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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Antipsychotic agent-induced deterioration of the visual system in first- 7

episode untreated patients with schizophrenia maybe self-limited: Findings
from a secondary small sample follow-up study based on a pilot follow-up
study
Chuanjun Zhuoa,c,d,e,f,g,1, , Feng Jia, Bo Xiaob,1, Xiaodong Linc,1, Ce Chenc, Deguo Jiangc,
⁎

Xiaoyan Mad, Ranli Lid, Sha Liue,f, Yong Xue,f, Wenqiang Wangg
a
School of Mental Health, Jining Medical University, Jining, Shandong 272119, China
b
Department of OTC center, Tianjin Medical University Affiliated Eye Hospital, Tianjin, 272004, China
c
Psychiatric-Neuroimaging-Genetics Laboratory, Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang 325000, China
d
Psychiatric-Neuroimaging-Genetics-Comorbidity Laboratory, Tianjin Mental Health Centre, Mental Health Teaching Hospital of Tianjin Medical University, Tianjin
Anding Hospital, Tianjin 300222, China
e
Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
f
MDT Center for Cognitive Impairment and Sleep Disorders, First Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
g
Co-collaboration Laboratory of China and Canada, Xiamen Xianyue Hospital and University of Alberta, Xiamen, Fujian 361000, China

A R TIC L E INFO A B S TR A C T

Keywords: Define changes in the visual cortex and retina in first-episode schizophrenia patients with visual disturbance
Schizophrenia (FUSCHVD) accompanied by antipsychotic agent treatment is important for guiding treatment. We examined the
Visual perception disturbances visual system prior to and after 3 years of antipsychotic-agent treatment in 48 patients with FUSCHVD and 50
Gray matter volume healthy controls, and after 3.5 years of antipsychotic-agent treatment in 12 patients with FUSCHVD and 12
Retinal thickness
healthy subjects who came from the cohort with 3 years of follow up. Reduction of the visual cortex gray matter
Self-limited
volume (GMV) was observed in patients compared to healthy controls, and impairments deteriorated accom-
panied with 3 years’ treatment with antipsychotic agents. Total retinal thickness was also reduced in patients but
did not deteriorated with treatment with antipsychotic agents. However, in the 12 patients who performed the
additional 6-month follow-up, GMV and total retinal thickness reductions did not demonstrate any further trend
in deterioration. These findings indicate that the reductions of GMV and retinal thickness may be self-limited.
Although these findings were consistent with previous reports, it was only observed in a small number of pa-
tients. Therefore, clinicians should remain pay greater attention to visual system impairment in FUSCHVD.

1. Introduction compared to other symptoms associated with schizophrenia, such as

Numerous studies have reported a high prevalence of visual dis-
turbances in patients with schizophrenia in the past decades
(Butler et al., 2008). Such disturbances in patients with schizophrenia
generally include both visual distortions and hallucinations
(Cutting and Dunne, 1986; Silverstein, 2016; Waters et al., 2014).
Previous studies have reported that more than half of patients with
schizophrenia experience visual disturbance symptoms (Cutting and
Dunne, 1986; Silverstein, 2016; Waters et al., 2014). However,
auditory hallucinations (Alderson-Day et al., 2015; Hugdahl, 2015,
2017; Upthegrove et al., 2016), research into the mechanisms involved
in visual disturbances has not been conducted. Subsequently, knowl-
edge is extremely limited regarding the course of pathological features
of visual distortions in schizophrenic patients and ways to improve
them.
Several laboratory studies have reported that schizophrenic patients
demonstrate functional deficits in the visual cortex and structural def-
icits in the retina (Calderone et al., 2013; Hebert et al., 2010;

Corresponding author at: Psychiatric-Neuroimaging-Genetics-Comorbidity Laboratory, Tianjin Mental Health center, Mental Health Teaching Hospital of Tianjin
⁎

Medical University, Tianjin Anding Hospital, Tianjin 300222, China.

