ORIGINAL CONTRIBUTION
Dry Eye Related to Commonly Used New Antidepressants Emel Koçer, MD,* Abdulkadir Koçer, MD,† Mustafa Özsütçü, MD,‡ Ali Emre Dursun, MD,* and İsmet Kırpınar, MD* Abstract: Antidepressants may have an impact on the course of eye dryness. The aim of this study was to investigate the effects of commonly used new antidepressants on eye wetting. Fifty-four patients using new antidepressants and 57 controls were recruited. The Beck Depression Scale and Beck Anxiety Scale questionnaires were completed by the patients, and drug use time and dosages were recorded. The Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the wetting result was recorded for each eye. Escitalopram, duloxetine, and venlafaxine were used by 27, 13, and 14 patients, respectively. The Schirmer test results in the patients were significantly lower than in the controls (P < 0.001). The patients using selective serotonin reuptake inhibitors (SSRIs) displayed lower wetting measurements (≤5 mm) compared with those using serotonin-norepinephrine reuptake inhibitors, which was independent of the duration of antidepressant usage (P < 0.05). Although SSRIs do not have anticholinergic adverse effects except paroxetine, we found that both SSRIs and serotonin-norepinephrine reuptake inhibitors increased the risk for eye dryness. The lower Schirmer test results of the SSRIs may be associated with a mechanism other than the anticholinergic system. An awareness of the drugs that contribute to dry eye will allow ophthalmologists, optometrists, and other physicians to better manage patients who have this problem. Key Words: antidepressant, depression, dry eye, Schirmer test (J Clin Psychopharmacol 2015;35: 411–413)
D
ry eye (DE) is a disorder resulting from tear deficiency or excessive evaporation, causing irritation to the interpalpebral ocular surface, and is associated with symptoms of ocular discomfort.1–4 Dry eye is a multifactorial disease, and one of the most prevalent eye diseases, and requires eye care, particularly among the elderly.1–6 A strong association between the use of antidepressant medications and DE risk was reported in several studies, including epidemiological studies.5–9 However, the presence of DE is normally underdiagnosed in clinical practice. This may be a methodological issue because the adverse effects in drug trials are often assessed via spontaneous reporting by patients or by closedended lists of symptoms not including DE. Therefore, DE is uncommon in clinical trial reports on antidepressant drugs, whereas dry mouth is prevalent. For example, the only ocular symptom on the list of 17 common adverse effects reported by patients taking antidepressants from a specific study was blurred vision, as reported by 85% of the patients.10 Moreover, the presence of DE has, to our knowledge, never been studied systematically in patients using new and widely prescribed antidepressants. Therefore, we investigated the prevalence of DE in patients with depression who were using antidepressants and compared the findings with those of age-matched controls. In
From the *Psychiatry Department, Bezmialem Vakıf University Medical Faculty; †Neurology Department, Istanbul Medeniyet University Medical Faculty; and ‡Ophtalmology Department, Bezmialem Vakıf University Medical Faculty, Istanbul, Turkey. Received December 15, 2014; accepted after revision May 1, 2015. Reprints: Emel Koçer, MD, Psychiatry Department, Bezmialem Vakıf University Medical Faculty, Namik Kemal Mah, Kirişhane Cad, İstanbul Sitesi, 20/24, Istanbul, Turkey (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000356
addition, we determined the correlation between clinical variables and DE.
MATERIALS AND METHODS The patients followed-up by a diagnosis of depression based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and a history of escitalopram (selective serotonin reuptake inhibitor [SSRI]), duloxetine (serotoninnorepinephrine reuptake inhibitor [SNRI]), or venlafaxine (SNRI) usage at least for 4 weeks in psychiatry outpatient clinics of our medical faculty were examined in this study. The patients using only high doses of venlafaxine were included in the study because high-dose venlafaxine had effect on noradrenergic and cholinergic system. The patients were excluded if they were aged younger than 16 years or older than 60 years, currently using xerogenic drugs that causes the oral cavity to be unusually dry (Table 1). Those with underlying human immunodeficiency virus infection, graft versus host disease, thyroid disease untreated with hormone, amyloidosis, lymphoma, prior head and neck radiation, sarcoidosis, chronic active hepatitis, renal insufficiency, and vasculitis were also excluded. In addition, those who used or who were using a tear substitute or those who were long-term contact lens wearers were excluded from the study. Cigarette smoking was another exclusion criterion. First, sociodemographic variables and the drugs that were used by the patients included in the study were recorded. Second, all patients completed the Beck Depression Scale and Beck Anxiety Scale.11,12 Third, all patients and age- and sex-matched controls were examined for tear volume by Schirmer test. Research in this study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from each participant before any related procedure was performed, and the study was approved by the local ethics committee.
