Retinal structural abnormalities in young adults with psychosis spectrum disorders

Journal Pre-proof Retinal structural abnormalities in young adults with psychosis spectrum disorders

Stefan Jerotic, Ivan Ristic, Slobodanka Pejovic, Marina Mihaljevic, Zorana Pavlovic, Dubravka Britvic, Zora Ignjatovic, Steven M. Silverstein, Nadja P. Maric PII:

S0278-5846(19)30673-6

DOI:

https://doi.org/10.1016/j.pnpbp.2019.109825

Reference:

PNP 109825

To appear in:

Progress in Neuropsychopharmacology & Biological Psychiatry

Received date:

10 August 2019

Revised date:

16 November 2019

Accepted date:

20 November 2019

Please cite this article as: S. Jerotic, I. Ristic, S. Pejovic, et al., Retinal structural abnormalities in young adults with psychosis spectrum disorders, Progress in Neuropsychopharmacology & Biological Psychiatry(2018), https://doi.org/10.1016/ j.pnpbp.2019.109825

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© 2018 Published by Elsevier.

Journal Pre-proof Retinal structural abnormalities in young adults with psychosis spectrum disorders Stefan Jerotic1 , Ivan Ristic2 , Slobodanka Pejovic1,2 , Marina Mihaljevic1,2 , Zorana Pavlovic1,2 , Dubravka Britvic1 , Zora Ignjatovic3 , Steven M. Silverstein4,5 , Nadja P. Maric1,2 1

Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade, Serbia Faculty of Medicine, University of Belgrade, Belgrade, Serbia 3 Milos Eye Hospital, Belgrade, Serbia 4 Rutgers – University Behavioral Health Care, Piscataway, NJ, USA 5 Departments of Psychiatry and Ophthalmology, Rutgers – Robert Wood Johnson Medical School, Piscataway, NJ, USA

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Corresponding author: Stefan Jerotic e-mail: [email protected] Address: Clinic for Psychiatry, Clinical Centre of Serbia – Pasterova 2, 11000 Belgrade, Serbia Telephone: +381 64 2887446

Journal Pre-proof Abstract

Background. Structural retinal architecture in living organisms became measurable with the development of optical coherence tomography (OCT) scanners. Single-layer analysis with spectral-domain OCT, among other techniques, may provide further insight into pathological changes in complex brain disorders such as psychosis spectrum disorders (PSD). Methods. This study investigated potential thinning of retinal layers (retinal nerve fiber layer RNFL, macular volume, macular thickness, ganglion cell-inner plexiform layer- GC-IPL, optic

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cup volume and cup-to-disk ratio) using a spectral-domain OCT device in 33 non-acute PSD

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patients (illness duration 5.9±3.9 years) and 35 healthy controls.

Results. In comparison to age and gender matched controls, patients had bilateral reductions in

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GC-IPL layer thickness and macular volume. Macular central subfield thinning was found in the right eye, while average macular thickness was lower in the left eye only. RNFL thinning was

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not observed in patients in comparison to controls, but we noticed that status of this layer could

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be affected by daily dose of antipsychotics and by illness duration. Conclusion. Taken together, our results reveal that retinal thinning is present in young adults with PSDs, but in comparison to the literature we found more prominent changes in both GC-IPL

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and macular volume/thickness, than in RNFL. Our findings may reflect synaptic loss and

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neuronal atrophy in non-acute young patients with psychosis.

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Key words: optical coherence tomography, psychosis, retina, schizophrenia

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1. Introduction In recent years, advances in optical imaging allowed for the emergence of a new approach to the structural assessment of retinal tissue. In particular, spectral domain optical coherence tomography (OCT) scanners allowed for the generation of high resolution crosssectional images of the retina (Schachat et al., 2017). By reaching axial resolutions lower than 5 micrometers, individual structures of the retina such as the retinal nerve fiber layer (RNFL),

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ganglion cell (GC) layer, and macula became observable with a high level of detail, supporting the concept that OCT provides close to an in vivo biopsy of the retina (Adhi and Duker, 2013).

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Retinal axons are non-myelinated and not concealed by the cranium. Thus, the retina could be examined as a unique model for observing neuronal changes in different neuropsychiatric

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conditions (London et al., 2013).

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Neuronal degeneration, in terms of retinal thinning and as measured by OCT, has been described in Alzheimer’s disease, Parkinson’s disease, and Multiple Sclerosis. In Parkinson’s

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disease, progressive RNFL thinning correlated with disease progression (Satue et al., 2013; Tian et al., 2011). RNFL loss in Multiple Sclerosis was associated with grey matter loss and relapse

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(Ratchford et al., 2013; Saidha et al., 2013). In Alzheimer’s disease, thinning of the GC layer was noticed even in the mild cognitive impairment stage (Paquet et al., 2007). These findings

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support the idea that the retina provides a window into the brain, and that retinal assessment can provide an efficient way to screen for central nervous system impairment.

