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286(2020)1
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Antipsychotic agent-induced deterioration of the visual system in first- 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

ARTICLEINFO
ABSTRACT
Keywords:
Schizophrenia Define changes in the visual cortex and retina in first-episode schizophrenia patients with visual disturbance
Visual perception disturbances (FUSCHVD) accompanied by antipsychotic agent treatment is important for guiding treatment. We examined the
Gray matter volume visual system prior to and after 3 years of antipsychotic-agent treatment in 48 patients with FUSCHVD and 50
Retinal thickness healthy controls, and after 3.5 years of antipsychotic-agent treatment in 12 patients with FUSCHVD and 12
Self-limited healthy subjects who came from the cohort with 3 years of follow up. Reduction of the visual cortex gray matter
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
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,
compared to other symptoms associated with schizophrenia, such as
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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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
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

disturbance symptoms in focused on the visual cortex in the

FUSCHVD patients. Voxel-based
morpho- metry (VBM) was used
to assess alterations in the gray
matter volume (GMV) of the
FUSCHVD patients and especially
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
C. Zhuo, et
Al.
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
3
deformation approach. Upon
preprocessing completion, a p < .05, then corrected
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).
3V\FKLDWU\5HVHDUFK2
86(2020}112906
The significance level was set at
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
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Table 1
Sociodemographic information and results of clinical examination.
FUSCHVD
Baseline FUSCHVD Three-year Follow- Healthy Controls Baseline Healthy controls Three-year t P
n = 48 up n = 50 Follow-up n = 50
n = 48

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
(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

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
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

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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 treatment 350.2 ± 28.7 µm 12.099 <0.001
Total retinal thickness differences in FUSCHVD patients before and after 3 years

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

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 reatment 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 t

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

Fig. 2. Total retinal thickness reduction in FUSCHVD patients and healthy
controls at the three-year follow-up (Double Y axis, left: retinal thickness re-
duction of patients, right: retinal thickness reduction of healthy controls).
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
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- tipsychotic agents
treatment end-point compared to the OCT data (Table 2). These findings
also suggested that the retinal thickness of patients with FUSCHVD
discontinued deterioration.
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

psychotic episode. These findings provided evidence that both visual al., 2009). The findings of this pilot study also indicated that the starting
cortex and retina impairment can be observed at any stage of schizo- from the origin of visual perception (retina) to higher visual perception
phrenia (Calderone et al., 2013; Hebert et al., 2010; Lencer et al., 2005; integration systems (visual cortex) all pathways might be affected in
Nagel et al., 2007; Onitsuka et al., 2007; Silverstein, 2016; Silverstein et patients with FUSCHVD.

5
C. Zhuo, et
Al.
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
Ethical approval
This pilot study's assessments were carried out in compliance with
the Declaration of Helsinki guidelines and approved by the
6
3V\FKLDWU\5HVHDUFK2
86(2020}112906
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.
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
C. Zhuo, et
Al.
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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