Clinical and Epidemiologic Research
Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography Wei Wei Lee,1 Iqbal Tajunisah,1 Kanagasundram Sharmilla,2 Mohammadreza Peyman,1 and Visvaraja Subrayan1 1Department 2
of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia Department of Psychiatry, University of Malaya, Kuala Lumpur, Malaysia
Correspondence: Iqbal Tajunisah, Department of Ophthalmology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; [email protected]. Submitted: June 4, 2013 Accepted: October 7, 2013 Citation: Lee WW, Tajunisah I, Sharmilla K, Peyman M, Subrayan V. Retinal nerve fiber layer structure abnormalities in schizophrenia and its relationship to disease state: evidence from optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54:7785–7792. DOI:10.1167/ iovs.13-12534
PURPOSE. We determined structural retinal nerve fiber layer (RNFL) changes in schizophrenia patients and established if the structural changes were related to the duration of the illness using spectral-domain optical coherence tomography (SD-OCT). METHODS. We recruited a total of 30 schizophrenic patients and 30 age-matched controls in the study. The schizophrenic patients were subdivided further to acute (n ¼ 5), chronic (n ¼ 13), and long-term chronic (n ¼ 12) subgroups depending on their duration of illness. Using SD-OCT, the peripapillary RNFL thickness, macula thickness, and macula volume measurements of schizophrenic patients and the control subjects were measured and compared at each location. RESULTS. Schizophrenic patients showed a statistically significant reduction in overall peripapillary RNFL thickness (cases, 94.70 6 9.88 lm; controls, 103.53 6 6.53 lm; P < 0.001), macula thickness (cases, 269.26 6 12.59 lm; controls, 284.83 6 9.76 lm; P < 0.001), and macula volume (cases, 9.61 6 0.45 mm3; controls, 10.17 6 0.35 lm; P < 0.001). Chronic and long-term chronic schizophrenic patients were found to have significant peripapillary RNFL thinning, macula thinning, and reduction of macula volume when compared to controls (P < 0.001). There also was a statistically significant reverse correlation (P < 0.05) of peripapillary RNFL thickness (r ¼ 0.36), macula thickness (r ¼ 0.38), and macula volume reduction (r ¼ 0.36) with the duration of schizophrenic illness. CONCLUSIONS. These results indicate that RNFL and macula thickness, as well as macula volume measurements are reduced in schizophrenic patients. The degree of thinning and reduction was more significant in the chronic phase of the disease and correlated with the duration of illness. These findings demonstrate that SD-OCT can be a useful tool for the diagnosis and monitoring the progression of this disease. Keywords: schizophrenia, retinal nerve fiber layer, SD-OCT, duration of illness
chizophrenia is a chronic and relapsing illness with generally incomplete remissions. It is characterized by an admixture of positive, negative, cognitive, and mood symptoms. Because of the pervasiveness of associated deficits and frequently lifelong course, it is among the top 10 leading causes of disease-related disability in the world.1 Neuroimaging studies have found evidence of significant reduction of total brain volume in schizophrenic patients compared to age-matched controls,2,3 and the brain volume reduction has been shown to be progressive.4–6 Neuroimaging studies also have shown grey matter volume deficits in those with chronic schizophrenia,7 those in their first episode of psychosis,8 those in the prodromal phase of illness,9 and those with high genetic risk of schizophrenia.10 However, the precise neuropathologic changes that may explain this grey matter volume deficit remains to be determined. Optical coherence tomography (OCT) is a noninvasive and fast imaging technique to assess the thickness of the retinal nerve fiber layer (RNFL), macula thickness, and volume. Imaging with OCT has been used to assess RNFL thickness in
