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Clinical and Epidemiologic Research  |   November 2013
Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography
Author Affiliations & Notes
  • Wei Wei Lee
    Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
  • Iqbal Tajunisah
    Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
  • Kanagasundram Sharmilla
    Department of Psychiatry, University of Malaya, Kuala Lumpur, Malaysia
  • Mohammadreza Peyman
    Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
  • Visvaraja Subrayan
    Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia
  • Correspondence: Iqbal Tajunisah, Department of Ophthalmology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; tajun69@yahoo.com
Investigative Ophthalmology & Visual Science November 2013, Vol.54, 7785-7792. doi:10.1167/iovs.13-12534
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      Wei Wei Lee, Iqbal Tajunisah, Kanagasundram Sharmilla, Mohammadreza Peyman, Visvaraja Subrayan; 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(12):7785-7792. doi: 10.1167/iovs.13-12534.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

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 = 5), chronic (n = 13), and long-term chronic (n = 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 ± 9.88 μm; controls, 103.53 ± 6.53 μm; P < 0.001), macula thickness (cases, 269.26 ± 12.59 μm; controls, 284.83 ± 9.76 μm; P < 0.001), and macula volume (cases, 9.61 ± 0.45 mm3; controls, 10.17 ± 0.35 μm; 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 = 0.36), macula thickness (r = −0.38), and macula volume reduction (r = −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.

Introduction
Schizophrenia 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. 46 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, 1113 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 sclerosis 17 and Alzheimer's disease, 18 and the OCT findings of significant RNFL thinning in these diseases correlated with the neurologic changes. 1216  
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 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. 2427 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. 1416,29 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 × 200 Scan” pattern, which performed raster scanning in a 6 × 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 90° sectors: superior, inferior, nasal, and temporal. The macula region OCT scan is based on the 6 × 6 mm data cube captured by the Macular Cube 512 × 128 scan. This analysis provided qualitative and quantitative evaluation of the retina. The Early Treatment Diabetic Retinopathy Study (ETDRS) grid, which consisted of one central circle of 500 μm 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 t-test. 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 <0.05 was accepted as statistically significant. 
Results
Patient Demographic
A total of 60 subjects was recruited for the study, of whom 30 were patients with schizophrenia and 30 were normal age-matched controls. Using the independent t-test, there was no significant difference between the mean age of schizophrenic patients (37.17 ± 10.67) and controls (35.97 ± 9.10), with the P value of 0.641 (Table 1). There were 32 male (53.3%) and 28 (46.7%) female subjects. The mean visual acuity score for schizophrenic patients was 100.00 ± 5.25 compared to 102.17 ± 3.64 for the control group, and this was not statistically significant (P = 0.068, Table 1). The 30 schizophrenic patients were subdivided further into 3 subgroups according to their duration of illness, acute (n = 5), chronic (n = 13), and long-term chronic (n = 12). 
Table 1
 
Demographic Characteristics
Table 1
 
Demographic Characteristics
Characteristic Schizophrenia Control Total P Value
Eyes, n 30 30
Age, y 0.641*
 Mean ± SD 37.17 ± 10.67 35.97 ± 9.10
Sex, n (%) 0.301†
 Male 18 (60.0) 14 (46.7) 32 (53.3)
 Female 12 (40.0) 16 (53.3) 28 (46.7)
Ethnicity, n (%) 0.734†
 Malay 7 (23.3) 9 (30.0) 16 (26.7)
 Chinese 17 (56.7) 16 (53.3) 33 (55.0)
 Indian 5 (16.7) 5 (16.7) 10 (16.7)
 Others 1 (3.3) 0 (0.0) 1 (1.7)
VAS 0.068*
 Mean ± SD 100.00 ± 5.25 102.17 ± 3.64
In this study, we found that there was no statistically significant difference between the right and left eyes in both groups for overall peripapillary RNFL thickness (P = 0.927), macula average thickness (P = 0.787), and macula volume (P = 0.909, see Figure). For further analysis, only the right eye was chosen. The Shapiro-Wilk test revealed that all the mean and standard deviations of the overall peripapillary RNFL thickness (P = 0.208), macula average thickness (P = 0.423), and macula volume (P = 0.354) have normal distribution of data. 
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).
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).
Comparison of RNFL Thickness
Comparison of the peripapillary RNFL thickness using the independent t-test showed that the mean overall thickness in schizophrenic patients (94.70 ± 9.88 μm) was significantly lower than that in the control group (103.53 ± 6.53 μm), with a P value of <0.001. The RNFL thickness in three of four quadrants of the peripapillary retinal area, superior (P < 0.001), inferior (P = 0.02), and temporal (P = 0.01), was significantly lower in schizophrenic patients when compared to normal controls. There was, however, no significant difference noted in the nasal peripapillary RNFL thickness (P = 0.13) between the two groups (Table 2). 
Table 2
 
