Retinal arteriolar and venular diameters are widened in patients with schizophrenia

Abstract

Cerebrovascular abnormalities have been discussed as pathological mechanisms involved in schizophrenia, particularly in the context of the genetic–inflammatory–vascular hypothesis.1 The cerebral and retinal microcirculation have similarities with respect to morphology and physiology. It can therefore be tested if retinal vessel changes occur in patients with schizophrenia. Larger diameters of retinal venules have been noted in schizophrenia,2, 3 while smaller retinal arteriolar diameters were recently shown in psychoses.3 Our study aimed to contribute new information to further test the hypothesis of the ‘eye as a window to the brain’ in the context of schizophrenia. We used fundus imaging to estimate the size of the retinal arterioles and venules in patients with schizophrenia, their healthy relatives, and unrelated controls. Additionally, we applied optical coherence tomography to estimate changes in retinal nerve fiber layers. Patients and their healthy relatives were recruited at the Department of Psychiatry, University Hospital Hradec Králové and the Department of Psychiatry, University Hospital Brno. Patients were aged 18 to 65 years, males or females, diagnosed with schizophrenia according to the DSM-5, with no other mental disorders present. The healthy first-degree relatives could not be age- and sex-matched satisfactorily, therefore we also recruited age- and sex-matched healthy controls with no known mental disorder. Additional exclusion criteria were hypertension, heart disease or stroke, and disorders potentially influencing retinal microvasculature, such as age-related macular degeneration or major deficits in visual acuity. All participants provided written informed consent. The project was approved by the Ethics Committees of the University Hospitals in Hradec Králové and Brno in the Czech Republic. Demographic and clinical variables were collected for all participants: age; sex; education; employment and marital status; tobacco dependence; and occurrence of cerebrovascular diseases, arterial hypertension, heart disease, stroke, varicose veins, and diabetes mellitus. In schizophrenia, patients' age at the time of the first psychotic episode, duration of schizophrenia, subtype of schizophrenia, and medication details were recorded (Table 1). Retinal imaging was performed at the Department of Ophthalmology, University Hospital Hradec Králové and in the Eye Clinic, University Hospital Brno. Fundus photographs of both eyes were taken using a digital fundus camera FF 450 + IR (Zeiss, Oberkochen, Germany) and spectral domain optical coherence tomography (Cirrus, HD-OCT, Zeiss Meditec, Oberkochen, Germany).4 The Vascular Assessment and Measurement Platform for Images of the Retina (VAMPIRE) software application was used to analyze the digital retinal images.5 The sizes of the retinal arterioles and venules were calculated in the region located 0.5–2.0 disc diameters from the optic disc margin. The vessel calibers were summarized for the six largest retinal arterioles and venules passing through the region and expressed as the central retinal artery equivalent and the central retinal vein equivalent.6 The study had three groups (Table 1): patients with schizophrenia (n = 39), their healthy first-degree relatives (n = 39), and sex- and age-matched controls not related to the other two groups (n = 32). The Mann–Whitney U-test was used to evaluate differences between patients and unrelated controls and between healthy relatives and unrelated controls. The Wilcoxon signed rank test was used to evaluate differences between patients and their healthy relatives. All statistical computations were performed using statistical software R.7 We found significantly wider arteriole diameter: in patients with schizophrenia compared to their healthy relatives (P < 0.05 for both eyes); in the group of patients compared to the unrelated controls (P < 0.0001 for both eyes); and in the healthy relatives compared to the unrelated controls (left eye: P < 0.001; right eye: P < 0.05). The venules of the patients and their healthy relatives were wider than those of the unrelated controls (patients vs unrelated controls: left eye: P < 0.01, right eye: P < 0.05; healthy relatives vs unrelated controls: P < 0.05 for both eyes). Few changes in the thickness of retinal layers from one group to another were detected (Table S1), except for the retinal ganglion cell layer in the inferior zone, which was significantly smaller in patients compared to healthy controls (P < 0.05 for both eyes). Possible mechanisms include blood vessel diameter changes caused by pericytes8 or smoking; compared with the general population, patients with schizophrenia are more likely to smoke (Table 1). However, we have been able to rule out smoking as a factor by additional statistical analyses (Supplementary information: Tables S2 and S3). The changes in the blood vessel morphology may represent a genuine novel structural correlate of schizophrenia. Pending resolution of conflicting evidence2, 3 and inclusion of genetic factors9 as well as confirmation by larger studies, the measurement of retinal blood vessel diameter could become a screening or diagnostic tool.10 This work was supported by the Czech Health Research Council, Ministry of Health of the Czech Republic (Grant Project No. NV16-27243A). The authors declare no conflicts of interest. Table S1. The comparison of retinal parameters between studied groups for oculus dexter (OD) and oculus sinister (OS). Table S2. Comparison of diameters of blood vessels between studied groups according to smoking status. Table S3. Comparison of diameters of blood vessels in smokers and non-smokers. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.