Introduction
Schizophrenia is a mental disorder with an as-yet-unknown etiology that affects about 1% of the population. It is characterized by the presence of productive and negative symptoms, as well as cognitive disorders. Among the many potential pathogenetic factors of this disease, neurodegenerative processes appear to play an important role (Wójciak et al. 2020).
The Biomarker Definition Working Group defined a biomarker in the context of pharmacological clinical trials as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological response to a therapeutic intervention” (Fuentes-Arderiu 2013; Atkinson et al. 2001). The search for biomarkers of schizophrenia to assess severity, predisposition to disease, prognosis and response to treatment is considered crucial, as it may help improve diagnosis or even individualize treatment for patients (Hosak et al. 2018). Expanding this search beyond genes, blood, and brain tissue could lead to the identification of other non-invasive and inexpensive markers (Silverstein et al. 2022). One promising type of biomarker of central nervous system abnormalities, including the progressive loss of brain tissue that accompanies schizophrenia and the resulting cognitive decline, may be abnormalities in the structure of the retina and optic disc (Silverstein et al. 2018; Pan et al. 2018).
In recent years, there has been growing interest in the somatic abnormalities present in schizophrenia, among which researchers have readily addressed the structure of the eye, including the retina and its vessels. There has also been no shortage of studies describing the effects of lipid metabolism or the role of brain-derived neurotrophic factor (BDNF) on the structure and function of the visual apparatus and their relationship to the observed abnormalities of psychiatric symptoms. The above-mentioned abnormalities have also been described in the context of negative symptoms or accompanying cognitive disturbances in the course of schizophrenia. This paper is a review of the above studies.
The retina and schizophrenia – the importance of eye examinations
The retina is the building block of the eye that receives visual stimuli. It consists of several layers of nerve cells belonging to the visual pathway, including cones and rods, bipolar cells and retinal ganglion cells. The highest density of receptors (cones and rods) forms the macula (Nowak and Bienias 2007; Provencio 2011). The eye is sometimes called the “window to the brain” because, like brain tissue, the retina develops from the neuroectoderm and its cells originate from brain cells (Pan et al. 2018). Thus, the structural changes of the retina observed in schizophrenic patients may reflect abnormalities occurring throughout the brain tissue (Hosak et al. 2018).
Schizophrenia meets some of the criteria for a neurodegenerative disorder, and the degenerative processes observed may be measurable specifically in the retina (Pan et al. 2018). Indeed, schizophrenic patients have abnormalities of this structure that include abnormalities of the retinal structure, dysfunction of photoreceptors and other cells belonging to the visual pathway, and disorders of the microcirculation supplying the retina (Wójciak et al. 2020). Therefore, the study of both the structure and function of the retina in patients with schizophrenia can complement the methods used so far, such as brain imaging or neuropsychological testing (Hosak et al. 2018).
Numerous studies published since 2015 have described abnormalities in both the structure of the retina as assessed by optical coherence tomography (OCT) and its function as examined using electroretinography (ERG) in patients with schizophrenia (Silverstein et al. 2020). Thinning of the retinal cell layers has been shown to be associated with disease progression, decreased brain volume, deterioration of cognitive function, and increased negative symptoms (Silverstein et al. 2022; Zhu et al. 2025). In addition, schizophrenic patients had an enlarged cup volume as well as an increased ratio of optic disc cup diameter to whole optic disc diameter (cup-to-disc ratio – CDR), indicating atrophy of optic nerve fibers and associated with increased cognitive impairment (Silverstein et al. 2018).
The growing importance of eye examination in the context of diseases of the nervous system is due to the low cost as well as the non-invasiveness of the mentioned tests. However, there are some limitations to retinal examination. This is because the results can be distorted by the influence of several factors – the course of the disease, long-term use of neuroleptic drugs, systemic comorbidities (e.g., diabetes, hypertension), obesity, psychoactive substance use, smoking, sex and gender, attention and arousal, and motivation, which affect the retina via serotonergic and histaminergic signals from the brain. It should be noted, however, that the afo-rementioned phenomena can also distort the results of other tests, such as imaging (Silverstein et al. 2020; Hosak et al. 2018). Another important limitation of the use of retinal examination is the evaluation of only a small part of the neural tissue, omitting the most important part of the brain for schizophrenia (Hosak et al. 2018).
Optical coherence tomography in schizophrenia
Optical coherence tomography is a non-invasive method of in vivo retinal imaging that allows measurements of retinal thickness (Schönfeldt-Lecuona et al. 2020). It is an imaging technique based on interferometry that can illustrate the structure of retinal layers reproducibly and rapidly at a resolution similar to that of microscopic sections (Pan et al. 2018; Schönfeldt-Lecuona et al. 2020).