Comparison of Peripapillary RNFL Thickness (μm), Macula Thickness (μm), and Macula Volume (mm3) Between Schizophrenia and Controls
Table 2
 
Comparison of Peripapillary RNFL Thickness (μm), Macula Thickness (μm), and Macula Volume (mm3) Between Schizophrenia and Controls
Group N Mean SD P Value*
Peripapillary RNFL thickness, μm
 Overall Schizophrenia 30 94.70 9.88 P < 0.001†
Control 30 103.53 6.53
 Superior Schizophrenia 30 114.87 17.96 P < 0.001†
Control 30 129.17 11.22
 Inferior Schizophrenia 30 125.60 16.55 P = 0.02†
Control 30 135.20 14.62
 Nasal Schizophrenia 30 70.20 12.66 P = 0.13
Control 30 74.50 8.76
 Temporal Schizophrenia 30 68.10 9.52 P = 0.01†
Control 30 75.17 11.04
Macula thickness, μm
 Macula average thickness Schizophrenia 30 269.27 12.59 P < 0.001†
Control 30 284.83 9.76
 Macula central thickness Schizophrenia 30 234.90 19.03 P = 0.046†
Control 30 244.97 19.24
Macula inner ring thickness
 Average Schizophrenia 30 302.48 14.88 P < 0.001†
Control 30 319.02 13.48
 Superior Schizophrenia 30 305.37 16.08 P < 0.001†
Control 30 324.17 15.32
 Inferior Schizophrenia 30 303.83 14.63 P < 0.001†
Control 30 319.33 13.33
 Nasal Schizophrenia 30 306.50 14.89 P < 0.001†
Control 30 321.77 16.17
 Temporal Schizophrenia 30 294.20 15.72 P < 0.001†
Control 30 310.80 13.16
Macula outer ring thickness
 Average Schizophrenia 30 265.57 12.39 P < 0.001†
Control 30 280.73 11.17
 Superior Schizophrenia 30 268.80 13.48 P < 0.001†
Control 30 284.80 14.09
 Inferior Schizophrenia 30 257.13 13.88 P = 0.001†
Control 30 270.13 13.52
 Nasal Schizophrenia 30 286.43 13.97 P < 0.001†
Control 30 305.90 10.67
 Temporal Schizophrenia 30 250.83 14.01 P = 0.001†
Control 30 262.10 11.42
Macula Volume (mm3)
 Macula Volume Schizophrenia 30 9.61 0.45 P < 0.001†
Control 30 10.17 0.35
Using the independent t-test, it was noted that the macula average thickness among schizophrenic patients (269.27 ± 12.59 μm) was significantly lower compared to the control group (284.83 ± 9.76 μm), with a P value of <0.001 (Table 2). Macula central thickness in schizophrenic patients (234.90 ± 19.03 μm) also was significantly lower compared to the control group (244.96 ± 19.24 μm), with a P value of 0.04 (Table 2). Furthermore, macula average inner ring segments (patients, 302.48 ± 14.87 μm; controls, 319.02 ± 13.48 μm; P < 0.001) and macula average outer ring segments (patients, 265.57 ± 12.39 μm; controls, 280.7 3 ± 11.17 μm; P < 0.001) also were significantly thinner in the schizophrenia group. Breakdown of the macula thickness inner and outer segments into quadrants showed statistically significant thinning of macula thickness in all quadrants in the schizophrenia group compared to the control group, as shown in Table 2
Macula volume (mm3) in schizophrenic patients (9.61 ± 0.45 mm3) also was significantly less than that in the control group (10.17 ± 0.35 mm3), with a P value of <0.001 as shown in Table 2
Comparison of RNFL Thickness According to Chronicity of Illness
Comparisons of RNFL thickness, macula thickness, and macula volume also were made according to the duration or chronicity of the schizophrenic illness. The mean of the overall peripapillary RNFL thickness was 103.53 ± 6.53 μm for the control group, 103.60 ± 6.35 μm for the acute group, 94.15 ± 6.63 μm for the chronic group, and 91.58 ± 12.15 μm for the long-term chronic group. There was a similar reduction in the mean of the macula thickness and macula volume according to the chronicity of illness as shown in Table 3
Table 3
 