several neurologic diseases, such as in multiple sclerosis,11–13 Alzheimer’s disease,14,15 and Parkinson’s disease.16 The retina is a good model for the study of these neurodegeneration diseases, since it lacks myelin. This means that any changes in the RNFL will reflect axonal damage, thus, providing us a window to the brain. Brain atrophy had been well established in multiple sclerosis17 and Alzheimer’s disease,18 and the OCT findings of significant RNFL thinning in these diseases correlated with the neurologic changes.12–16 Schizophrenia has been associated with deficits in visual perception and processing as evidenced by previous studies.19,20 It has been postulated that this could be due to dopamine dysregulation, as Djamgoz et al.21 have established that dopamine is a major neurotransmitter and modulator in the retina. Lack of retinal dopamine is believed to alter visual processing by modification of receptive field properties of ganglion cells.21 Bodis-Wollner et al.22 have shown in an animal model that retina with dopaminergic deficiency loses a subset of retinal amacrine cells. It also remains to be determined whether dopamine dysregulation actually causes any structural
Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783
7785
S
IOVS j November 2013 j Vol. 54 j No. 12 j 7786
RNFL Structure in Schizophrenia TABLE 1. Demographic Characteristics Characteristic Schizophrenia Eyes, n
Control
30
Total
30
Age, y
0.641*
Mean 6 SD
37.17 6 10.67
Sex, n (%) Male Female
35.97 6 9.10 0.301†
18 (60.0) 12 (40.0)
14 (46.7) 16 (53.3)
32 (53.3) 28 (46.7)
7 17 5 1
9 16 5 0
16 33 10 1
Ethnicity, n (%)
0.734†
Malay Chinese Indian Others
(23.3) (56.7) (16.7) (3.3)
(30.0) (53.3) (16.7) (0.0)
VAS Mean 6 SD
P Value
(26.7) (55.0) (16.7) (1.7) 0.068*
100.00 6 5.25
102.17 6 3.64
* Independent t-test. † Pearson v2 test.
defects of the optic nerve and retinal layers in schizophrenic patients. Previous studies done for Parkinson’s disease, also a disease with dopamine abnormalities, showed significant loss of RNFL thickness.16 However, Parkinson’s disease is at the other end of the spectrum, where the dopamine levels are low compared to the raised level in schizophrenic patients. Neural excitotoxicity due to excess of glutamate also was suggested to contribute to the neurodegenerative process of schizophrenia.23 Histologic analyses of presynaptic neurons and physiologic recordings from postsynaptic cells have shown that photoreceptor, bipolar, and ganglion cells release glutamate as their neurotransmitter, and multiple glutamate receptors have been identified in the retina.24–27 Glutamate has been shown to act as a neurotoxin, which exerts its toxic effect causing destruction of retinal ganglion cells.28 In neurologic diseases, such as Parkinson’s and Alzheimer’s, where loss of RNFL thickness have been shown, pathologic activation of glutamate receptors is thought to be a final common pathway leading to neuronal damage in the course of the disease.14–16,29 However, it still remains to be confirmed if excessive glutamate causes any structural damage to optic nerve and retinal layers in schizophrenic patients, thus, explaining the visual processing deficits observed in these patients. With evidences of visual processing and grey matter volume deficits in schizophrenia,2,3,19,20 evaluation of structural RNFL with OCT may establish tissue loss, which can explain the abnormalities mentioned above. The main aim of our study was to evaluate the RNFL thickness in schizophrenic patients using spectral domain OCT (SD-OCT), and to compare the peripapillary RNFL thickness, macula thickness, and macula volume between these patients and the normal control population. We also evaluated schizophrenic patients in different phases of the disease, acute, chronic, and long-standing chronic, to see if there was any significant difference in the RNFL structure according to the chronicity of the disease.