Schirmer Test Measurement Schirmer test determines whether the eye produces enough tears to keep it moist. Schirmer test measure change in tear by the observed wetting of a standardized paper strip placed over the inferior eyelid over a given period.13 The patients sat with their eyes closed for 5 minutes before the strips were removed. The length of wet area starting from the notch corresponding to the lower eyelid margin was measured. Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the test result was recorded in millimeter for each eye. After that, wet areas were classified as greater than 5 mm and 5 mm or less at 1 or both eyes.13,14 The patients with 5 mm or less result were recorded as the patients having DE. All tests were performed on both eyes by the same researcher.
Statistical Analysis Statistical analysis was performed using SPSS for Windows, version 11. Clinical features of the patients were evaluated. Mean values and standard deviations were calculated for all variables. The Mann-Whitney U test and Spearman test were used to analyze differences in median and relationship between the wetting measures of patients and controls because of abnormal distribution in the patients. The median and minimum-maximum values were used in tables. One-way analysis of variance, Student t test, and
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411
Journal of Clinical Psychopharmacology • Volume 35, Number 4, August 2015
Koçer et al
wettings (P = 0.00). The right eye and left eye wettings were similar with results of 10.44 (5.84) mm and 10.50 (5.42) mm, respectively, in the patients. After classification of wettings as greater than 5 mm or 5 mm or less in the Schirmer test, we have found that there was a strong correlation between antidepressant use and DE (P < 0.000, Table 2). In the comparison of 3 drugs evaluated in the study, wetting measures were similar (P > 0.05, Table 3). On the other hand, the patients using SSRIs revealed lower wetting measurements (≤5 mm) in comparison to the patients using SNRIs. Ten patients (18.8% of 54 eyes of the patients) had DE in the SNRI group and 19 patients (35% of 54 eyes of the patients) had DE in the SSRI group. The relationships between drug dosages and wetting measurements were not statistically significant in the evaluation of each group. There was not a relationship between the time duration of drug use and wetting measurement either (P = 0.57). In the evaluation of each drug, only venlafaxine use duration negatively correlated to wetting, which was 5 mm or less (r = −0.76, P = 0.002). In addition, the correlations between DE and other parameters such as age, sex, anxiety, and depression scales were not significant.
TABLE 1. Well-Known Causes Related to DE Xerogenic drugs associated with an increased risk for DE •β-Blockers •Diuretics •Antihistamines •Anxiolytics •Neuroleptics •Anticholinergics •Parasympatholytics •Steroids •Oral contraceptives •Antiparkinsonian drugs •Clonidine •Drugs including pseudoephedrine Diseases associated with an increased risk for DE • Arthritis • Sjögren syndrome • Lupus erythematous • Ocular rosacea • Allergy • Thyroid disease • Depression • Poorer self-rated health • Hypertension • Benign prostatic hypertension
DISCUSSION
Pearson test were used for other variables. The level of statistical significance was set at P < 0.05.