Comparisons Between Control Group and Schizophrenia Subgroups According to Chronicity of Illness
Table 3
 
Comparisons Between Control Group and Schizophrenia Subgroups According to Chronicity of Illness
N Mean SD
Overall peripapillary RNFL thickness, μm
 Control 30 103.53 6.53
 Acute 5 103.60 6.35
 Chronic 13 94.15 6.63
 Long term chronic 12 91.58 12.15
Macula average thickness, μm
 Control 30 284.83 9.76
 Acute 5 278.20 8.07
 Chronic 13 271.08 10.25
 Long term chronic 12 263.58 14.28
Macula volume, mm3
 Control 30 10.17 0.35
 Acute 5 9.94 0.31
 Chronic 13 9.69 0.36
 Long term chronic 12 9.44 0.52
Using a multivariable ANOVA with post hoc LSD test, the overall RNFL thickness was shown to be significantly reduced in the chronic schizophrenia group (P = 0.004) and the long-term chronic schizophrenia group (P < 0.001) when compared to controls. Comparison between the subgroups of schizophrenia revealed significant RNFL thickness changes between the acute and chronic groups (P = 0.028), and between the acute and long-term chronic groups (P = 0.006). Comparison between the chronic and the long-term chronic groups did not show any significant difference in the peripapillary RNFL thinning (P = 0.423, Table 4). 
Table 4
 
Multiple Comparisons Between Controls Group With Schizophrenic Subgroups According to Chronicity of Illness
Table 4
 
Multiple Comparisons Between Controls Group With Schizophrenic Subgroups According to Chronicity of Illness
Subgroup I Subgroup J Mean Difference, I − J SE P Value*
Overall peripapillary RNFL thickness, μm
Control Acute −0.067 3.85 0.986
Chronic 9.38 2.64 0.001†
LT Chr 11.95 2.72 <0.001†
Acute Chronic 9.45 4.19 0.028†
LT Chr 12.02 4.24 0.006†
Chronic LT Chr 2.57 3.19 0.423
Macula average thickness, μm Control Acute 6.63 5.22 0.209
Chronic 13.76 3.59 <0.001†
LT Chr 21.25 3.69 <0.001†
Acute Chronic 7.12 5.68 0.215
LT Chr 14.62 5.75 0.014†
Chronic LT Chr 7.49 4.32 0.088
Macula volume, mm3 Control Acute 0.230 0.189 0.229
Chronic 0.478 0.130 0.001†
LT Chr 0.728 0.134 <0.001†
Acute Chronic 0.248 0.206 0.235
LT Chr 0.498 0.209 0.020†
Chronic LT Chr 0.251 0.157 0.116
The post hoc LSD test also showed that the macula average thickness and macula volume were reduced significantly in the chronic and long-term chronic schizophrenia groups when compared to controls (P < 0.05). There also were significant differences between the acute and long-term chronic groups (P < 0.05, Table 4). However, there were no other significant changes in the macula average thickness and macula volume among the other subgroups. 
Correlation between the peripapillary RNFL thickness and the duration of illness was analyzed using the Pearson correlation test. Among the schizophrenic patients, there was a significant reverse correlation between the overall and specifically in the superior quadrant region of the peripapillary RNFL thickness, as shown in Table 5. Similarly, there also were significant reverse correlations between macula thickness and macula volume with the duration of illness as shown in Table 5
Table 5
 