MATERIALS
AND
METHODS
This was a case-control prospective study conducted in University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia, between August 2012 and March 2013. This study was done in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice guidelines. Institutional
Review Board approval was obtained from the Medical Ethics Board of UMMC. Informed consent was obtained from all participants or their guardians after explanation of the nature of study. We recruited 30 consecutive schizophrenic patients who met the requirements for the inclusion and exclusion criteria into the study. The schizophrenic patients consisted of those admitted to the adult Psychiatry ward for an acute attack of schizophrenia, as well as chronic patients attending the Psychiatric clinic for follow-up in UMMC during the period of the study. Only patients more than 18 years old were recruited. The schizophrenic patients underwent a detailed psychiatric examination to confirm diagnosis based on the DSM IV-TR criteria,30 and an assessment by the means of the Positive and Negative Syndrome Scale (PANSS)31 interview. Schizophrenic patients were subdivided further into ‘‘acute,’’ ‘‘chronic,’’ and ‘‘long-term chronic’’ subgroups.31 The acute schizophrenia group consisted of patients who were diagnosed recently with a duration of illness of 2 years or less, the chronic schizophrenia group consisted of patients with a duration of illness of more than 2 years up to 10 years, and the long-term chronic schizophrenia group consisted of patients with a duration of illness of more than 10 years.31 At the same time, 30 age-matched controls were recruited among the hospital staffs and volunteers. These control subjects were age, sex, and racially matched with the patients. The control subjects underwent a structured clinical interview to screen out psychiatric disorders using the Structured Clinical Interview for DSM-IV (SCID) guidelines.30 Participants with conditions that might affect the retinal nerve fiber structures were excluded from this study. These conditions included any ocular pathology, such as macular degeneration or optic neuropathies, including glaucoma, history of ocular trauma, or ocular diseases, recent ocular surgery within the past three months, previously known history of hypotensive crisis, and any history of intracranial or intraorbital space-occupying lesions that can affect the visual pathway. Also excluded from the study were any patients or control subjects with known diabetes mellitus, with myopia more than 2.0 diopters (D), and eyes with significant media opacities precluding ocular examination or OCT measurement. All the study participants were subjected to a full ophthalmologic evaluation. Best corrected visual acuity of each eye was measured with a Snellen chart and refraction was performed for all. Slit-lamp biomicroscopy of the anterior segment and IOP measurements using Goldman tonometry were performed in all participants to exclude ocular pathologies. This was followed by a dilated fundus examination performed with the 90 D condensing lens. Subsequently, the measurement of peripapillary RNFL thickness and macula thickness, and macula volume were taken for both eyes using the Spectral Domain Cirrus OCT Model 4000 (Carl Zeiss Meditech, Jena, Germany). Scan signal strength of 7 or greater was deemed acceptable. For the peripapillary RNFL measurement, 3-dimensional (3D) cube OCT data were obtained using the ‘‘Optic Disc Cube 200 3 200 Scan’’ pattern, which performed raster scanning in a 6 3 6 mm square centered on the optic nerve head. After creating an RNFL thickness map from this data set, the software automatically determined the disc center and then extracted a circumpapillary circle (3.4 mm in diameter) from the cube data set for RNFL thickness measurement. The RFNL parameters evaluated were the global RNFL average (in micrometers), and RNFL thickness in 4 quadrants and in 12 clock hour positions. The RNFL measurements in quadrants were evaluated in the four 908 sectors: superior, inferior, nasal, and temporal. The macula region OCT scan is based on the 6 3 6 mm data cube captured by the Macular Cube 512 3 128 scan. This analysis provided
RNFL Structure in Schizophrenia
IOVS j November 2013 j Vol. 54 j No. 12 j 7787
FIGURE. An example of a report obtained with SD-OCT from a patient with schizophrenia. (A) Shows macula thickness and volume. Top middle diagram: retinal thickness of quadrants between the ILM and RPE (ILM-RPE) is indicated. The central macula shows the foveola that is surrounded by the four quadrants of inner macula showing the para foveola. The average macular thickness shown in the bottom right table. (B) Shows the peripapillary RNFL of both eyes. The average RNFL thickness for the right (OD) and left (OS) eyes is indicated (top middle). Also, RNFL thickness of quadrants and sectors is shown (bottom middle).