RESULTS We assessed the frequency of DE among 54 patients with antidepressant use in comparison to 57 healthy controls. The sociodemographic variables and Schirmer test results were shown in Table 2. Twenty-seven patients were using escitalopram (mean [SD] dosage, 17.78 [4.24] mg/d); 13 patients were using duloxetine (mean [SD] dosage, 48.46 [15.19] mg/d), and 14 patients were using venlafaxine (mean [SD] dosage, 166.07 [31.94] mg/d). Comparison of drug-related results was shown in Table 3. The observed wetting measurements in patients were lower than controls in both eyes (P < 0.000, Table 2). There was also a significant positive correlation between the right and left eyes for
Dry eye patients experience tear film instability with potential damage accompanied by inflammation of the ocular surface.1,3,13,14 This condition is a frequently underrecognized clinical condition and poses strong etiological and management challenges.1,3,7,10 Many studies reported that the DE incidence increased significantly with age and female sex; in subjects with arthritis, Sjögren syndrome, lupus erythematous, ocular rosacea, allergy, and thyroid disease not treated with hormone; in subjects using antihistamines, antianxiety medications, antidepressants, oral steroids, vitamins, β-blockers, and diuretics; and in subjects with poorer self-rated health.7,9,15–17 Depression, hypertension, and benign prostatic hypertension were also associated with an increased risk for DE.2,6,7 Dry eye–related diseases were shown in Table 1. An association between antidepressant use, particularly tricyclic antidepressants and SSRIs, and DE, with decreased lacrimal secretion being the likely mechanism, has been reported in several studies.5–8,16,18 Experimental rat studies suggested that parasympathetic denervation of the human lacrimal gland may induce DE through reduced tear flow and lacrimal protein secretion as well as the activation of inflammatory changes in the gland.19,20 Chronic exposure to histamine and 5-hydroxytryptamine altered the functions thought to be involved in the secretory process, and neuronal release of 5-hydroxytryptamine may be involved in the acute regulation of lacrimal secretion in a broad range of species.19,20
TABLE 2. Sociodemographic and Schirmer Test Findings of Subjects in Comparison Variable
Patients (n = 54)
Age, mean (SD), y Sex Male Female Right eye wetting, mean (SD), median, mm* Left eye wetting, mean (SD), median, mm No. subjects with wetting Right eye >5 mm Right eye ≤5 mm Left eye >5 mm Left eye ≤5 mm
Controls (n = 57)
34.7 (7.9)
34.6 (6.2)
12 42 10.4 (5.8), 9 10.5 (5.4), 10
15 42 12.3 (0.7), 12 12.2 (0.6), 12
39 15 40 14
57 0 57 0
F
t
5.93
0.07
Z
P 0.95 0.62
−3.95 −3.76
0.00 0.00 0.00 0.00
Italic data indicates all values are 5 mm Right eye ≤5 mm Left eye >5 mm Left eye ≤5 mm Beck Depression Scale score, mean (SD) Beck Anxiety Scale score, mean (SD) Duration of drug, mean (SD), wk
In the present study, we demonstrated a significantly higher prevalence of DE among patients using SSRIs, which was independent of dosage. Serotonin-norepinephrine reuptake inhibitors having a pseudo-anticholinergic effect was associated with less DE in comparison. Because SSRIs do not have anticholinergic adverse effects, we hypothesize that DE related to SSRIs is associated with a mechanism other than the anticholinergic system. In the present study, the presence of DE was independent of age, female sex, drug use duration, and drug dosage. As a limitation, this study is a case-control study with a low numbered sample and not a randomized trial. However, we believe it is the most targeted study performed to date because we controlled for all modifiable risk factors related to DE in the present study. A further question is whether depression is related to DE. However, we found no such association. In summary, escitalopram, a commonly used SSRI, seemed to induce DE. Although DE is not commonly reported in clinical trials of antidepressant drugs, we believe that this may be a methodological issue because adverse effects in such trials are often assessed by spontaneous patient reporting or closed-ended lists of the symptoms that do not include DE. Awareness of the drugs that contribute to DE will allow ophthalmologists and other physicians to better manage patients with this problem. ACKNOWLEDGMENT The authors thank all the people who meet the criteria for authorship of this article (persons who have made a substantive intellectual contribution to the submitted manuscript). AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. REFERENCES 1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75–92. 2. Schaumberg DA, Dana R, Buring JE, et al. Prevalence of dry eye disease among US men: estimates from the physicians' health studies. Arch Ophthalmol. 2009;127:763–768.