Correlation Between Peripapillary RNFL (μm), Macula Thickness (μm), and Macula Volume (mm3) With Duration of Illness (Years)
Table 5
 
Correlation Between Peripapillary RNFL (μm), Macula Thickness (μm), and Macula Volume (mm3) With Duration of Illness (Years)
Pearson Correlation P Value
Peripapillary RNFL thickness, μm
 Overall −0.364 0.048*
 Superior −0.449 0.013*
 Inferior −0.189 0.318
 Nasal −0.232 0.216
 Temporal −0.024 0.901
Macula thickness, μm
 Average thickness −0.385 0.036*
 Central thickness −0.253 0.178
 Average inner ring thickness −0.408 0.025*
 Average outer ring thickness −0.373 0.042*
 Macula volume, mm3 −0.362 0.049*
No correlation was noted between the overall peripapillary RNFL thickness (Pearson correlation −0.002, P = 0.992), macula thickness (Pearson correlation 0.053, P = 0.782), and macula volume (Pearson correlation 0.055, P = 0.771) with the PANSS score, suggesting no correlation of RNFL thickness with symptoms of disease. 
Discussion
Schizophrenia is a complex neurocognitive disorder. With clear evidence that there are early visual processing deficits in schizophrenia, 19,20 OCT evaluation of structural RNFL loss will be useful to determine if there is RNFL thinning, which may contribute to the deficits in visual perception and processing. 
In this case–control study, the RNFL thickness in the peripapillary and macula region was shown to be significantly thinner in schizophrenic patients compared to normal controls. The macula volume also was significantly reduced compared to normal controls. This correlated with previous neuroimaging studies that showed grey matter volume reduction in schizophrenic patients compared to healthy controls. 7,8 The new findings of this study support the evidence that schizophrenia is a progressive neurodegenerative disease, 1216 and that this degeneration is widespread and is measurable in the retina. 
Breakdown of the peripapillary RNFL into quadrants also revealed significant thinning in all the quadrants except in the nasal quadrant. The Beijing Eye Study 32 has shown previously that the RNFL thickness in the normal population is significantly different in all four quadrants. A possible explanation as to why no statistically significant thinning was noted over the nasal region could be due to the oblique insertion of the optic nerve head into sclera in most eyes. 33 Another reason could be due to the location of the central retinal vessel trunk, which usually is in the nasal part of the optic nerve head, 33 thus, obscuring accurate measurements of the nasal RNFL thickness. 
Our study also showed that the overall macula thickness and all the macula perimeters were significantly thinner in the schizophrenic patients compared to healthy controls. Also, a statistically significant macula volume reduction was seen in schizophrenic patients compared to healthy controls. To the best of our knowledge, this is the first study in schizophrenic patients that showed statistically significant peripapillary RNFL thinning, macula thinning, and macula volume reduction compared to normal controls. 
In a prior study of 10 schizophrenic patients, statistically significant thinning was found over the nasal quadrant, but not in the other quadrants. 34 This contradicted with our finding of overall peripapillary RNFL thinning except at the nasal quadrant. This could be due to the small sample size and the use of Stratus OCT in Francisco's study compared to Cirrus OCT in our study. Cirrus HD-OCT is the most recent development in OCT imaging that uses spectral-domain technology, which improves data acquisition due to a higher scanning speed (60–100 times faster) and axial resolution (3.5–8 vs. 8–10 μm with conventional time domain-OCT) enabling high-resolution, 3D volume sampling. 3537 Cirrus HD-OCT also has a higher reproducibility rate compared to Stratus OCT, making measurements more reliable. 38  
Another study by Chu et al. 39 showed that there was no difference in the RNFL thickness and macula volume in 38 schizophrenic patients compared to healthy controls. This finding was disagreed with by Cabezon et al., 40 who showed significant overall and superior peripapillary RNFL thinning in his 30 schizophrenic patients. Chu et al. 39 suggested that unmyelinated axons in schizophrenic patients remained unaffected by the disease process. However, it must be pointed out that the study of Chu et al. 39 used the Stratus OCT with lower resolution that may be inadequate to detect the subtle abnormalities. On the other hand, Cabezon et al. 40 found an overall peripapillary RNFL thinning in the schizophrenic patients without any statistically significant thinning in the macula region. This contradicted our findings of significant overall peripapillary RNFL thinning with corresponding macula fiber thinning, supporting a generalized structural RNFL loss in schizophrenic patients. We believe our detection rate is higher because we used Cirrus OCT as opposed to Stratus OCT in those earlier studies. 
