Schizophrenia in Translation: Why the Eye?

Abstract

Schizophrenia is increasingly recognized as a systemic disease, characterized by dysregulation in multiple physiological systems (eg, neural, cardiovascular, endocrine). Many of these changes are observed as early as the first psychotic episode, and in people at high risk for the disorder. Expanding the search for biomarkers of schizophrenia beyond genes, blood, and brain may allow for inexpensive, noninvasive, and objective markers of diagnosis, phenotype, treatment response, and prognosis. Several anatomic and physiologic aspects of the eye have shown promise as biomarkers of brain health in a range of neurological disorders, and of heart, kidney, endocrine, and other impairments in other medical conditions. In schizophrenia, thinning and volume loss in retinal neural layers have been observed, and are associated with illness progression, brain volume loss, and cognitive impairment. Retinal microvascular changes have also been observed. Abnormal pupil responses and corneal nerve disintegration are related to aspects of brain function and structure in schizophrenia. In addition, studying the eye can inform about emerging cardiovascular, neuroinflammatory, and metabolic diseases in people with early psychosis, and about the causes of several of the visual changes observed in the disorder. Application of the methods of oculomics, or eye-based biomarkers of non-ophthalmological pathology, to the treatment and study of schizophrenia has the potential to provide tools for patient monitoring and data-driven prediction, as well as for clarifying pathophysiology and course of illness. Given their demonstrated utility in neuropsychiatry, we recommend greater adoption of these tools for schizophrenia research and patient care.

Precision psychiatry and Research Domain Criteria: Implications for clinical trials and future practice

“…97 In schizophrenia, shrinkage of the retinal neural layers occurs in parallel with illness progression, brain volume loss, and cognitive impairment, and represents a means of assessing pathophysiology and treatment efficacy in patients. 98 The integration of large-scale analysis of datasets from highthroughput sequencing and genotyping technologies, broadspectrum omics studies in combination with the wealth of data from neuroimaging, consortia, repositories, and smartphone apps, can be achieved using artificial intelligence (AI) and machinelearning technologies (eg, support vector machines, modern neural-network algorithms, cross-validation procedures), thus affording new insights into complex patterns in brain, behavior, and genes. 99 These multifaceted initiatives could advance our understanding of disease pathology and accelerate the transition from current DSM classifications to a biological-based redefinition of major psychiatric disorders.…”

“…Other biological analyses such as oculomics, which measures nonophthalmological anatomical and physiological biomarkers in the eye, have also shown promise as biomarkers of brain health 97 . In schizophrenia, shrinkage of the retinal neural layers occurs in parallel with illness progression, brain volume loss, and cognitive impairment, and represents a means of assessing pathophysiology and treatment efficacy in patients 98 …”

Genetic polymorphism and neuroanatomical changes in schizophrenia

“…A remarkably interesting finding is the visual impairment associated with schizophrenia [ 170 ]. So, it is demonstrated (again) that the disorder is one of, if not the most complex psychiatric disorder.…”

“…In addition to deficits (in the brain) caused by neurodevelopment there are also neurodegenerative deficits, even at the level of the corneal nerve, which is thinned [ 171 ]. A decrease in volume has also been observed, which implies microvascular changes in the retina, directly proportional influenced by the evolution of the disorder [ 170 , 172 , 173 ]. These pathologies are specific to the elderly, but psychosis triggers them from the onset, or even earlier.…”

Eye-brain connections revealed by multimodal retinal and brain imaging genetics in the UK Biobank

“…The retina is embryonically formed as part of the diencephalon, which later becomes the thalamus, thus being developmentally related to specific brain regions. Consequently, the retina has been considered a unique window into altered brain structure/function 1,3 and brain disorders 4 , such as Alzheimer's disease [5][6][7][8] , Parkinson's disease 9 , stroke 10,11 , cerebral small vessel disease 12 , schizophrenia 13 , cognitive decline 11,14,15 , and many others. For example, it has been extensively studied that retinal neurodegeneration can be used as an easily accessible biomarker to identify individuals at high risk of developing Alzheimer's disease or those with preclinical Alzheimer's disease 6,8,[16][17][18] .…”