E-mail address: chuanjunzhuotjmh@ieee.org (C. Zhuo).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.psychres.2020.112906
Received 6 December 2019; Received in revised form 29 February 2020; Accepted 29 February 2020
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C. Zhuo, et al.
Lencer et al., 2005; Nagel et al., 2007; Onitsuka et al., 2007;
Silverstein, 2016; Silverstein et al., 2009). Although these findings do
not provide sufficient information to clarify the pathological features in
these patients, they have provided an important rationale for further
study to precisely characterize the pathological features of visual dis-
turbances in patients with psychosis and to further investigate protec-
tive strategies for visual system impairments in patients with schizo-
phrenia (Garcia-Portilla et al., 2019; Grano et al., 2015; Guidotti and
Grayson, 2011; Hebert et al., 2010). Although many researchers have
called for long-term studies to dynamically characterize the patholo-
gical features of visual disturbances in schizophrenia, very few studies
have characterized structural and functional impairments to the visual
system in first-episode untreated schizophrenia patients who experi-
ence visual disturbances (FUSCHVD) (Silverstein, 2016). Patients with
schizophrenia require long-term treatment with antipsychotics. Al-
though there have been studies investigating the effects of antipsychotic
agents on the visual pathway (including the primary visual cortex and
the retina), long-term cohort studies are needed to explore the effects of
antipsychotics on the visual system (Silverstein, 2016). Information
relative to the dynamic impairments of the visual system and the effects
of antipsychotics on visual systems are critical to better understand the
mechanisms involved in visual disturbances and would provide an
important rationale for establishing strategies of improvement.
The retina is an important component of the visual mechanism.
Previous studies reported an impaired retinal thickness in patients with
schizophrenia. (London et al., 2013; Phillips et al., 2015) Likewise,
changes in the visual cortex's function have also been reported
(Lee et al., 2019; Reavis et al., 2017a,b). These studies have converged
to propose that both the visual cortex and retinal thickness may be co-
impaired in patients with schizophrenia; however, further study is ne-
cessary. Inspired by the aforementioned suggestions and the idea pro-
posed by Silverstein (Uhlhaas and Silverstein, 2005), we conducted a
pilot follow-up study to investigate the dynamic pathological features
of the structure and function of the retina and primary visual cortex in
patients with FUSCHVD, and explored the effects of antipsychotic
agents on these pathological features. We hypothesized that 1) the
primary visual cortex and retinal thickness may be impaired in patients
with FUSCHVD; 2) the primary visual cortex and retinal thickness im-
pairment may gradually worsen over the course of the disease; and 3)
treatment with antipsychotic agents may have influenced the visual
cortex and retina.
2. Methods
2.1. Baseline information acquisition
2.1.1. Patients
This pilot study's assessments were carried out in compliance with
the Declaration of Helsinki guidelines and approved by the institutional
ethics committee of Tianjin Anding Hospital. All patients were educated
regarding the potential of deleterious effects pertaining to their medi-
cation. All patients as well as the control group were informed re-
garding their participation's risk factors. All participants provided a
written informed consent. In this pilot study, we recruited both the
patients at baseline with FUSCHVD and the healthy individuals for the
control group from five institutes (Tianjn Anding Hospital, Wenzhou
Seventh Peoples Hospital, Jining Medical University Affiliated Second
Hospital, Mental Health Institutes of Shanxi Medical University,
Xiamen Xianyue Hospital) from 1 August 2016 to 31 December 2019.
For FUSCHVD patients, the inclusion criteria were:
1) fulfilment of the Diagnostic and Statistical Manual of Mental
Disorders-4th Edition-Text Revision (DSM-IV-TR)criteria for schizo-
phrenia 2) first episode of schizophrenia and first diagnosis in a mental
health professional hospital 3) no treatment with antipsychotic agents
at least 3 weeks before participation in this pilot study 4) visual dis-
turbance symptoms distinguished by 18 visual disturbance-related