Schizophrenia has been associated with deficits in visual perception and processing as evidenced by the previous studies done, 19,20 but the structural abnormalities have not been documented. Our study has shown significant structural thinning of RNFL in schizophrenic patients that could explain the deficits in visual perception and processing in these patients. 
Interestingly in our study, the thinning of the RNFL and the macula volume reduction also were found to be worse in the chronic phase of the disease compared to the control group. We found that the overall peripapillary RNFL thickness and also the superior peripapillary thickness were correlated inversely with the duration of illness, and this correlation was statistically significant. There also were statistically significant reverse correlations of macula thickness and macula volume with duration of illness. This correlated with well-established neuroimaging study findings that showed progression of brain volume reduction over the years. 46 This also may suggest an ongoing neurochemical or morphologic process behind this illness. 
The role of the dopaminergic system in visual performance has been well established. 41 Visual functions controlled partially by dopamine, such as contrast sensitivity and color vision deficits, have been observed in dopaminergic pathologies, like Parkinson's disease. 4244 The RNFL has been documented in this group of patients to be thinner compared to controls. Hence the role of dopamine has been postulated to be involved not only in the functional, but also the structural deficits. Contrast sensitivity deficits 41 and color vision deficits 45 also have been observed in schizophrenia patients. Therefore, the RNFL thinning observed in our study could be attributed to the dopamine dysregulation. Dopamine affects color discrimination more over the tritan axis due to the sparsely distributed blue cones and lack of off-center/on-surround inhibition. 44 Although the hue discrimination deficit in schizophrenia is not tritan axis–specific, there are general color discrimination deficits documented in schizophrenic patients. 45 Moreover, tritan axis–specific color discrimination deficit have been documented in other disease conditions with elevated dopamine, such as Gilles de la Tourette Syndrome. 41 Shuwairi et al. 45 even suggested that dopamine excess may produce general dysfunction in color discrimination, while dopamine deficiency may produce hue deficit, which is axis-specific. Degree of susceptibility of dopaminergic degeneration is not clearly established. 21 However, the retina with dopaminergic deficiency has been shown to lose a subset of retinal amacrine cells. 22 It is possible to postulate that dysregulated dopamine input to ganglion cells may lead to abnormal production of glutamate and affect the efficacy of the neurochemical systems contributing to atrophy of these fibers. Therefore, the RNFL thinning observed in our study could be an effect of neurodegeneration or neurochemical dysregulation. 
We tried to minimize the sources of error in our study. Nonetheless, we recognized several limitations to our study. The duration of illness is based on the date of first documented presentation at the time of examination. This may not reflect the actual duration of illness, as the patient may have had the illness for months or years before first presentation. Unfortunately, there is no actual method to calculate accurately the duration of illness based on the history from the patient or their relatives due to the inconsistency of the duration of symptoms. However, due to the need for standardization of data collection for analysis, the duration is calculated from date of presentation at the time of examination. Most of our patients also were receiving antipsychotic medications at the time of data collection, and it is impossible to exclude the potential effects of these drugs on our findings. There also was some difficulty in recruiting patients with acute onset of illness who were cooperative and stable enough to be able to perform OCT of a good quality. Hence, the small sample size in this subgroup may mask the actual RNFL findings in this subgroup of patients. 
Neuroimaging has been an important established method to measure the volumetric brain volume reduction and progression of schizophrenic disease. 33 Using correlation between OCT findings and MRI findings, OCT can have a major role in detecting worsening of neuronal degeneration by measuring the RNFL thickness. Imaging with OCT also can be adopted in other cases to predict disease outcome in the first few years of illness 4 and to screening the ultra high risk group before the first episode of psychosis. 10 With more researches in the future, it is hoped that OCT can be a useful investigative tool in schizophrenia and can be used to monitor the progression of disease. 
Acknowledgments
Supported by a grant for Scientific Research from the University of Malaya (High Impact Research No. H-20001-00-E000057). 
Disclosure: W.W. Lee, None; I. Tajunisah, None; K. Sharmilla, None; M. Peyman, None; V. Subrayan, None 
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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).
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).
Table 1
 