qualitative and quantitative evaluation of the retina. The Early Treatment Diabetic Retinopathy Study (ETDRS) grid, which consisted of one central circle of 500 lm radius (the foveal region), an inner and outer ring, each divided into four quadrants, was centered automatically on the fovea with the Fovea Finder. Retinal thickness values, from the inner limiting membrane (ILM) to the RPE, in micrometers, were compared to normative data. The statistical analysis in this study was done using the Statistical Package for Social Sciences (SPSS) version 21 (SPSS, Inc., Chicago, IL). The independent t-test was used to analyze if the cases and controls were age-matched. The Shapiro-Wilk test was used to evaluate if the data followed a normal distribution. The statistical differences in the RNFL thickness, macula thickness, and macula volume between schizophrenic patients and controls were determined by an independent ttest. The differences between the schizophrenic subgroups and controls were analyzed with a multivariable ANOVA test followed by the post hoc least significant difference (LSD) test. The RNFL thickness, macula thickness, and macula volume were correlated with the duration of illness using the Pearson correlation analysis. A level of
Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography Wei Wei Lee,1 Iqbal Tajunisah,1 Kanagasundram Sharmilla,2 Mohammadreza Peyman,1 and Visvaraja Subrayan1 1Department 2
of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia Department of Psychiatry, University of Malaya, Kuala Lumpur, Malaysia
Correspondence: Iqbal Tajunisah, Department of Ophthalmology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; [email protected]. Submitted: June 4, 2013 Accepted: October 7, 2013 Citation: Lee WW, Tajunisah I, Sharmilla K, Peyman M, Subrayan V. Retinal nerve fiber layer structure abnormalities in schizophrenia and its relationship to disease state: evidence from optical coherence tomography. Invest Ophthalmol Vis Sci. 2013;54:7785–7792. DOI:10.1167/ iovs.13-12534
PURPOSE. We determined structural retinal nerve fiber layer (RNFL) changes in schizophrenia patients and established if the structural changes were related to the duration of the illness using spectral-domain optical coherence tomography (SD-OCT). METHODS. We recruited a total of 30 schizophrenic patients and 30 age-matched controls in the study. The schizophrenic patients were subdivided further to acute (n ¼ 5), chronic (n ¼ 13), and long-term chronic (n ¼ 12) subgroups depending on their duration of illness. Using SD-OCT, the peripapillary RNFL thickness, macula thickness, and macula volume measurements of schizophrenic patients and the control subjects were measured and compared at each location. RESULTS. Schizophrenic patients showed a statistically significant reduction in overall peripapillary RNFL thickness (cases, 94.70 6 9.88 lm; controls, 103.53 6 6.53 lm; P < 0.001), macula thickness (cases, 269.26 6 12.59 lm; controls, 284.83 6 9.76 lm; P < 0.001), and macula volume (cases, 9.61 6 0.45 mm3; controls, 10.17 6 0.35 lm; P < 0.001). Chronic and long-term chronic schizophrenic patients were found to have significant peripapillary RNFL thinning, macula thinning, and reduction of macula volume when compared to controls (P < 0.001). There also was a statistically significant reverse correlation (P < 0.05) of peripapillary RNFL thickness (r ¼ 0.36), macula thickness (r ¼ 0.38), and macula volume reduction (r ¼ 0.36) with the duration of schizophrenic illness. CONCLUSIONS. These results indicate that RNFL and macula thickness, as well as macula volume measurements are reduced in schizophrenic patients. The degree of thinning and reduction was more significant in the chronic phase of the disease and correlated with the duration of illness. These findings demonstrate that SD-OCT can be a useful tool for the diagnosis and monitoring the progression of this disease. Keywords: schizophrenia, retinal nerve fiber layer, SD-OCT, duration of illness