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During the last decade, OCT time-domain and spectral-domain technology have been used by several research groups to study structural retinal abnormalities in psychiatric disorders, particularly in patients with schizophrenia. According to the most recent meta-analysis published by Lizano et al, 2019, heterogeneous samples of patients with schizophrenia had thinning of the peripapillary retinal nerve fiber layer (RNFL), reductions in ganglion cell layer/inner plexiform layer (GCL-IPL) thickness, and reduction in macular volume (MV), while there were no changes in choroidal or macular thickness (Lizano et al., 2019). In general, patient samples included in past studies contained only those with schizophrenia or schizoaffective disorder, and so the generalizability of prior findings to the broader class of psychosis spectrum disorders is unknown. At the same time, past studies have been characterized by heterogeneity in terms of illness duration and phase of the disorder

Journal Pre-proof (acute/chronic patients), age (ranges were wide, typically 18-65) and medication dosages (Ascaso et al., 2015; Celik et al., 2016; Chu et al., 2012; Lee et al., 2013; Lizano et al., 2019; Silverstein et al., 2018; Yılmaz et al., 2016). Moreover, different generations of OCT scanners were used, with older studies using lower resolution time-domain devices, which was another limitation to the generalizability of some of these findings. To the best of our knowledge, by using high resolution spectral-domain OCT device this study will be first to provide OCT retinal single-layer analysis in young adults diagnosed with psychosis

spectrum

disorder

(specifically,

schizophrenia,

schizoaffective

disorder

and

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unspecified psychosis not due to a substance or known physiological condition), taking into

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account symptom status, antipsychotic daily dose and duration of illness. 2. Method

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2.1. Subjects

This cross-sectional study included 33 subjects with psychosis spectrum disorders

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according to the tenth revision of the International Classification of Diseases (ICD-10: Mental

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and Behavioral Disorders, codes F20.x, F25.x and F29) and 35 healthy controls from Belgrade and surroundings. The psychosis group (PSD) and the control group (Con) were matched by age and sex.

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We used a mixed diagnostic group, but one in which all diagnostic subgroups are considered to have a common psychopathological basis (according to current diagnostic criteria

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for schizophrenia and other primary psychotic disorders, the occurrence of typical psychosis

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symptoms for at least a certain period of time has to be fulfilled). Written informed consent was obtained from all participants prior to the assessment. The study design was approved by the Medical Ethics Committee of the Clinical Center of Serbia. The study was conducted in accordance with the Declaration of Helsinki. Patients from the outpatient service of University Clinic for Psychiatry, Clinical Centre of Serbia, Belgrade (Serbia) were asked to participate if in remission (according to the standardized remission criteria) (Van Os et al., 2006) and if time elapsed from the diagnosis was not exceeding 15 years. Diagnosis was made by a clinical psychiatrist and Mini International Neuropsychiatric Interview was used to confirm primary diagnosis and to exclude other psychiatric disorders (Lecrubier et al., 1997). Inclusion criteria for both the PSD and Con groups were 18-40 years of age and being able and willing to give informed consent. Exclusion criteria

Journal Pre-proof were as follows: a) presence of hypertension, diabetes or other systemic and neurological disorders known to affect the visual system; b) refractive error of over ±2 spheric diopters; c) any primary ophthalmological disorder (e.g., glaucoma, macular degeneration); d) previous head injury with loss of consciousness; e) history of substance or alcohol abuse and f) mental retardation. Beside the fact that acute patients were expected to be less able to provide quality OCT data (due to agitation, movement artifacts, problems sustaining visual fixation, etc.), the decision to include only non-acute patients in the present study was made based upon previous data that

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retinal parameters could be affected by different phases of the illness (acute episode vs. other),

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and especially by neuroinflammatory swelling of retinal tissue in acute phases, which could mask baseline levels of retinal layer thinning (Ascaso et al., 2015).

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In the consecutive visits to our department during the one-year study period, we screened 38 patients. Five of them did not enter the study: two patients were excluded because there was

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history of recent psychoactive substance abuse, one patient was not in remission (did not meet

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the PANSS remission criteria) and two patients were not willing to give informed consent for the examination. All others who fulfilled criteria during the index period were included. All participants underwent a complete medical examination in order to exclude potential

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subjects with somatic comorbidities. To exclude ocular pathology, all study participants underwent a full ophthalmological examination. Best corrected visual acuity was measured with

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a Snellen chart. Slit-lamp biomicroscopy of the anterior segment and intra ocular pressure

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measurements were performed for all participants. All ophthalmological assessment was performed at the Miloš Eye Hospital in Belgrade (Serbia).