Demographic Characteristics
Table 1
 
Demographic Characteristics
Characteristic Schizophrenia Control Total P Value
Eyes, n 30 30
Age, y 0.641*
 Mean ± SD 37.17 ± 10.67 35.97 ± 9.10
Sex, n (%) 0.301†
 Male 18 (60.0) 14 (46.7) 32 (53.3)
 Female 12 (40.0) 16 (53.3) 28 (46.7)
Ethnicity, n (%) 0.734†
 Malay 7 (23.3) 9 (30.0) 16 (26.7)
 Chinese 17 (56.7) 16 (53.3) 33 (55.0)
 Indian 5 (16.7) 5 (16.7) 10 (16.7)
 Others 1 (3.3) 0 (0.0) 1 (1.7)
VAS 0.068*
 Mean ± SD 100.00 ± 5.25 102.17 ± 3.64
Table 2
 
Comparison of Peripapillary RNFL Thickness (μm), Macula Thickness (μm), and Macula Volume (mm3) Between Schizophrenia and Controls
Table 2
 
Comparison of Peripapillary RNFL Thickness (μm), Macula Thickness (μm), and Macula Volume (mm3) Between Schizophrenia and Controls
Group N Mean SD P Value*
Peripapillary RNFL thickness, μm
 Overall Schizophrenia 30 94.70 9.88 P < 0.001†
Control 30 103.53 6.53
 Superior Schizophrenia 30 114.87 17.96 P < 0.001†
Control 30 129.17 11.22
 Inferior Schizophrenia 30 125.60 16.55 P = 0.02†
Control 30 135.20 14.62
 Nasal Schizophrenia 30 70.20 12.66 P = 0.13
Control 30 74.50 8.76
 Temporal Schizophrenia 30 68.10 9.52 P = 0.01†
Control 30 75.17 11.04
Macula thickness, μm
 Macula average thickness Schizophrenia 30 269.27 12.59 P < 0.001†
Control 30 284.83 9.76
 Macula central thickness Schizophrenia 30 234.90 19.03 P = 0.046†
Control 30 244.97 19.24
Macula inner ring thickness
 Average Schizophrenia 30 302.48 14.88 P < 0.001†
Control 30 319.02 13.48
 Superior Schizophrenia 30 305.37 16.08 P < 0.001†
Control 30 324.17 15.32
 Inferior Schizophrenia 30 303.83 14.63 P < 0.001†
Control 30 319.33 13.33
 Nasal Schizophrenia 30 306.50 14.89 P < 0.001†
Control 30 321.77 16.17
 Temporal Schizophrenia 30 294.20 15.72 P < 0.001†
Control 30 310.80 13.16
Macula outer ring thickness
 Average Schizophrenia 30 265.57 12.39 P < 0.001†
Control 30 280.73 11.17
 Superior Schizophrenia 30 268.80 13.48 P < 0.001†
Control 30 284.80 14.09
 Inferior Schizophrenia 30 257.13 13.88 P = 0.001†
Control 30 270.13 13.52
 Nasal Schizophrenia 30 286.43 13.97 P < 0.001†
Control 30 305.90 10.67
 Temporal Schizophrenia 30 250.83 14.01 P = 0.001†
Control 30 262.10 11.42
Macula Volume (mm3)
 Macula Volume Schizophrenia 30 9.61 0.45 P < 0.001†
Control 30 10.17 0.35
Table 3
 