chizophrenia is a chronic and relapsing illness with generally incomplete remissions. It is characterized by an admixture of positive, negative, cognitive, and mood symptoms. Because of the pervasiveness of associated deficits and frequently lifelong course, it is among the top 10 leading causes of disease-related disability in the world.1 Neuroimaging studies have found evidence of significant reduction of total brain volume in schizophrenic patients compared to age-matched controls,2,3 and the brain volume reduction has been shown to be progressive.4–6 Neuroimaging studies also have shown grey matter volume deficits in those with chronic schizophrenia,7 those in their first episode of psychosis,8 those in the prodromal phase of illness,9 and those with high genetic risk of schizophrenia.10 However, the precise neuropathologic changes that may explain this grey matter volume deficit remains to be determined. Optical coherence tomography (OCT) is a noninvasive and fast imaging technique to assess the thickness of the retinal nerve fiber layer (RNFL), macula thickness, and volume. Imaging with OCT has been used to assess RNFL thickness in
several neurologic diseases, such as in multiple sclerosis,11–13 Alzheimer’s disease,14,15 and Parkinson’s disease.16 The retina is a good model for the study of these neurodegeneration diseases, since it lacks myelin. This means that any changes in the RNFL will reflect axonal damage, thus, providing us a window to the brain. Brain atrophy had been well established in multiple sclerosis17 and Alzheimer’s disease,18 and the OCT findings of significant RNFL thinning in these diseases correlated with the neurologic changes.12–16 Schizophrenia has been associated with deficits in visual perception and processing as evidenced by previous studies.19,20 It has been postulated that this could be due to dopamine dysregulation, as Djamgoz et al.21 have established that dopamine is a major neurotransmitter and modulator in the retina. Lack of retinal dopamine is believed to alter visual processing by modification of receptive field properties of ganglion cells.21 Bodis-Wollner et al.22 have shown in an animal model that retina with dopaminergic deficiency loses a subset of retinal amacrine cells. It also remains to be determined whether dopamine dysregulation actually causes any structural
Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783
7785
S
IOVS j November 2013 j Vol. 54 j No. 12 j 7786
RNFL Structure in Schizophrenia TABLE 1. Demographic Characteristics Characteristic Schizophrenia Eyes, n
Control
30
Total
30
Age, y
0.641*
Mean 6 SD
37.17 6 10.67
Sex, n (%) Male Female
35.97 6 9.10 0.301†
18 (60.0) 12 (40.0)
14 (46.7) 16 (53.3)
32 (53.3) 28 (46.7)
7 17 5 1
9 16 5 0
16 33 10 1
Ethnicity, n (%)
0.734†
Malay Chinese Indian Others
(23.3) (56.7) (16.7) (3.3)
(30.0) (53.3) (16.7) (0.0)
VAS Mean 6 SD
P Value
(26.7) (55.0) (16.7) (1.7) 0.068*
100.00 6 5.25
102.17 6 3.64
* Independent t-test. † Pearson v2 test.
defects of the optic nerve and retinal layers in schizophrenic patients. Previous studies done for Parkinson’s disease, also a disease with dopamine abnormalities, showed significant loss of RNFL thickness.16 However, Parkinson’s disease is at the other end of the spectrum, where the dopamine levels are low compared to the raised level in schizophrenic patients. Neural excitotoxicity due to excess of glutamate also was suggested to contribute to the neurodegenerative process of schizophrenia.23 Histologic analyses of presynaptic neurons and physiologic recordings from postsynaptic cells have shown that photoreceptor, bipolar, and ganglion cells release glutamate as their neurotransmitter, and multiple glutamate receptors have been identified in the retina.24–27 Glutamate has been shown to act as a neurotoxin, which exerts its toxic effect causing destruction of retinal ganglion cells.28 In neurologic diseases, such as Parkinson’s and Alzheimer’s, where loss of RNFL thickness have been shown, pathologic activation of glutamate receptors is thought to be a final common pathway leading to neuronal damage in the course of the disease.14–16,29 However, it still remains to be confirmed if excessive glutamate causes any structural damage to optic nerve and retinal layers in schizophrenic patients, thus, explaining the visual processing deficits observed in these patients. With evidences of visual processing and grey matter volume deficits in schizophrenia,2,3,19,20 evaluation of structural RNFL with OCT may establish tissue loss, which can explain the abnormalities mentioned above. The main aim of our study was to evaluate the RNFL thickness in schizophrenic patients using spectral domain OCT (SD-OCT), and to compare the peripapillary RNFL thickness, macula thickness, and macula volume between these patients and the normal control population. We also evaluated schizophrenic patients in different phases of the disease, acute, chronic, and long-standing chronic, to see if there was any significant difference in the RNFL structure according to the chronicity of the disease.