2.2. Socio-demographic and clinical assessment A socio-demographic interview included information related to age, sex, level of education, employment and marital status. Prior to the OCT session, clinical assessment included: a) administration of the Positive and Negative Syndrome Scale (PANSS) remission criteria subscale (Van Os et al., 2006) to confirm non-acute state of PSD participants (i.e., scores not higher than 3 on eight diagnostically relevant symptoms on the PANSS): 1. Delusions; 2. Unusual thought

content;

3.

Hallucinatory

behavior;

4.

Conceptual disorganization; 5.

Mannerisms/posturing; 6. Blunted affect; 7. Passive/apathetic social withdrawal; 8. Lack of

Journal Pre-proof spontaneity and flow of conversation; and b) examination of the drug prescription from the medical records (to generate chlorpromazine dose equivalents for antipsychotic medications for the week prior to the OCT session, calculated according to Gardner et al. (Gardner et al., 2010)).

2.3. Optical coherence tomography All retinal measurements were acquired using the Cirrus 4000 spectral domain HD-OCT device (Carl Zeiss Inc). Measurements were taken in both eyes separately in all participants. Retinal variables included: peripapillary RNFL thickness; RNFL quadrant thickness (superior,

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inferior, nasal, temporal), RNFL symmetry, GC-IPL layer thickness, macular central subfield

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thickness, macula average thickness, macular volume, optic cup volume and cup-to-disk (C/D) ratio. Scans with signal strength of over 7 were deemed acceptable and were included in further

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analyses.

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2.4. Statistical analyses

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All statistical analyses were performed using SPSS 21 (IBM corp.) After initial testing for normality (Shapiro-Wilks test), differences between primary groups (PSD and Con) were tested using independent samples t-test or Chi-square test. Differences between the diagnostic

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subgroups were explored using univariate analysis of variance ANOVA. Correlations between OCT parameters and sociodemographic/clinical variables were assessed by Pearson or Spearman

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coefficients. Effect sizes (Cohen’s d) are reported in all cases where significant differences were

3. Results

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observed. Level of statistical significance was set at p=0.05.

3.1. Sociodemographic and clinical characteristics Sociodemographic and clinical characteristics of the sample are shown in Table 1. There were no differences in sex [χ2(1)=0.019, p=0.89], age [t(65)=-0.262, p=0.79], or education [χ2(6)=4.703, p=0.58] between the groups. Clinical characteristics of the PSD group were: duration of illness (DOI)= 5.9±3.9 years, age when the disorder was diagnosed= 27.2±5.8 years; duration of antipsychotic treatment= 5.0±3.8

years,

dose

of antipsychotic medication (chlorpromazine

–

CPZ equivalent)=

220.3±132.0 mg. Mean total score on PANSS remission criteria in PSD group was 13.3±3.1.

Journal Pre-proof The distribution of diagnoses in PSD sample (ICD-10) were: F20.x (n=13), F25.x (n=10), F29 (n=10). Sociodemographic and clinical characteristics of diagnostic subgroups were as follows: F20.x – mean age 31.4±5.4 years, CPZ equivalents 285.7±157.1 mg, DOI 6.5±4.3 years, PANSS remission score 14.0±3.2; F25.x – mean age 34.3±5.6 years, CPZ equivalents 145.8±103.8 mg, DOI 5.7±3.7 years, PANSS remission score 12.9±3.0; F29.x – mean age 33.9±7.3 years, CPZ equivalents 218.5±84.6, DOI 5.4±3.8 years, PANSS remission score 13.1±3.6. ANOVA univariate analysis showed no significant differences between the subgroups

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in any of the given parameters.

3.2. OCT parameters

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Mean age, year (SD) Sex (% male) Education, college university (%) Mean dose of antipsychotics 220.3 (132.0) (chlorpromazine equivalent), mg (SD) Duration of illness, years 5.9 (3.9) (SD) PANSS remission scores 13.3 (3.1)

Controls n=35 32.5 (9.9) 51.4% 51.0

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Patients n=33 33.1 (6.1) 53.1% or 45.8

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Table 1. Sociodemographic and clinical characteristics of the sample

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When the two primary groups were compared (PSD vs. Con), differences were observed in macular parameters and GC+IPL. Patients had lower MV central subfield thickness that reached statistical significance in the right eye only ([t(53.358), p=0.03], Cohen’s d=0.48). Mean total macular volume was lower in patients in both the right eye ([t(66.835), p=0.04], Cohen’s d=0.53) and the left eye ([t(66.614), p=0.02], Cohen’s d=0.57). Total average macular thickness was lower in patients in the left eye ([t(65.391), p=0.03], Cohen’s d=0.54) while it showed a trend towards thinning in the right eye ([t(63.928), p=0.05], Cohen’s d=0.49). The PSD group had lower GC+IPL thickness in the right ([t(63.985), p=0.03], Cohen’s d=0.52) and left eye ([t(63.985), p=0.02], Cohen’s d=0.57). No other significant differences were observed between the PSD and Con groups. (Table 2). When diagnostic subgroups were compared, no differences in any of the retinal parameters were observed.