3V\FKLDWU\5HVHDUFK
items of the Bonn Scale for Assessment of Basic Symptoms (BSABS)
(score > 16) 5) age 18–30 years 6) all participants must be right-
handed and 7) glycosylated hemoglobin levels within the normal range.
Exclusion criteria for FUSCHVD patients were: 1) treatment with anti-
psychotic therapeutics within 3 weeks prior to enrollment 2) contra-
indications for magnetic resonance imaging (MRI) 3) ophthalmic dis-
eases and diseases affecting the retina 4) evidence of substance abuse 5)
prevalence of any disease that could cause visual disturbances, such as
hyperglycemia, hyperlipidemia, or muscae volitantes 6) other systemic
diseases, (e.g. respiratory, cardiovascular, endocrine, neurological,
liver, or kidney disease) chronic diseases, history of loss of conscious-
ness for more than five minutes for any reason or previous head trauma
and (7) IQ < 80. Participants for the healthy control group\ were re-
cruited from hospital staff and adult medical students. The exclusion
criteria for healthy controls were as follows: (1) psychiatric disorders or
first-degree relatives with psychotic disorders as assessed by two pro-
fessional psychiatrists using the structured clinical interview SCI-DNP
version (diagnosed by a professional psychiatrist using SCI-D, None
Patient Version)_ (2) moderate to severe physical disease (e.g. re-
spiratory, cardiovascular, endocrine, neurological, liver, or kidney
disease) (3) currently receiving electroconvulsive therapy(ECT) (4)
history of loss of consciousness for more than five minutes for any
reason (5) being left-handed as determined by the Annett Hand
Preference Questionnaire (6) ophthalmic disease (7) high myopia (8)
contraindication for MRI (9) IQ < 80 and (10) diseases that could cause
visual disturbances such as those distinguished by a history of loss of
consciousness for over five minutes for any reason.
2.1.2. Pilot study follow-up design
Previous studies of patients with schizophrenia have shown that
brain gray matter impairment occurred in the first 2–3 years following
the first treatment with antipsychotic agents. The impairment mode
occurred from the posterior to anterior brain and from top to bottom
(Ellison-Wright et al., 2008; Goghari et al., 2013; Guo et al., 2019;
Hirayasu et al., 2001; Ohtani et al., 2018; Vita et al., 2012). These
important findings suggested that the visual cortex (occipital lobe) may
be one of the first brain regions to be affected in patients with first
episode schizophrenia. Information regarding retina impairment pat-
terns in patients with schizophrenia is scarce. Silverstein et al. (2016)
proposed that follow-up studies should be conducted to dynamically
monitor changes to the retina as a research hot spot in patients with
schizophrenia experiencing visual disturbances. Based on these pivotal
studies and inspired by Silverstein's ideas, we designed a follow-up
study aimed to characterize both the dynamical characteristics of the
brain cortex and retinal thickness impairments following the first epi-
sode of visual disturbances in untreated patients with schizophrenia up
to three years following treatment with antipsychotic agents. In this
pilot study, patients with FUSCHVD were treated based according to the
Chinese guidelines for the treatment of schizophrenia. To reduce study
dropout rate, individuals enrolled in the study were interviewed on a
weekly basis. Researchers involved in the study were blinded to specific
treatments received by any given patient. An ophthalmologist was in-
vited to participate in the study to ensure that retinal alterations at
follow-up were not caused by other confounding factors. Moreover,
glycosylated hemoglobin and serum lipid levels were assessed to avoid
confounders, which could influence retinal thickness. All participated
on a voluntary basis and provided written informed consents prior to
data acquisition. All study procedures were approved by the Ethics
Committee of Tianjin Anding Hospital.
2.2. Assessment methods
The Positive and Negative Syndrome Scale (PANSS) (Liechti et al.,
2017) was adopted to assess the psychotic symptoms of the patients’
schizophrenia. The 18 items related to visual disturbances on the BSABS
score (Oshima et al., 2010) were used to quantitatively assess visual
C. Zhuo, et al.
disturbance symptoms in FUSCHVD patients. Voxel-based morpho-
metry (VBM) was used to assess alterations in the gray matter volume
(GMV) of the FUSCHVD patients and especially focused on the visual
cortex in the occipital lobe (Kim et al., 2017). Optical coherence to-
mography (OCT) was used to assess structural alterations in the retina
(Schonfeldt-Lecuona et al., 2016).
2.3. MRI data acquisition
To ensure consistency and accuracy, the five institutions where data
were collected used the same MRI scanner and parameters and the same
OCT system and parameters. All MRI parameters were setup by one se-
nior professional MRI technician. All the parameters of OCT were setup
by a senior ophthalmologist. MRIs were performed using a 3.0-T MR
system (Discovery MR750, General Electric, Milwaukee, WI, USA). A
tight and comfortable foam pad was used to reduce head motion to the
largest extent, and earplugs were adopted to reduce scanner noise.
Sagittal 3D T1-weighted images were acquired by brain volume se-
quences with the following parameters: repetition time (TR) = 8.2 ms;
echo time (TE) = 3.2 ms; inversion time (TI) = 450 ms; flip angle
(FA) = 12°; field of view (FOV) = 256 mm × 256 mm; matrix =
256 × 256; and slice thickness = 1 mm, no gap; 188 sagittal slices.
2.4. OCT data acquisition
Retinal images of both eyes were obtained using an OCT-4000
system (Zeiss, Germany) (http://www.medwow.com/used-optical-
coherence-tomography-oct-equipment/zeiss/cirrus-4000-oct/481_400_
55737.med). Prior to each scan, participants' chins were positioned on a
rest. Subjects were asked to focus on an external fixation target. Each
scan consisted of 500 A/B-scans and 50 B-scans, with 5 frames per B-
scan. Scans containing ≥5 consecutive B-scan frames of the foveal
center with no movement artifacts were included in the data analysis.
The 5 s volumetric scans (10 mm × 5 mm) of the fovea centralis were
identified by marked thickening in the outer segment layer (OSL)
(DICOM Conformance Statement Cirrus 6.5 – ZEISS https://www.zeiss.
com/content/dam/Meditec/; DRCR.NET Image Acquisition Protocol
Optical Coherence. publicfiles.jaeb.org/drcrnet/Misc/DRCRnet_Zeiss_
Cirrus_Procedures_2009-08-12.pdf https://www.zeiss.com; https://
www.emseye.com/products/zeiss-cirrus-4000-spectral-domain-oct).
2.5. MRI data analysis
According to previous studies, regions of interest in the primary
visual cortex were V1/V2, V3, V3A, V4, V8, fusiform gyrus, and V5 in
the occipital cortex (Abdollahi et al., 2014; Wandell et al., 2005;
Wandell and Winawer, 2011). GMV prior to treatment was compared to
GMV following antipsychotic agent treatment. GMV values were ad-
ditionally compared between patients and health control group parti-
cipants at baseline. Structural MRI data were preprocessed using the
CAT12 function in the Statistical Parametric Mapping (SPM12) soft-
ware package (SPM12, Wellcome Department of Cognitive Neurology,
London, UK; http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). All
images were reoriented to a matching origin point. Probability maps
were overlaid on individual images determining the non-linear de-
formation field. Tissue was classified as cerebrospinal fluid, gray, or
white matter. Native-space tissue segments were correlated with those
of the standard Montreal Neurological Institute template using an af-
finity registration algorithm. Inter-individual differences regarding
head position or orientation during MRI scanning were corrected. Dif-
feomorphic anatomical registration was performed for individual gray-
matter images. Inter-individual registration was refined with the ex-
ponentiated lie algebra (DARTEL) toolbox. Gray-matter image-intensity
was adjusted by either compressing or expanding the surrounding
voxels. To correct for individual brain sizes when comparing GMV va-
lues, images of gray-matter tissue were modulated with a non-linear