0.51 0.44 0.17 0.42
0.83 0.043 0.001
5. Lee AJ, Lee J, Saw SM, et al. Prevalence and risk factors associated with dry eye symptoms: a population based study in Indonesia. Br J Ophthalmol. 2002;86:1347–1351. 6. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older population. Optom Vis Sci. 2008;85:668–674. 7. Apostol S, Filip M, Dragne C, et al. Dry eye syndrome. Etiological and therapeutic aspects. Oftalmologia. 2003;59:28–31. 8. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501–526. 9. Chia EM, Mitchell P, Rochtchina E, et al. Prevalence and associations of dry eye syndrome in an older population: the Blue Mountains Eye Study. Clin Experiment Ophthalmol. 2003;31:229–232. 10. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65:959–965. 11. Ulusoy M, Şahin NH, Erkmen H. Turkish version of the Beck Anxiety Inventory: psychometric properties. J Cogn Psychother. 1998;12:163–172. 12. Hisli N. Beck Depresyon Ölçeğinin bir Türk örnekleminde geçerlilik ve güvenirliği. Psychol J. 1988;6:118–122. 13. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:900–907. 14. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–558. 15. Wong J, Lan W, Ong LM, et al. Non-hormonal systemic medications and dry eye. Ocul Surf. 2011;9:212–226. 16. Celik L, Kaynak T, Ozerdem A, et al. Disappointment of patients on antidepressant therapy after excimer laser treatment. J Cataract Refract Surg. 2006;32:1775–1776. 17. Jaanus SD. Ocular side effects of selected systemic drugs. Optom Clin. 1992;2:73–96. 18. Hudson JI, Perahia DG, Gilaberte I, et al. Duloxetine in the treatment of major depressive disorder: an open-label study. BMC Psychiatry. 2007;7:43.
3. Perry HD. Dry eye disease: pathophysiology, classification, and diagnosis. Am J Manag Care. 2008;14:79–87.
19. McDonald ML, Wang Y, Selvam S, et al. Cytopathology and exocrine dysfunction induced in ex vivo rabbit lacrimal gland acinar cell models by chronic exposure to histamine or serotonin. Invest Ophthalmol Vis Sci. 2009;50:3164–3175.
4. Kim KW, Han SB, Han ER, et al. Association between depression and dry eye disease in an elderly population. Invest Ophthalmol Vis Sci. 2011;52: 7954–7958.
20. Klyce SD, Palkama KA, Härkönen M, et al. Neural serotonin stimulates chloride transport in the rabbit corneal epithelium. Invest Ophthalmol Vis Sci. 1982;23:181–192.
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.psychopharmacology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
413
Dry Eye Related to Commonly Used New Antidepressants Emel Koçer, MD,* Abdulkadir Koçer, MD,† Mustafa Özsütçü, MD,‡ Ali Emre Dursun, MD,* and İsmet Kırpınar, MD* Abstract: Antidepressants may have an impact on the course of eye dryness. The aim of this study was to investigate the effects of commonly used new antidepressants on eye wetting. Fifty-four patients using new antidepressants and 57 controls were recruited. The Beck Depression Scale and Beck Anxiety Scale questionnaires were completed by the patients, and drug use time and dosages were recorded. The Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the wetting result was recorded for each eye. Escitalopram, duloxetine, and venlafaxine were used by 27, 13, and 14 patients, respectively. The Schirmer test results in the patients were significantly lower than in the controls (P < 0.001). The patients using selective serotonin reuptake inhibitors (SSRIs) displayed lower wetting measurements (≤5 mm) compared with those using serotonin-norepinephrine reuptake inhibitors, which was independent of the duration of antidepressant usage (P < 0.05). Although SSRIs do not have anticholinergic adverse effects except paroxetine, we found that both SSRIs and serotonin-norepinephrine reuptake inhibitors increased the risk for eye dryness. The lower Schirmer test results of the SSRIs may be associated with a mechanism other than the anticholinergic system. An awareness of the drugs that contribute to dry eye will allow ophthalmologists, optometrists, and other physicians to better manage patients who have this problem. Key Words: antidepressant, depression, dry eye, Schirmer test (J Clin Psychopharmacol 2015;35: 411–413)
D