Comparisons Between Control Group and Schizophrenia Subgroups According to Chronicity of Illness
Table 3
 
Comparisons Between Control Group and Schizophrenia Subgroups According to Chronicity of Illness
N Mean SD
Overall peripapillary RNFL thickness, μm
 Control 30 103.53 6.53
 Acute 5 103.60 6.35
 Chronic 13 94.15 6.63
 Long term chronic 12 91.58 12.15
Macula average thickness, μm
 Control 30 284.83 9.76
 Acute 5 278.20 8.07
 Chronic 13 271.08 10.25
 Long term chronic 12 263.58 14.28
Macula volume, mm3
 Control 30 10.17 0.35
 Acute 5 9.94 0.31
 Chronic 13 9.69 0.36
 Long term chronic 12 9.44 0.52
Table 4
 
Multiple Comparisons Between Controls Group With Schizophrenic Subgroups According to Chronicity of Illness
Table 4
 
Multiple Comparisons Between Controls Group With Schizophrenic Subgroups According to Chronicity of Illness
Subgroup I Subgroup J Mean Difference, I − J SE P Value*
Overall peripapillary RNFL thickness, μm
Control Acute −0.067 3.85 0.986
Chronic 9.38 2.64 0.001†
LT Chr 11.95 2.72 <0.001†
Acute Chronic 9.45 4.19 0.028†
LT Chr 12.02 4.24 0.006†
Chronic LT Chr 2.57 3.19 0.423
Macula average thickness, μm Control Acute 6.63 5.22 0.209
Chronic 13.76 3.59 <0.001†
LT Chr 21.25 3.69 <0.001†
Acute Chronic 7.12 5.68 0.215
LT Chr 14.62 5.75 0.014†
Chronic LT Chr 7.49 4.32 0.088
Macula volume, mm3 Control Acute 0.230 0.189 0.229
Chronic 0.478 0.130 0.001†
LT Chr 0.728 0.134 <0.001†
Acute Chronic 0.248 0.206 0.235
LT Chr 0.498 0.209 0.020†
Chronic LT Chr 0.251 0.157 0.116
Table 5
 
Correlation Between Peripapillary RNFL (μm), Macula Thickness (μm), and Macula Volume (mm3) With Duration of Illness (Years)
Table 5
 
Correlation Between Peripapillary RNFL (μm), Macula Thickness (μm), and Macula Volume (mm3) With Duration of Illness (Years)
Pearson Correlation P Value
Peripapillary RNFL thickness, μm
 Overall −0.364 0.048*
 Superior −0.449 0.013*
 Inferior −0.189 0.318
 Nasal −0.232 0.216
 Temporal −0.024 0.901
Macula thickness, μm
 Average thickness −0.385 0.036*
 Central thickness −0.253 0.178
 Average inner ring thickness −0.408 0.025*
 Average outer ring thickness −0.373 0.042*
 Macula volume, mm3 −0.362 0.049*
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