3V\FKLDWU\5HVHDUFK
deformation approach. Upon preprocessing completion, a quality check
was performed using the CAT12 toolbox to evaluate the homogeneity of
the gray matter. For group analysis, segmented images of gray matter
were smoothed with an 8-mm Gaussian Kernel. This step increased the
signal-to-noise ratio and decreased the effects of misregistration be-
tween images, thus increasing statistical normality. Both automated
anatomical labeling atlas software and anatomical atlases were used to
identify the most significant clusters. After observing significant dif-
ferences between groups in GMV V1/V2, V3, V3A, V4, fusiform gyrus,
and V5 regions, mean GMV values were extracted.
2.6. OCT data analysis
The manual segmentation of individual layers of the retina was
performed using an ImageJ macro (Schneider et al., 2012; Wandell and
Winawer, 2011). B-scan images were randomized prior to analysis.
Average individual and combined layer thickness measurements re-
lative to the foveal center (0 µm) were extracted from three macular
regions: (1) the foveal region = −750 to 750 µm; (2) the nasal par-
afoveal region = −1500 to −750 µm; and (3) the temporal parafoveal
region = 750 to 1500 µm.
2.7. Statistical analysis
The clinical and demographic data for all three groups were com-
pared by two-sample t-tests or, when necessary, a chi-square test. The
GMV, OCT, and BSABS score data were compared between the fol-
lowing groups: (1) FUSCHVD patients and healthy controls at baseline
(2) FUSCHVD patients after three years of treatment and healthy con-
trols (3) FUSCHVD patients at baseline to FUSCHVD patients after three
years of antipsychotic treatment (4) healthy controls after three years
with FUSCHVD after three years of treatment with antipsychotic agents.
GMV values were compared using voxel-wise two-sample t-tests, with
total intracranial volume, age, sex, and educational level as covariates
(Shan et al., 2019). The significance level was set at p < .05, then
corrected according to the Gaussian random field theory (voxel sig-
nificance: p < .001, cluster significance: p < .05). The Bonferroni
correction method was used for multiple comparisons with REST soft-
ware to limit type I errors. Pearson's correlation analyses between ab-
normal GMV and OTC values and PANSS and BSABS parameters were
carried out with a significance threshold of p < .05 (Shan et al., 2019).
3. Results
3.1. Sociodemographic information and clinical examination
As of December 31, 2015, data from 48 patients with FUSCHVD and
50 healthy control group participants were enrolled. Sociodemographic
information and clinical findings for these participants are listed in
Table 1. Age, sex, and education level did not significantly differ be-
tween groups. The BSABS scores in patients with schizophrenia were
lower than those in healthy controls. While psychotic symptoms (as
measured by the PNASS) were decreased following three years of
treatment with antipsychotic agents in 43.14% of patients, visual dis-
turbance (as measured by the BSABS score) symptoms were more fre-
quent following treatment. Visual disturbances symptom severity scores
increased by 8.12% over the course of 3 years of treatment (Table 1).
The maximum score increase in BSABS score was 4, while the minimum
score increase was 1. The mean increase in the score was 2.3 (increase
rate: 8.12%).
3.2. Changes in GMV after antipsychotic treatment in FUSCHVD patients
and in healthy controls
Compared to healthy control group participants at baseline, we
observed smaller GMV in the sub-regions V1/V2, V3, V4, fusiform
C. Zhuo, et al. 3V\FKLDWU\5HVHDUFK