ry eye (DE) is a disorder resulting from tear deficiency or excessive evaporation, causing irritation to the interpalpebral ocular surface, and is associated with symptoms of ocular discomfort.1–4 Dry eye is a multifactorial disease, and one of the most prevalent eye diseases, and requires eye care, particularly among the elderly.1–6 A strong association between the use of antidepressant medications and DE risk was reported in several studies, including epidemiological studies.5–9 However, the presence of DE is normally underdiagnosed in clinical practice. This may be a methodological issue because the adverse effects in drug trials are often assessed via spontaneous reporting by patients or by closedended lists of symptoms not including DE. Therefore, DE is uncommon in clinical trial reports on antidepressant drugs, whereas dry mouth is prevalent. For example, the only ocular symptom on the list of 17 common adverse effects reported by patients taking antidepressants from a specific study was blurred vision, as reported by 85% of the patients.10 Moreover, the presence of DE has, to our knowledge, never been studied systematically in patients using new and widely prescribed antidepressants. Therefore, we investigated the prevalence of DE in patients with depression who were using antidepressants and compared the findings with those of age-matched controls. In
From the *Psychiatry Department, Bezmialem Vakıf University Medical Faculty; †Neurology Department, Istanbul Medeniyet University Medical Faculty; and ‡Ophtalmology Department, Bezmialem Vakıf University Medical Faculty, Istanbul, Turkey. Received December 15, 2014; accepted after revision May 1, 2015. Reprints: Emel Koçer, MD, Psychiatry Department, Bezmialem Vakıf University Medical Faculty, Namik Kemal Mah, Kirişhane Cad, İstanbul Sitesi, 20/24, Istanbul, Turkey (e‐mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000356
addition, we determined the correlation between clinical variables and DE.
MATERIALS AND METHODS The patients followed-up by a diagnosis of depression based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and a history of escitalopram (selective serotonin reuptake inhibitor [SSRI]), duloxetine (serotoninnorepinephrine reuptake inhibitor [SNRI]), or venlafaxine (SNRI) usage at least for 4 weeks in psychiatry outpatient clinics of our medical faculty were examined in this study. The patients using only high doses of venlafaxine were included in the study because high-dose venlafaxine had effect on noradrenergic and cholinergic system. The patients were excluded if they were aged younger than 16 years or older than 60 years, currently using xerogenic drugs that causes the oral cavity to be unusually dry (Table 1). Those with underlying human immunodeficiency virus infection, graft versus host disease, thyroid disease untreated with hormone, amyloidosis, lymphoma, prior head and neck radiation, sarcoidosis, chronic active hepatitis, renal insufficiency, and vasculitis were also excluded. In addition, those who used or who were using a tear substitute or those who were long-term contact lens wearers were excluded from the study. Cigarette smoking was another exclusion criterion. First, sociodemographic variables and the drugs that were used by the patients included in the study were recorded. Second, all patients completed the Beck Depression Scale and Beck Anxiety Scale.11,12 Third, all patients and age- and sex-matched controls were examined for tear volume by Schirmer test. Research in this study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from each participant before any related procedure was performed, and the study was approved by the local ethics committee.
Schirmer Test Measurement Schirmer test determines whether the eye produces enough tears to keep it moist. Schirmer test measure change in tear by the observed wetting of a standardized paper strip placed over the inferior eyelid over a given period.13 The patients sat with their eyes closed for 5 minutes before the strips were removed. The length of wet area starting from the notch corresponding to the lower eyelid margin was measured. Schirmer test was performed without prior instillation of topical anesthesia to the ocular surface, and the test result was recorded in millimeter for each eye. After that, wet areas were classified as greater than 5 mm and 5 mm or less at 1 or both eyes.13,14 The patients with 5 mm or less result were recorded as the patients having DE. All tests were performed on both eyes by the same researcher.