Journal Pre-proof DOI correlated negatively with mean RNFL in the right eye (r=-0.46, p=0.01), while for the left eye this correlation was of borderline significance (r=-0.37, p=0.06). Negative correlations with DOI were also found for the superior RNFL quadrant in both right (r=-0.58, p=0.00) and left eye (r=-0.45, p=0.01). No significant associations were found between the DOI and other retinal parameters. Mean dose of antipsychotic medication (chlorpromazine equivalent) correlated negatively only with inferior RNFL quadrant thickness in the left eye (r=-0.41, p=0.03). The rest of the correlations between mean dose of antipsychotics (CPZ equivalent) and retinal parameters were

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as follows: Right RNFL, r=-0.05, p=0.78; Left RNFL, r=-0.12, p=0.55; Right superior RNFL,

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r=-0.02, p=0.92; Left superior RNFL, r=0.07, p=0.71; Right inferior RNFL, r=-0.07, p=0.72, Right temporal RNFL, r=-0.11, p=0.58; Left temporal RNFL, r=0.20, p=0.31; Right nasal

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RNFL, r=0.02, p=0.90; Left nasal RNFL, r=-0.13, p=0.51; RNFL Symmetry, r=-0.13, p=0.44; Right macular central subfield thickness, r=0.12, p=0.54; Left macular central subfield thickness,

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r=0.08, p=0.54; Right Macula Volume, r=0.27, p=0.18; Left Macula volume, r=-0.14, p=0.50,

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Right Macula average thickness, r=0.25, p=0.20; Left Macula average thickness, r=0.17, p=0.41; Right GC+IPL average thickness, r=0.34, p=0.08; Left GC+IPL average thickness, r=0.14,

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r=0.07, p=0.70.

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p=0.48; Right GC+IPL minimum thickness, r=0.34, p=0.08; Left GC+IPL minimum thickness,

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Table 2. Mean (SDs) of the study parameters in primary groups. Column 4 displays p values of group comparisons. All subjects Cohen’s d Controls (n=35) PSD (n=33) p Right RNFL 93.60 (8.05) 94.12 (7.99) 0.79 0.06 Left RNFL 93.74 (7.52) 90.19 (18.00) 0.29 0.25 Right superior RNFL 111.11 (14.26) 113.64 (13.58) 0.46 0.18 Left superior RNFL 118.00 (12.33) 117.77 (12.89) 0.94 0.01 Right inferior RNFL 123.71 (14.44) 121.87 (13.84) 0.58 0.13 Left inferior RNFL 121.87 (12.92) 119.74 (11.96) 0.65 0.17 Right temporal 65.05 (9.92) 63.16 (9.02) 0.42 0.19 RNFL Left temporal RNFL 64.34 (9.10) 62.19 (9.02) 0.34 0.23 Right nasal RNFL 74.60 (11.60) 77.48 (12.24) 0.33 0.24 Left nasal RNFL 70.88 (10.35) 72.87 (13.65) 0.55 0.16 RNFL Symmetry 85.60 (8.64) 86.40 (8.62) 0.71 0.09 Right macular 261.82 (13.86) 252.66 (21.48) 0.04 0.48 central subfield

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0.32 0.53 0.57 0.49 0.54 0.52 0.57 0.28 0.34 0.11 0.32 0.25 0.44 0.45 0.33 0.23 0.49 layer