Table 1
Sociodemographic information and results of clinical examination.
FUSCHVD Baseline FUSCHVD Three-year Follow-up Healthy Controls Baseline Healthy controls Three-year t P
n = 48 n = 48 n = 50 Follow-up n = 50

Age 21.5 ± 1.7 24.5 ± 1.7 22.0 ± 1.7 25.0 ± 2.3 0.188 .903
Sex (M/F) 23/25 23/25 25/25 25/25 0.189 .561
Educational Level 16.2 ± 3.4 16.0 ± 3.4 16.2elio 16.0e3.4 0.246 .598
PANSS 80.9 ± 12.5 46.0 ± 15.4 35.4S3.4 36.1S3.5 *9.230 <0.001
BSABS Total Score 28.3 ± 2.7 30.6 ± 4.2 5.2 ± 2.2 6.1 ± 3.0 *−1.181 .047
Chlorpromazine Equivalent 497.5 ± 220.5

⁎
Comparison of FUSCHVD at baseline to FUSCHVD at three-year follow-up.

Fig. 1. GMV impairment among different groups in pilot study and secondary follow up study. A) GMV impairment among different groups in pilot study(48 Patients
vs. 50 HCs). B) GMV impairment among different groups in secondary follow up study(12 Patients, 12 well matched Health controls).

gyrus, and V5 (Fig. 1A) in FUSCHVD patients. More notably, following
three years of treatment, compared to the patients baseline MRI data,
we observed that GMV in the V1/V2, V3, V4, fusiform gyrus, and V5
subregions were sharply reduced (mean reduction extent was 3.45%).
However, healthy controls compared to their baseline MRI data fol-
lowing three years did not show significant differences (Fig. 1A).
Compared to healthy controls after 3 years, GMV reduction in the pa-
tients after three years treatment was also significantly reduced.
(Fig. 1A).
3.3. Alterations in OCT after antipsychotic treatment in FUSCHVD patients
and in healthy controls
In this pilot study, we observed total retinal thickness was sig-
nificantly reduced in patients with FUSCHVD compared to healthy
controls at baseline (Table 2). Compared to FUSCHVD patients’ OCT
data at baseline, we observed that significant differences between
FUSCHVD and healthy controls (Table 2). After three years of anti-
psychotic agent treatment, we observed that total retinal thickness was
significantly reduced in the patients with FUSCHVD. The specific dif-
ferences in total retinal thickness were as follows: Foveal region
(260.9 µm ± 7.9 µm vs. 223.5 µm ± 6.0 µm, reduction rate 15%,
p < .001), the temporal parafoveal region (326.0 µm ± 15.3 µm vs.
300.3 µm ± 12.3 µm, reduction rate 8%, p < .001), and the nasal
parafoveal region (317.5 µm ± 11.3 µm vs. 278.2 µm ± 14.9 µm,
reduction rate 12%, p < .001). In FUSCHVD patients, the mean total
retinal thickness decreased 37.4 µm (range, 5.5–38.3 µm) in the foveal
region, 26.0 µm (range, 6.5–35.4 µm) in the temporal parafoveal re-
gion, and 39.2 µm (range, 14.5–49.3 µm) in the nasal parafoveal region
(Table 2, Fig. 2). No significant reduction in total retinal thickness was
observed among healthy controls over a three-year follow-up period
(Table 2, Fig. 2).
3.4. Relationship between alterations in GMV and retinal thickness in the
FUSCHVD patients
The correlation coefficients between GMV reduction in the visual
cortex and retinal thinning were 0.23 (p < .05) in the fovea, 0.43
(p < .05) in the parafoveal region, and 0.29 (p < 0.05) in the nasal
parafoveal region.
3.5. Relationship between GMV, retinal thickness, and BSABS scores in
FUSCHVD patients after three years of treatment
After three years of treatment, the GMV reduction rate negatively
correlated with the increase in BSABS score in FUSCHVD patients
(r = −0.42, p < .05). Similarly, the correlation coefficient between the
retinal thickness reduction and the BSABS scores were −0.54 in the
foveal region, −1.01 (p < .05) in the temporal parafoveal region, and
−0.67 (< 0.05) in the nasal parafoveal region.
3.6. Progression of GMV and retinal thickening after the initial 3-year
treatment with antipsychotics
In this pilot follow-up study, we observed that the reduction rated in
the visual cortex was 3.45%. Previous studies reported that the GMV
reduction in the entire brain usually occurred 2–3 years after admin-
istration of antipsychotic agents and the reduction was no more than