Statistical Analysis Statistical analysis was performed using SPSS for Windows, version 11. Clinical features of the patients were evaluated. Mean values and standard deviations were calculated for all variables. The Mann-Whitney U test and Spearman test were used to analyze differences in median and relationship between the wetting measures of patients and controls because of abnormal distribution in the patients. The median and minimum-maximum values were used in tables. One-way analysis of variance, Student t test, and
Journal of Clinical Psychopharmacology • Volume 35, Number 4, August 2015
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
411
Journal of Clinical Psychopharmacology • Volume 35, Number 4, August 2015
Koçer et al
wettings (P = 0.00). The right eye and left eye wettings were similar with results of 10.44 (5.84) mm and 10.50 (5.42) mm, respectively, in the patients. After classification of wettings as greater than 5 mm or 5 mm or less in the Schirmer test, we have found that there was a strong correlation between antidepressant use and DE (P < 0.000, Table 2). In the comparison of 3 drugs evaluated in the study, wetting measures were similar (P > 0.05, Table 3). On the other hand, the patients using SSRIs revealed lower wetting measurements (≤5 mm) in comparison to the patients using SNRIs. Ten patients (18.8% of 54 eyes of the patients) had DE in the SNRI group and 19 patients (35% of 54 eyes of the patients) had DE in the SSRI group. The relationships between drug dosages and wetting measurements were not statistically significant in the evaluation of each group. There was not a relationship between the time duration of drug use and wetting measurement either (P = 0.57). In the evaluation of each drug, only venlafaxine use duration negatively correlated to wetting, which was 5 mm or less (r = −0.76, P = 0.002). In addition, the correlations between DE and other parameters such as age, sex, anxiety, and depression scales were not significant.
TABLE 1. Well-Known Causes Related to DE Xerogenic drugs associated with an increased risk for DE •β-Blockers •Diuretics •Antihistamines •Anxiolytics •Neuroleptics •Anticholinergics •Parasympatholytics •Steroids •Oral contraceptives •Antiparkinsonian drugs •Clonidine •Drugs including pseudoephedrine Diseases associated with an increased risk for DE • Arthritis • Sjögren syndrome • Lupus erythematous • Ocular rosacea • Allergy • Thyroid disease • Depression • Poorer self-rated health • Hypertension • Benign prostatic hypertension
DISCUSSION
Pearson test were used for other variables. The level of statistical significance was set at P < 0.05.
RESULTS We assessed the frequency of DE among 54 patients with antidepressant use in comparison to 57 healthy controls. The sociodemographic variables and Schirmer test results were shown in Table 2. Twenty-seven patients were using escitalopram (mean [SD] dosage, 17.78 [4.24] mg/d); 13 patients were using duloxetine (mean [SD] dosage, 48.46 [15.19] mg/d), and 14 patients were using venlafaxine (mean [SD] dosage, 166.07 [31.94] mg/d). Comparison of drug-related results was shown in Table 3. The observed wetting measurements in patients were lower than controls in both eyes (P < 0.000, Table 2). There was also a significant positive correlation between the right and left eyes for
Dry eye patients experience tear film instability with potential damage accompanied by inflammation of the ocular surface.1,3,13,14 This condition is a frequently underrecognized clinical condition and poses strong etiological and management challenges.1,3,7,10 Many studies reported that the DE incidence increased significantly with age and female sex; in subjects with arthritis, Sjögren syndrome, lupus erythematous, ocular rosacea, allergy, and thyroid disease not treated with hormone; in subjects using antihistamines, antianxiety medications, antidepressants, oral steroids, vitamins, β-blockers, and diuretics; and in subjects with poorer self-rated health.7,9,15–17 Depression, hypertension, and benign prostatic hypertension were also associated with an increased risk for DE.2,6,7 Dry eye–related diseases were shown in Table 1. An association between antidepressant use, particularly tricyclic antidepressants and SSRIs, and DE, with decreased lacrimal secretion being the likely mechanism, has been reported in several studies.5–8,16,18 Experimental rat studies suggested that parasympathetic denervation of the human lacrimal gland may induce DE through reduced tear flow and lacrimal protein secretion as well as the activation of inflammatory changes in the gland.19,20 Chronic exposure to histamine and 5-hydroxytryptamine altered the functions thought to be involved in the secretory process, and neuronal release of 5-hydroxytryptamine may be involved in the acute regulation of lacrimal secretion in a broad range of species.19,20