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thickness Left macular central 261.64 (14.76) 255.75 (20.90) 0.19 subfield thickness Right Macula 10.34 (0.41) 10.14 (0.34) 0.04 Volume Left Macula Volume 10.33 (0.38) 10.12 (0.35) 0.02 Right Macula 287.23 (11.38) 282.00 (9.68) 0.05 average thickness Left Macula average 286.97 (10.58) 281.34 (9.95) 0.03 thickness Right GC+IPL 84.80 (5.24) 82.19 (4.73) 0.03 average thickness Left GC+IPL average 84.82 (5.32) 81.93 (4.63) 0.02 thickness Right GC+IPL 81.88 (7.27) 80.08 (5.33) 0.25 minimum thickness Left GC+IPL 82.85 (5.56) 81.00 (5.28) 0.17 minimum thickness Right average C/D 0.47 (0.17) 0.49 (0.13) 0.50 ratio Left average C/D 0.44 (0.16) 0.49 (0.15) 0.23 ratio Right vertical C/D 0.44 (0.17) 0.48 (0.14) 0.27 ratio Left vertical C/D 0.40 (0.17) 0.47 (0.14) 0.08 ratio Right rim area 1.37 (0.30) 1.49 (0.22) 0.09 Left rim area 1.40 (0.27) 1.49 (0.26) 0.20 Right cup volume 0.15 (0.13) 0.18 (0.15) 0.37 Left cup volume 0.12 (0.12) 0.19 (0.16) 0.05 RNFL - retinal nerve fiber layer; GC-IPL - ganglion cell layer and inner plexiform

4. Discussion

The major finding of our study is that young patients with a psychosis spectrum disorder and relatively short illness duration had bilateral thinning of the GC-IPL layer, reduction in macular volumes and in macular thickness, as well as unilateral macular central subfield thinning. On the contrary, on all RNFL variables, the analyses yielded no differences between patients and controls. Our correlation analyses indicated, however, that RNFL thickness was in negative correlation with DOI, and that there is a possible association with daily antipsychotic dose.

Journal Pre-proof In contrast to most of the studies done with patients with schizophrenia (a few of them examining combined schizoaffective disorder and schizophrenia), our results showed no thinning of the RNFL, while at the same time GC-IPL layer thickness was reduced in our sample, with considerable effect sizes. To date, few studies have examined the GC-IPL layer in schizophrenia, in contrast to RNFL and macula thickness, which have been examined in nearly all studies (Ascaso et al., 2015; Celik et al., 2016; Chu et al., 2012; Lee et al., 2013; Schönfeldt-Lecuona et al., 2019; Silverstein et al., 2018; Yılmaz et al., 2016). One reason for this is that only newer generations of OCT devices with high resolutions are able to reliably discriminate this retinal

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segment. Multiple points are of importance in interpreting this GC-IPL layer reduction, in the

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absence of RNFL thinning. Some investigators in fields other than psychosis research have suggested that GC-IPL thickness has superior reproducibility over peripapillary RNFL, and is

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more sensitive to retinal pathology (González-López et al., 2014; Saidha et al., 2011). Moreover, taking primary glaucoma as the prototypical disorder with retinal neuron loss, the ability of GC-

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IPL thickness to discriminate subclinical retinal thinning between healthy and eyes with early

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glaucoma is very high and comparable to the combination of the strongest parameters historically used for the prediction of this disorder (Mwanza et al., 2011). Some authors have proposed that the cell loss in GC-IPL, as well as RNFL, could be

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associated with retrograde trans-synaptic axonal degeneration (RTSD), with the primary insult presenting itself in higher CNS centers, namely lateral geniculate nucleus (LGN) of the thalamus

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or V1 (Lizano et al., 2019; Silverstein et al., 2018). Both structural and functional pathological

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changes in the thalamus and in V1 have been observed in patients with schizophrenia (Cho et al., 2019; Dorph‐ Petersen et al., 2007). Therefore, it is possible that loss of neurons or neuropil in V1 could lead to loss of LGN axons or cells projecting to V1, and loss of retinal ganglion cell bodies or axons projecting to LGN. However, although RTSD is an intriguing potential mechanism of retinal thinning in schizophrenia, there is currently no direct evidence for it. Another possibility is that the aforementioned effects are connected with excessive synaptic pruning, a process that is associated with the loss of cortical grey matter described in schizophrenia (Sekar et al., 2016). However, for now, these proposed pathophysiological mechanisms of retinal cell loss in psychosis remain only hypotheses. Our finding of negative associations between the duration of illness and RNFL thinning suggests that progression through the natural course of the disorder, and especially towards a

Journal Pre-proof more chronic and disabled presentation, could be a reason why other studies with older/more chronic samples found RNFL thinning whereas we did not. Substantiating this line of reasoning is the recent study of Schonefeld-Lacuna et al. Although they found RNFL thinning in patients (combined schizophrenia and schizoaffective disorder group), they showed strong negative associations between the duration of illness and RNFL volume (Schönfeldt-Lecuona et al., 2019). Interestingly, Chu et al also found no evidence of RNFL thinning when examining patients with mean age and mean illness duration similar to our sample (Chu et al., 2012). However, while they also found no macular volume reductions, it should be taken into account

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that the device the authors used was an older generation time-domain OCT device.