C. Zhuo, et al. 3V\FKLDWU\5HVHDUFK

Table 2
Retinal total thickness differences among different groups.
Total retinal thickness differences in FUSCHVD patients and Health controls

FUSCHVDN=48 Healthy controls N = 50 t P-value

Temporal Parafoveal Region 326.0 µm ± 15.3 µm 360.4 ± 25.6 µm 11.425 <0.001

Foveal Region 260.9 µm ± 7.9 µm 292.5 ± 30.2 µm 10.487 <0.001
Nasal Parafoveal Region 317.5 µm ± 11.3 µm 350.2 ± 28.7 µm 12.099 <0.001
Total retinal thickness differences in FUSCHVD patients before and after 3 years treatment

Baseline N = 48 3 year follow-up N = 50 t P-value

Temporal Parafoveal Region 326.0 µm ± 15.3 µm 300.3 µm ± 12.3 µm 30.20 <0.001

Foveal Region 260.9 µm ± 7.9 µm 213.5 µm ± 6.0 µm 36.01 <0.001
Nasal Parafoveal Region 317.5 µm ± 11.3 µm 278.2 µm ± 14.9 µm 22.32 <0.001
Total retinal thickness differences in healthy controls before and after 3 years

Baseline N = 48 3 year follow-up N = 50 t P-value

Temporal Parafoveal Region 360.4 ± 25.6 µm 362.0 ± 29.3 µm 0.380 .566

Foveal Region 292.5 ± 30.2 µm 287.0 ± 36.5 µm 0.997 .059
Nasal Parafoveal Region 350.2 ± 28.7 µm 353.2 ± 10.0 µm 0.257 .688
Total retinal thickness differences in FUSCHVD patients before 3 years and 3.5 treatment

3.5 years follow up N = 12 3 year follow-up N = 12 t P-value

Temporal Parafoveal Region 309.8 µm ± 21.5 µm 306.3 µm ± 10.5 µm 0.257 .722

Foveal Region 208.4 µm ± 14.0 µm 210.0 µm ± 18.5 µm 0.568 .400
Nasal Parafoveal Region 278.2 µm ± 23.1 µm 280.4 µm ± 16.5 µm 0.117 .842

consent was acquired prior to the secondary follow-up study. However,

only 12 patients (maintaining treatment at the same dosage of anti-
psychotic agents) and 17 health controls according to the criteria. We
re-acquired MRI and OCT data between August 5, 2019 and February
15, 2020, while acquiring clinical information at the same time. The
methods used for MRI and OCT data acquisition and statistical analysis
were the same as those used in the pilot follow-up study.

3.6.2. Results of the secondary follow-up study

Upon conclusion of the secondary 6 month follow-up, we observed a
sizeable GMV reduction in patients with FUSCHVD compared to their
respective baseline MRI data. The extent of the brain's GMV reduction
was 1.9% (Fig. 1B); however, the visual cortex's reduction rate was
3.57%, making it higher than the whole brain's reduction rate. For-
tunately, compared to the MRI data obtained at the 3-year anti-
psychotic agent treatment end-point, we observed no significant dif-
ferences. These findings suggested no further deterioration in the
brain's GMV. Furthermore, we observed no significant differences in the
reduction rate of total retinal thickness at the end of the 3.5-year an-
Fig. 2. Total retinal thickness reduction in FUSCHVD patients and healthy
tipsychotic agents treatment end-point compared to the OCT data
controls at the three-year follow-up (Double Y axis, left: retinal thickness re-
(Table 2). These findings also suggested that the retinal thickness of
duction of patients, right: retinal thickness reduction of healthy controls).
patients with FUSCHVD discontinued deterioration.