MATERIALS
AND
METHODS
This was a case-control prospective study conducted in University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia, between August 2012 and March 2013. This study was done in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice guidelines. Institutional
Review Board approval was obtained from the Medical Ethics Board of UMMC. Informed consent was obtained from all participants or their guardians after explanation of the nature of study. We recruited 30 consecutive schizophrenic patients who met the requirements for the inclusion and exclusion criteria into the study. The schizophrenic patients consisted of those admitted to the adult Psychiatry ward for an acute attack of schizophrenia, as well as chronic patients attending the Psychiatric clinic for follow-up in UMMC during the period of the study. Only patients more than 18 years old were recruited. The schizophrenic patients underwent a detailed psychiatric examination to confirm diagnosis based on the DSM IV-TR criteria,30 and an assessment by the means of the Positive and Negative Syndrome Scale (PANSS)31 interview. Schizophrenic patients were subdivided further into ‘‘acute,’’ ‘‘chronic,’’ and ‘‘long-term chronic’’ subgroups.31 The acute schizophrenia group consisted of patients who were diagnosed recently with a duration of illness of 2 years or less, the chronic schizophrenia group consisted of patients with a duration of illness of more than 2 years up to 10 years, and the long-term chronic schizophrenia group consisted of patients with a duration of illness of more than 10 years.31 At the same time, 30 age-matched controls were recruited among the hospital staffs and volunteers. These control subjects were age, sex, and racially matched with the patients. The control subjects underwent a structured clinical interview to screen out psychiatric disorders using the Structured Clinical Interview for DSM-IV (SCID) guidelines.30 Participants with conditions that might affect the retinal nerve fiber structures were excluded from this study. These conditions included any ocular pathology, such as macular degeneration or optic neuropathies, including glaucoma, history of ocular trauma, or ocular diseases, recent ocular surgery within the past three months, previously known history of hypotensive crisis, and any history of intracranial or intraorbital space-occupying lesions that can affect the visual pathway. Also excluded from the study were any patients or control subjects with known diabetes mellitus, with myopia more than 2.0 diopters (D), and eyes with significant media opacities precluding ocular examination or OCT measurement. All the study participants were subjected to a full ophthalmologic evaluation. Best corrected visual acuity of each eye was measured with a Snellen chart and refraction was performed for all. Slit-lamp biomicroscopy of the anterior segment and IOP measurements using Goldman tonometry were performed in all participants to exclude ocular pathologies. This was followed by a dilated fundus examination performed with the 90 D condensing lens. Subsequently, the measurement of peripapillary RNFL thickness and macula thickness, and macula volume were taken for both eyes using the Spectral Domain Cirrus OCT Model 4000 (Carl Zeiss Meditech, Jena, Germany). Scan signal strength of 7 or greater was deemed acceptable. For the peripapillary RNFL measurement, 3-dimensional (3D) cube OCT data were obtained using the ‘‘Optic Disc Cube 200 3 200 Scan’’ pattern, which performed raster scanning in a 6 3 6 mm square centered on the optic nerve head. After creating an RNFL thickness map from this data set, the software automatically determined the disc center and then extracted a circumpapillary circle (3.4 mm in diameter) from the cube data set for RNFL thickness measurement. The RFNL parameters evaluated were the global RNFL average (in micrometers), and RNFL thickness in 4 quadrants and in 12 clock hour positions. The RNFL measurements in quadrants were evaluated in the four 908 sectors: superior, inferior, nasal, and temporal. The macula region OCT scan is based on the 6 3 6 mm data cube captured by the Macular Cube 512 3 128 scan. This analysis provided
RNFL Structure in Schizophrenia
IOVS j November 2013 j Vol. 54 j No. 12 j 7787
FIGURE. An example of a report obtained with SD-OCT from a patient with schizophrenia. (A) Shows macula thickness and volume. Top middle diagram: retinal thickness of quadrants between the ILM and RPE (ILM-RPE) is indicated. The central macula shows the foveola that is surrounded by the four quadrants of inner macula showing the para foveola. The average macular thickness shown in the bottom right table. (B) Shows the peripapillary RNFL of both eyes. The average RNFL thickness for the right (OD) and left (OS) eyes is indicated (top middle). Also, RNFL thickness of quadrants and sectors is shown (bottom middle).
qualitative and quantitative evaluation of the retina. The Early Treatment Diabetic Retinopathy Study (ETDRS) grid, which consisted of one central circle of 500 lm radius (the foveal region), an inner and outer ring, each divided into four quadrants, was centered automatically on the fovea with the Fovea Finder. Retinal thickness values, from the inner limiting membrane (ILM) to the RPE, in micrometers, were compared to normative data. The statistical analysis in this study was done using the Statistical Package for Social Sciences (SPSS) version 21 (SPSS, Inc., Chicago, IL). The independent t-test was used to analyze if the cases and controls were age-matched. The Shapiro-Wilk test was used to evaluate if the data followed a normal distribution. The statistical differences in the RNFL thickness, macula thickness, and macula volume between schizophrenic patients and controls were determined by an independent ttest. The differences between the schizophrenic subgroups and controls were analyzed with a multivariable ANOVA test followed by the post hoc least significant difference (LSD) test. The RNFL thickness, macula thickness, and macula volume were correlated with the duration of illness using the Pearson correlation analysis. A level of