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Following this line of reasoning, it could be hypothesized that the first mark of the disorder presence/progression is the loss of GC-IPL which could be followed with RNFL

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thinning as the disorder progresses. On the other hand, it should be taken into account that astrogliosis principally occurs in the RNFL and may contribute to falsely increased measured

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RNFL thickness (Green et al., 2010; Saidha et al., 2013) and increased neuroinflammation in

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psychosis may be more likely to occur in the first years of the disorder (i.e. in younger patients) (Kahn and Sommer, 2015).

It has been previously noted that inflammation can influence retinal

measurements (Ascaso et al., 2015), and as such, the presence of astrogliosis may confound the

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ability of OCT to measure RNFL thickness as accurately as GC-IPL, also potentially explaining some of the discrepancies between positive and negative thinning findings in RNFL.

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The possibility that medications could play a role in retinal layer thinning is important to

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be studied. Antipsychotic medication affects dopaminergic transmission and may reduce brain volumes (Ho et al., 2011). Because both D1- and D2- type receptors are observed in the retina, the potential effects of retinal dopamine blockade on atrophy of post-synaptic retinal cells is a potential mechanism operative in PSD that should be explored further (Silverstein and Rosen, 2015). Evidence on the effects of antipsychotic therapy on the retina in the literature is still unclear. One of the reasons is the omission of the analysis of medication equivalents in relation to retinal structures in most OCT studies. The present study found only one significant correlation only between a retinal variable and daily antipsychotic dose (with inferior RNFL quadrant thickness), suggesting minimal medication effects overall. An earlier study showed no associations between chlorpromazine dosages and RNFL, or the central field of macula, although a positive correlation was found with optic cup volume (Silverstein et al., 2018). It should be

Journal Pre-proof noted that the chlorpromazine dosages in our sample were lower than in the study of Silverstein et al. (mean 220 mg vs. 462 mg, respectively) and that both studies measured chlorpromazine equivalents which reflected only the daily dose and not lifetime exposure. Thus, we are in agreement with the authors of the most recent meta-analysis (Lizano et al., 2019), that more research is needed in investigating the potential confounding effects of medication on retinal layer thickness. Reductions in both macular thickness and macular volume have been found in some studies examining schizophrenia spectrum subjects, as is the case in our investigation. On the

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one hand, it is not surprising that our study showed both macular and GC-IPL thinning, since the

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GC-IPL thickness is measured at the macular region, so these correlations are expected. On the other hand, thinning of the macula could occur at any level between the inner limiting membrane

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and retinal pigment epithelium. The damage to retinal cells comprising the macula can happen from two directions – ascending (from the photoreceptor and pigment epithelium direction) and

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descending (following lateral geniculate nucleus damage and subsequent GC-IPL cell loss). The

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most recent meta-analysis found evidence for macular volume reduction but no evidence for macular thinning. Referring to these findings, the authors commented on the low number of studies which analyzed these parameters (Lizano et al., 2019), and suggested that further studies

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are needed to determine the extent and causes of macular changes in schizophrenia. Overall, this research has several limitations, including the use of a cross-sectional

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design, small sample size to further elaborate heterogeneous diagnostic groups and relatively

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high number of participants with unspecified non-organic psychosis. Nevertheless, even with the current number of participants and the inclusion of aforementioned subgroup of psychotic patients, our study was able to detect thinning of several retinal layers in PSD, as a group of disorders with idiopathic psychosis as a core element and antipsychotic drugs as the common therapy. We recognize, however, that while inclusion of heterogeneous diagnostic groups is advantageous if the underlying condition is indeed on a spectrum, it can also be a confound if the current diagnoses do indeed reflect separate diseases. We believe that studying the issue using both approaches is important until a better understanding of the conditions is gained. Taken together, the findings of GC-IPL thinning of previous studies were replicated in our PSD sample. Moreover, we demonstrated that these retinal findings are not specific to schizophrenia, but are found across psychosis spectrum conditions. Based on some of the

Journal Pre-proof findings that originate from ophthalmology and neurology research (previously discussed), it could be hypothesized that changes in GC-IPL might be more informative in following the course and progression of psychotic disorders, than is the case with RNFL. Nevertheless, conclusions on its potential usefulness have to be substantiated with longitudinal investigations, starting before first clinical presentation of psychosis, i.e. in ultra-high-risk subjects.

Financial support This research received no specific grant from any funding agency, commercial or not-for-profit

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Conflicts of interest

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None.

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Ethical standards

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The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the

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Literature

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Helsinki Declaration of 1975, as revised in 2008.