2% (Smieskova et al., 2009; Vita et al., 2012). Considering the reduc-
tion rate of GMV in the visual cortex was more than 2%, and the lack
previous reports concerning the reduction of retinal thickness, we in-
vestigated whether these changes would stabilize compared to the GMV
reduction in patients with schizophrenia or demonstrate a continuous
deterioration pattern.
3.6.1. Procedure of the secondary follow-up study
Following we investigated whether GMV and retinal thickness im-
pairments in patients with FUSCHVD would stabilize or demonstrate a
continuous deterioration pattern. Therefore, we invited patients who
completed a 3 year treatment and maintained the same dosage of an-
tipsychotic agents for more than 3.5 years from baseline.
Simultaneously, the control group was also recruited from the pilot
database who were more than 3.5 years from baseline. All participants
volunteered to be enrolled in the secondary study. Written informed
4. Discussion
This is the first pilot and secondary follow-up study to combine MRI
and OTC data to investigate the dynamic trajectory of the visual cortex
and retinal thickness impairments in patients with FUSCHVD. Notably,
in this pilot and secondary follow-up study, three phenomena were
worthy of addressing. First, the visual cortex and retinal thickness im-
pairments were observed in FUSCHVD patients at baseline. Second, the
visual cortex and retinal thickness impairment showed a gradual de-
teriorating pattern within 3 years of antipsychotic agent treatment
commencement in patients with FUSCHVD. Third, in the secondary
follow-up study, the visual cortex and retinal thickness impairment
deterioration did not continue and demonstrated a stable pattern.
As mentioned above, we observed a visual cortex and retinal
thickness impairment in FUSCHVD patients at baseline. These findings
indicated that visual system impairment might occur prior to the first


C. Zhuo, et al.
psychotic episode. These findings provided evidence that both visual
cortex and retina impairment can be observed at any stage of schizo-
phrenia (Calderone et al., 2013; Hebert et al., 2010; Lencer et al., 2005;
Nagel et al., 2007; Onitsuka et al., 2007; Silverstein, 2016;
Silverstein et al., 2009). The findings of this pilot study also indicated
that the starting from the origin of visual perception (retina) to higher
visual perception integration systems (visual cortex) all pathways might
be affected in patients with FUSCHVD.
More notably, visual disturbance symptoms in FUSCHVD patients
worsened, even though the psychotic symptoms of schizophrenia were
alleviated. Likewise, the visual cortex and retinal thickness impairment
demonstrated a gradual deterioration pattern within the 3 years fol-
lowing the administration of antipsychotic agent treatment in patients
with FUSCHVD. These findings indicated that treatment with anti-
psychotic agents might exacerbate visual cortex and the retina im-
pairments. Moreover, the extent of visual cortex and retinal thickness
deterioration in patients with FUSCHVD were associated with a dete-
rioration of scores assessed by 18-items regarding visual disturbances in
the BSABS score. These findings suggested that the visual disturbances
experienced by the patients with FUSCHVD may have a pathophysio-
logical basis. These findings also indicate that, although antipsychotic
agents can alleviate the overall severity of schizophrenia symptoms,
they worsen visual disturbance symptoms and further damage both the
visual sensory organs and the visual cortex. Thus, the visual cortex and
retina changes in the FUSCHVD patients treated with antipsychotic
agents should be closely monitored.
Additional notable findings were observed in the secondary follow-
up study. The study showed that the visual cortex and retinal thickness
impairment did not continue to deteriorate and demonstrated a stable
pattern following three years of antipsychotic agents treatment. These
findings indicated that impairments in both the visual cortex and retinal
thickness were possibly self-limited in patients with FUSCHVD. In ad-
dition, these findings are consistent with previous studies that focused
on cortex impairments and dynamically changing brain models in
schizophrenia (Hulshoff Pol and Kahn, 2008; Kuo and Pogue-
Geile, 2019; Palaniyappan et al., 2016; Smieskova et al., 2009;
Vita et al., 2012). The findings of our secondary follow-up study also
suggested that the retinal impairment observed in patients with
FUSCHVD also had self-limiting features; this phenomenon provides a
rationale for further study.
In summary, our pilot and secondary follow-up studies provide
evidence that it is critical for clinicians to screen schizophrenic patients
for structural and functional impairments of the visual system at initial
diagnosis.
4.1. Limitations
The current study has some limitations that must be considered
when interpreting its results. First, very small samples in the secondary
follow up weaken the strength of our findings; however, we provide a
clue for further study. Second, while effects of treatment with anti-
psychotic agents on the primary visual cortex were examined, higher
order cortical brain regions that are known to participate in visual
perception were not analyzed, thus resulting in limiting our under-
standing of the pathological features of FUSCHVD. Third, due to a lack
of patient compliance with OCT scanning, we were unable to acquire
data for each retinal layer which limited our findings' precision. Fourth,
although we identified a correlation between decreased retinal thick-
ness and structural impairments in the visual cortex, it distinguishing
the cause was not possible. Additional studies (perhaps animal studies)
are necessary to identify an effective treatment target. Fifth, the sec-
ondary follow-up study was based on our pilot follow-up. The validity
of this method has not been reported in previous studies, hence, a
further study is needed to test the validity of this approach. Sixth, in the
secondary follow-up study, the follow up time was only 6 months and
the sample number was smaller, thus the data cannot provide enough