TABLE 2. Sociodemographic and Schirmer Test Findings of Subjects in Comparison Variable
Patients (n = 54)
Age, mean (SD), y Sex Male Female Right eye wetting, mean (SD), median, mm* Left eye wetting, mean (SD), median, mm No. subjects with wetting Right eye >5 mm Right eye ≤5 mm Left eye >5 mm Left eye ≤5 mm
Controls (n = 57)
34.7 (7.9)
34.6 (6.2)
12 42 10.4 (5.8), 9 10.5 (5.4), 10
15 42 12.3 (0.7), 12 12.2 (0.6), 12
39 15 40 14
57 0 57 0
F
t
5.93
0.07
Z
P 0.95 0.62
−3.95 −3.76
0.00 0.00 0.00 0.00
Italic data indicates all values are 5 mm Right eye ≤5 mm Left eye >5 mm Left eye ≤5 mm Beck Depression Scale score, mean (SD) Beck Anxiety Scale score, mean (SD) Duration of drug, mean (SD), wk
In the present study, we demonstrated a significantly higher prevalence of DE among patients using SSRIs, which was independent of dosage. Serotonin-norepinephrine reuptake inhibitors having a pseudo-anticholinergic effect was associated with less DE in comparison. Because SSRIs do not have anticholinergic adverse effects, we hypothesize that DE related to SSRIs is associated with a mechanism other than the anticholinergic system. In the present study, the presence of DE was independent of age, female sex, drug use duration, and drug dosage. As a limitation, this study is a case-control study with a low numbered sample and not a randomized trial. However, we believe it is the most targeted study performed to date because we controlled for all modifiable risk factors related to DE in the present study. A further question is whether depression is related to DE. However, we found no such association. In summary, escitalopram, a commonly used SSRI, seemed to induce DE. Although DE is not commonly reported in clinical trials of antidepressant drugs, we believe that this may be a methodological issue because adverse effects in such trials are often assessed by spontaneous patient reporting or closed-ended lists of the symptoms that do not include DE. Awareness of the drugs that contribute to DE will allow ophthalmologists and other physicians to better manage patients with this problem. ACKNOWLEDGMENT The authors thank all the people who meet the criteria for authorship of this article (persons who have made a substantive intellectual contribution to the submitted manuscript). AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. REFERENCES 1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75–92. 2. Schaumberg DA, Dana R, Buring JE, et al. Prevalence of dry eye disease among US men: estimates from the physicians' health studies. Arch Ophthalmol. 2009;127:763–768.
0.51 0.44 0.17 0.42
0.83 0.043 0.001
5. Lee AJ, Lee J, Saw SM, et al. Prevalence and risk factors associated with dry eye symptoms: a population based study in Indonesia. Br J Ophthalmol. 2002;86:1347–1351. 6. Moss SE, Klein R, Klein BE. Long-term incidence of dry eye in an older population. Optom Vis Sci. 2008;85:668–674. 7. Apostol S, Filip M, Dragne C, et al. Dry eye syndrome. Etiological and therapeutic aspects. Oftalmologia. 2003;59:28–31. 8. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs. 2010;24:501–526. 9. Chia EM, Mitchell P, Rochtchina E, et al. Prevalence and associations of dry eye syndrome in an older population: the Blue Mountains Eye Study. Clin Experiment Ophthalmol. 2003;31:229–232. 10. Hu XH, Bull SA, Hunkeler EM, et al. Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry. 2004;65:959–965. 11. Ulusoy M, Şahin NH, Erkmen H. Turkish version of the Beck Anxiety Inventory: psychometric properties. J Cogn Psychother. 1998;12:163–172. 12. Hisli N. Beck Depresyon Ölçeğinin bir Türk örnekleminde geçerlilik ve güvenirliği. Psychol J. 1988;6:118–122. 13. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:900–907. 14. Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–558. 15. Wong J, Lan W, Ong LM, et al. Non-hormonal systemic medications and dry eye. Ocul Surf. 2011;9:212–226. 16. Celik L, Kaynak T, Ozerdem A, et al. Disappointment of patients on antidepressant therapy after excimer laser treatment. J Cataract Refract Surg. 2006;32:1775–1776. 17. Jaanus SD. Ocular side effects of selected systemic drugs. Optom Clin. 1992;2:73–96. 18. Hudson JI, Perahia DG, Gilaberte I, et al. Duloxetine in the treatment of major depressive disorder: an open-label study. BMC Psychiatry. 2007;7:43.
3. Perry HD. Dry eye disease: pathophysiology, classification, and diagnosis. Am J Manag Care. 2008;14:79–87.
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