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Adhi, M., Duker, J.S., 2013. Optical coherence tomography–current and future applications. Curr. Opin. Ophthalmol. 24, 213. Ascaso, F.J., Rodriguez-Jimenez, R., Cabezón, L., López-Antón, R., Santabárbara, J., De la Cámara, C., Modrego, P.J., Quintanilla, M.A., Bagney, A., Gutierrez, L., Cruz, N., Cristóbal, J.A., Lobo, A., 2015. Retinal nerve fiber layer and macular thickness in patients with schizophrenia: Influence of recent illness episodes. Psychiatry Res. 229, 230–236. https://doi.org/10.1016/J.PSYCHRES.2015.07.028 Celik, M., Kalenderoglu, A., Sevgi Karadag, A., Bekir Egilmez, O., Han-Almis, B., Şimşek, A., 2016. Decreases in ganglion cell layer and inner plexiform layer volumes correlate better with disease severity in schizophrenia patients than retinal nerve fiber layer thickness: Findings from spectral optic coherence tomography. Eur. Psychiatry 32, 9–15. https://doi.org/10.1016/J.EURPSY.2015.10.006 Cho, K.I.K., Kwak, Y. Bin, Hwang, W.J., Lee, J., Kim, M., Lee, T.Y., Kwon, J.S., 2019. Microstructural changes in higher-order nuclei of the thalamus in patients with first-episode psychosis. Biol. Psychiatry 85, 70–78. Chu, E.M.Y., Kolappan, M., Barnes, T.R.E., Joyce, E.M., Ron, M.A., 2012. A window into the brain: An in vivo study of the retina in schizophrenia using optical coherence tomography. Psychiatry Res. - Neuroimaging 203, 89–94.

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https://doi.org/10.1016/j.pscychresns.2011.08.011 Dorph‐ Petersen, K., Pierri, J.N., Wu, Q., Sampson, A.R., Lewis, D.A., 2007. Primary visual cortex volume and total neuron number are reduced in schizophrenia. J. Comp. Neurol. 501, 290–301. Gardner, D.M., Murphy, A.L., O’Donnell, H., Centorrino, F., Baldessarini, R.J., 2010. International consensus study of antipsychotic dosing. Am. J. Psychiatry 167, 686–693. https://doi.org/10.1176/appi.ajp.2009.09060802 González- López, J.J., Rebolleda, G., Leal, M., Oblanca, N., Muñoz-Negrete, F.J., CostaFrossard, L., Álvarez-Cermeño, J.C., 2014. Comparative diagnostic accuracy of ganglion cell-inner plexiform and retinal nerve fiber layer thickness measures by Cirrus and spectralis optical coherence tomography in relapsing-remitting multiple sclerosis. Biomed Res. Int. 2014. https://doi.org/10.1155/2014/128517 Green, A.J., McQuaid, S., Hauser, S.L., Allen, I. V, Lyness, R., 2010. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain 133, 1591–1601. Ho, B.-C., Andreasen, N.C., Ziebell, S., Pierson, R., Magnotta, V., 2011. Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Arch. Gen. Psychiatry 68, 128–137. Kahn, R.S., Sommer, I.E., 2015. The neurobiology and treatment of first-episode schizophrenia. Mol. Psychiatry 20, 84. Lecrubier, Y., Sheehan, D. V, Weiller, E., Amorim, P., Bonora, I., Sheehan, K.H., Janavs, J., Dunbar, G.C., 1997. The Mini International Neuropsychiatric Interview (MINI). A short diagnostic structured interview: reliability and validity according to the CIDI. Eur. psychiatry 12, 224–231. Lee, W.W., Tajunisah, I., Sharmilla, K., Peyman, M., Subrayan, V., 2013. Retinal Nerve Fiber Layer Structure Abnormalities in Schizophrenia and Its Relationship to Disease State: Evidence From Optical Coherence Tomography. Investig. Opthalmology Vis. Sci. 54, 7785. https://doi.org/10.1167/iovs.13-12534 Lizano, P., Bannai, D., Lutz, O., Kim, L.A., Miller, J., Keshavan, M., 2019. A Meta-analysis of Retinal Cytoarchitectural Abnormalities in Schizophrenia and Bipolar Disorder. Schizophr. Bull. https://doi.org/10.1093/schbul/sbz029 London, A., Benhar, I., Schwartz, M., 2013. The retina as a window to the brain—from eye research to CNS disorders. Nat. Rev. Neurol. 9, 44. Mwanza, J.-C., Oakley, J.D., Budenz, D.L., Chang, R.T., O’Rese, J.K., Feuer, W.J., 2011. Macular ganglion cell–inner plexiform layer: automated detection and thickness reproducibility with spectral domain–optical coherence tomography in glaucoma. Invest. Ophthalmol. Vis. Sci. 52, 8323–8329. Paquet, C., Boissonnot, M., Roger, F., Dighiero, P., Gil, R., Hugon, J., 2007. Abnormal retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci. Lett. 420, 97–99. Ratchford, J.N., Saidha, S., Sotirchos, E.S., Oh, J.A., Seigo, M.A., Eckstein, C., Durbin, M.K., Oakley, J.D., Meyer, S.A., Conger, A., 2013. Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning. Neurology 80, 47–54. Saidha, S., Sotirchos, E.S., Oh, J., Syc, S.B., Seigo, M.A., Shiee, N., Eckstein, C., Durbin, M.K., Oakley, J.D., Meyer, S.A., 2013. Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. JAMA Neurol.