3V\FKLDWU\5HVHDUFK
evidence for us to clarify our self-limited postulation. Hence, our con-
clusion should be carefully explained, and we remain inclined to ad-
dress the importance of monitoring the GMV and WM reductions in the
clinical practices, especially in the first 5 years treatment duration.
Seventh, both in this pilot and the secondary study, we only selected
patients with FUSCHVD. This sample bias could not be avoided; hence,
an enlarged sample including schizophrenia patients with no VD
symptoms is needed to exclude sample bias. Eighth, in the secondary
follow-up studies, some patients' antipsychotic agent treatment strate-
gies were altered, hence, this confounding factor may have influenced
our findings, even though we excluded patients with changes in treat-
ment dosage. Ninth, in this study, at baseline, we enrolled 150 patients
with FUSCHVD; however, only data from 48 patients were suitable for
use. Thus, the influence of the high drop-out rates should be considered,
in future studies to avoid effects caused by unbalanced samples. Tenth,
although the five institutes participating in the study all used the same
type of MRI scanner and OCT system and the same analysis parameters,
we are unable to ensure that this method avoided influences due to
technical differences. Hence, in future studies, we should test for con-
sistency of the tested samples from each of the participating centers.
5. Conclusion
Despite the limitations outlined above, to the best of our knowledge,
this is the first pilot and secondary follow-up study combining MRI and
OTC to investigate the dynamic trajectory of visual cortex and retinal
thickness impairments in patients with FUSCHVD. More notably, in this
pilot and secondary follow-up study, three important phenomena were
addressed. First, impairment of the visual cortex and retinal thickness
were observed in patients with FUSCHVD at baseline. Second, the vi-
sual cortex and retinal thickness impairment demonstrated a gradual
deterioration pattern within the 3 years of starting treatment with an-
tipsychotic agents in patients with FUSCHVD. Third, in the secondary
follow-up study, the visual cortex and retinal thickness impairment did
not continue to deteriorate and demonstrated a stable pattern; however,
it is only observed in the small samples.
Funding
This work was supported by grants from the National Natural
Science Foundation of China (81871052 to C.Z., 81801679 and
81571319 to Y.X.), the Key Projects of the Natural Science Foundation
of Tianjin, China (17JCZDJC35700 to C.Z.), the Tianjin Health Bureau
Foundation (2014KR02 to C.Z.), the National Key Research and
Development Program of China (2016YFC1307004 to Y.X.), the Shanxi
Science and Technology Innovation Training Team's Multidisciplinary
Team for Cognitive Impairment (201705D131027 to Y.X.), the Zhejiang
Public Welfare Fund Project (LGF18H090002 to D.J), and the key
project of the Wenzhou Science and Technology Bureau (ZS2017011 to
X.L) .
Author statement
This paper has not been published elsewhere in whole or in part. All
authors have read and approved the content, and agree to submit it for
consideration for publication in Psychiatry Research. There are no
ethical/legal conflicts involved in the article.
Author contributions
All authors made substantial, direct, and intellectual contributions
to the work, and approved it for publication.
Role of the funding source
None.
C. Zhuo, et al.
Ethical approval
This pilot study's assessments were carried out in compliance with
the Declaration of Helsinki guidelines and approved by the institutional
ethics committee of Tianjin Anding Hospital. All procedures performed
in studies involving human participants were in accordance with the
ethics standards of the institutional and national research committee
and with the 1964 Helsinki Declaration and its later amendments or
comparable ethics standards. Written informed consent was obtained
from all individual participants included in this study.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgments
We would like to express our heartfelt thanks to Professor
Silverstein, whose proposed idea encouraged us to investigate the pa-
thological features of the visual system's impairments and investigate
their blocking strategies.
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