors go on to conclude the need to “investigate whether newer agents, especially high-potency medications” cause anterior subcapsular cataracts (ASC) or whether a certain threshold of drug exposure must be attained before cataracts develop. However, there is little evidence to suggest that “high-potency” phenothiazines such as fluphenazine are any more likely to cause cataracts than chlorpromazine.3 Moreover, establishing a causal relationship between use of high-potency phenothiazines and cataract formation would be fraught with confounding factors. For example, management of individuals with severe psychotic disorders requiring fluphenazine often requires multiple drug therapy. In addition, as demonstrated by the findings displayed by McCarty et al, schizophrenia alone may influence cataract formation. The use however, of high-potency phenothiazines, which are associated with a significant risk of extrapyrimadal side effects, is likely to decrease with the recent introduction of drugs such as quetiapine. Quetiapine (Seroquel) is a dibenzothiazepine derivative marketed for use in various psychiatric disorders such as schizophrenia.4 Quetiapine appears to be a highly effective antipsychotic agent with a more favorable side-effect profile compared to high-potency phenothiazines.4 Interestingly, Seroquel is also associated with cataract formation. Preclinical dog studies with Seroquel demonstrated the association of abnormalities within the crystalline lens characterized by “focal triangular irregularities” in the posterior lens sutures (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). Dog lens abnormalities noted with quetiapine use occurred with long-term (1 year) administration at 4 times the maximum human dose.4 Animal studies suggested that quetiapine may interfere with cholesterol synthesis de novo; however, a relationship between quetiapine induced hypocholesteremia and human cataract formation has not been determined (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). Unlike phenothiazines, human cataract formation associated with the use of dibenzothiazepine derivatives such as Seroquel has not been firmly established or characterized. Phase III studies conducted prior to the introduction of Seroquel did not show any relationship between formation of lens opacities and quetiapine administration (Zeneca Pharmaceutical Inc., personal communication, Wilmington, DE, 30 March 1999). However, Phase IV studies are being planned by the manufacturer of Seroquel to further explore the potential relationship between quetiapine and human cataract formation. BRUCE I. GAYNES, OD, PHARMD Chicago, IL
5
Ophthalmology Volume 107, Number 1, January 2000 References 1. Grant WM. Toxicology of the Eye: Drugs, Chemicals, Plants, Venoms. 2nd ed. Springfield, IL: Thomas, 1974:1008. 2. Deluise VP, Flynn JT. Asymmetric anterior segment changes induced by chlorpromazine. Ann Ophthalmol 1981;13: 953–5. 3. Gualtieri CT, Lefler WH, Guimond M, Staye JI. Corneal and lenticular opacities in mentally retarded young adults with thioridazine and chlorpromazine. Am J Psychiatry 1982;139: 1178 – 80. 4. Goren JL, Levin GM. Quetiapine, an atypical antipsychotic. Pharmacotherapy 1998;18:1183–94.
Author’s reply Dear Editor: Dr. Gaynes has provided some very useful additional information concerning new psychotropic medications in use and their potential for causing cataract. We would like to address a few of the issues he raised in his letter. We agree with Dr. Gaynes that it would be useful to separate the potential effect of the separate phenothiazines in relation to cataract. However, we have insufficient statistical power in our study to evaluate the drugs separately. We also acknowledge the potential limitation of the self-reported data in the Melbourne Visual Impairment Project. With any epidemiologic study such as ours, we are reliant on the self-reported information about some exposures. As we stated in our methods section, slit-lamp examination and/or photography was used to document the lens opacities of all study participants. Photographs were available for more than 90% of the study populations. Subjects who were categorized as not having cataract according to our definition did not necessarily have clear lenses. Their level of opacity was just not severe enough to be categorized as having a cataract. Finally, we agree that it would be difficult to separate the potential effect of schizophrenia versus the medication on the development of cataract. This would require prospective data collection on a large number of patients. However, we do feel that it would be worthwhile. CATHY MCCARTY, PHD East Melbourne, VIC, Australia
Excimer Laser Photorefractive Keratectomy The following two letters address an article that appeared in the February 1999 issue of the Journal: Ophthalmic Procedure Preliminary Assessment: Excimer Laser Photorefractive Keratectomy (PRK) for Myopia and Astigmatism (Ophthalmology 1999;106:422–37) Dear Editor: I would like to congratulate those who write ophthalmic procedures preliminary assessments because they are of great interest and, in my opinion, have a great impact on ophthalmologists all over the world. I would like to comment on the article’s section concerning complications of such surgery, in particular endothelial cell loss. The authors state that “Four studies examined a
6
total of 149 eyes pre- and post-PRK to evaluate changes in endothelial cell densities and morphology . . . ,” and cite references 58 to 61. In reviewing these references, I found that reference 60 did not deal with the corneal endothelium. I would also recommend that the sentence be changed to read, “Among the articles we chose four . . . ,” because the reader could mistakenly believe that four (or maybe three) papers have been published on that topic, when at least six other studies1– 6 have been published in peer reviewed literature. How could the author forget the first historical study published by Amano and Shimizu?1 In the author’s opinion if these articles do not deserve to be cited, this change in wording could be supported by the exact criteria used for the choice, and not just a generic statement in the beginning of the article. Again, in my opinion, these kinds of articles have a great impact on the ophthalmological field all over the world, including areas that are not fluent in English. Every effort should be made to be very precise and thus avoid confusion. NICOLA ROSA, MD Naples, Italy References 1. Amano S, Shimizu K. Corneal endothelial changes after excimer laser photorefractive keratectomy. Am J Ophthalomol 1993;116:692– 4. 2. Cennamo G, Rosa N, Guida E, et al. Evaluation of corneal thickness and endothelial cells before and after excimer laser photorefractive keratectomy. Refract Corneal Surg 1994;10: 137– 41. 3. Perez-Santonja JJ, Meza J, Moreno E, et al. Short-term corneal endothelial changes after photorefractive keratectomy. Refract Corneal Surg 1994;10(2 suppl):S194 – 8. 4. Rosa N, Cennamo G, Del Prete A, et al. Effects on the corneal endothelium six months following photorefractive keratectomy. Ophthalmologica 1995;209:17–20. 5. Cennamo G, Rosa N, Del Prete A, et al. The corneal endothelium 12 months after photorefractive keratectomy in high myopia. Acta Ophthalmol Scand 1997;75:128 –30. 6. Rosa N, Cennamo G, Del Prete A, et al. Endothelial cells evaluation two years after photorefractive keratectomy. Ophthalmologica 1997;211:32–9.
Dear Editor: In the ophthalmic procedures preliminary assessment there is, as would be expected, a lengthy discussion of the complication of elevated intraocular pressure caused by the postoperative use of steroids, either topical prednisolone acetate or fluorometholone. However, another important known complication, cataract formation—also commonly attributed to the postoperative use of topical steroids—is barely mentioned on page 426 and only vaguely suggested on page 429. Steroidinduced cataract is usually given more attention in discussions of complications of photorefractive keratectomy (PRK); indeed, it has been documented in case reports. For example, in a 24-year-old woman a posterior subcapsular cataract after PRK was associated with 4 months of intensive postoperative treatment with fluorometholone.1 To underscore the reality of cataract formation subsequent to excimer laser corneal ablation, Figures 1 and 2 reveal the bilateral postoperative cataracts in one of my