Journal Pre-proof

Jo

ur

na

lP

re

-p

ro

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70, 34–43. Saidha, S., Syc, S.B., Ibrahim, M.A., Eckstein, C., Warner, C. V, Farrell, S.K., Oakley, J.D., Durbin, M.K., Meyer, S.A., Balcer, L.J., 2011. Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography. Brain 134, 518–533. Satue, M., Garcia-Martin, E., Fuertes, I., Otin, S., Alarcia, R., Herrero, R., Bambo, M.P., Pablo, L.E., Fernandez, F.J., 2013. Use of Fourier-domain OCT to detect retinal nerve fiber layer degeneration in Parkinson’s disease patients. Eye 27, 507. Schachat, A., Sadda, S., Hinton, D., Wilkinson, P., Wiedemann, P., 2017. Ryan’s Retina, in: Retina. https://doi.org/10.1016/B978-0-323-40197-5.00095-5 Schönfeldt-Lecuona, C., Kregel, T., Schmidt, A., Kassubek, J., Dreyhaupt, J., Freudenmann, R.W., Connemann, B.J., Gahr, M., Pinkhardt, E.H., 2019. Retinal single- layer analysis with optical coherence tomography (OCT) in schizophrenia spectrum disorder. Schizophr. Res. Sekar, A., Bialas, A.R., De Rivera, H., Davis, A., Hammond, T.R., Kamitaki, N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., Genovese, G., Rose, S.A., Handsaker, R.E., Daly, M.J., Carroll, M.C., Stevens, B., McCarroll, S.A., 2016. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183. https://doi.org/10.1038/nature16549 Silverstein, S.M., Paterno, D., Cherneski, L., Green, S., 2018. Optical coherence tomography indices of structural retinal pathology in schizophrenia. Psychol. Med. 48, 2023–2033. https://doi.org/10.1017/S0033291717003555 Silverstein, S.M., Rosen, R., 2015. Schizophrenia and the eye. Schizophr. Res. Cogn. 2, 46–55. https://doi.org/10.1016/J.SCOG.2015.03.004 Tian, T., Zhu, X.-H., Liu, Y.-H., 2011. Potential role of retina as a biomarker for progression of Parkinson’s disease. Int. J. Ophthalmol. 4, 433. Van Os, J., Burns, T., Cavallaro, R., Leucht, S., Peuskens, J., Helldin, L., Bernardo, M., Arango, C., Fleischhacker, W., Lachaux, B., Kane, J.M., 2006. Standardized remission criteria in schizophrenia. Acta Psychiatr. Scand. https://doi.org/10.1111/j.1600-0447.2005.00659.x Yılmaz, U., Küçük, E., Ülgen, A., Özköse, A., Demircan, S., Ulusoy, D.M., Zararsız, G., 2016. Retinal Nerve Fiber Layer and Macular Thickness Measurement in Patients with Schizophrenia. Eur. J. Ophthalmol. 26, 375–378. https://doi.org/10.5301/ejo.5000723

Journal Pre-proof Author statement

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S.J. designed the study, conducted experimental assessments, did primary data analyses, drafted and edited the manuscript. I.R. assisted in experimental assessments and data analyses. S.P., M.M., Z.P. and D.B. drafted and edited parts of the manuscript. Z.I., N.M. and S.S. assisted in designing the study, data interpretation and drafting the manuscript.

Journal Pre-proof Ethical standards The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and

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with the Helsinki Declaration of 1975, as revised in 2008.

Journal Pre-proof Conflicts of interest

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None.

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Optical coherence tomography scanners provide insights into retinal changes in neuropsychiatric disorders Bilateral thinning in ganglionic cell-inner plexiform layer (GC-IPL), as well as reductions in macular volume and thickness were found in young adults with psychosis spectrum disorders Retinal nerve fiber layer (RNFL) was not observed in this patient group Changes in GC-IPL in might be informative in following the course and progression of psychotic disorders

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