Structural changes occurring in the brain of schizophrenic patients are also observable in the retina, allowing observation of the central nervous system (Schönfeldt-Lecuona et al. 2016). The axons of the retinal ganglion cells that make up the retinal nerve fiber layer (RNFL), which make up the first segment of the visual pathway, are not myelinated, so they can be assessed for neurodegenerative changes (Schönfeldt-Lecuona et al. 2020). OCT can assess the retinal nerve fiber layer thickness (RNFLT), as well as macular thickness (MT) and macular volume (MV) (Schönfeldt-Lecuona et al. 2020; Pan et al. 2018). The retinal abnormalities observed in these studies may be markers in schizophrenia spectrum disorders (Komatsu et al. 2022).
In one study, patients with schizophrenia spectrum disorders showed significantly reduced thickness of the retinal nerve fiber layer and inner nuclear layer (INL), as well as reduced macular thickness and volume. In addition, the thickness of the RNFL and the zone surrounding the central fovea of the retina was shown to be associated with the duration of the disease and higher doses of neuroleptic drugs (per equivalent dose of chlorpromazine) (Schönfeldt-Lecuona et al. 2016). Another study using OCT demonstrated extensive retinal thinning in people with schizophrenia spectrum disorders, which was independent of the influence of systemic and ocular factors (age, gender, spherical equivalent, intraocular pressure, body mass index, diabetes, hypertension, smoking and OCT signal strength) (Boudriot et al. 2022). A meta-analysis including 23 studies showed a reduction in peripapillary retinal nerve fiber layer (pRNFL) thickness, average macular thickness (MT) and macular volume (MV), as well as macular ganglion cell–inner plexiform layer (mGCIPL) thickness, and an enlarged cup volume in people with schizophrenia compared to healthy individuals (Boudriot et al. 2022; Komatsu et al. 2022). However, these studies were mostly cross-sectional, and longitudinal studies may be needed to clarify the relationship between these changes and clinical factors (Komatsu et al. 2022). In another study, a group of people with schizophrenia showed no difference in the thickness of the RNFL, ganglion cell layer–inner plexiform layer (GCL-IPL), and macula relative to a control group, while a reduction in the thickness of the aforementioned retinal structural elements was associated with the presence of diabetes and hypertension (Silverstein et al. 2018). Miller et al. (2020) observed a reduction in macular volume on eye examination in schizophrenic patients, while no difference was found in RNFL thickness compared to healthy subjects. Interestingly, the study used two different OCT devices (Spectralis and Cirrus OCT), and the results were independent of the device used. Other studies have shown that age-related retinal neural tissue loss progresses more rapidly in people with schizophrenia spectrum disorders. This suggests that information obtained from OCT may be a marker of accelerated aging in people with psychotic symptoms, but should take into account the metabolic status of the patients (Kurtulmus et al. 2023; Blose et al. 2023).
The neuropathological basis of the structural changes of the retina in schizophrenia and their clinical implications are still unknown. However, one study (Kurtulmus et al. 2023) noted the association of poor executive functioning with decreased thickness of the right and left inner plexiform layer and macula, the correlation of composite attention score with thickness of the right IPL and left macula, executive function with thickness of the left IPL, immediate memory VMPT (Verbal Memory Processes Test) with thicker RNFL of both eyes, higher dose of chlorpromazine equivalents with decreased thickness of the right GCL and left RNFL, and longer disease duration with increased thickness of the left and right IPL and right GCL. However, this study did not observe a significant association between OCT measurements and cognitive impairment. Another group of researchers found a significant reduction in macular thickness in patients with psychosis, particularly the inner layer of the macula. This may be indicative of ongoing inflammatory, degenerative, or vascular processes that may be occurring concurrently in the brain (Joe et al. 2018).
Another meta-analysis (Pan et al. 2018) showed significantly reduced retinal nerve fiber layer thickness in its inferior, nasal, and temporal quadrants in schizophrenic patients relative to healthy subjects, while no such differences were found in the superior quadrant. In general, the average thickness of the RNFL in the periventricular region of the retina was lower in patients with the disease, although some studies found no differences in RNFL thickness at all between patients with schizophrenia and healthy subjects. Based on the results, the researchers concluded that OCT could, by measuring the thickness of retinal nerve fibers, detect the progression of neuronal degeneration and provide a diagnostic tool for schizophrenia. Table 1 presents a summary of OCT findings in patients with schizophrenia.
Electroretinography and its role in schizophrenia
Electroretinography is a test used to assess retinal function, which reflects the activity of its cells. In an ERG test, the electrical potentials generated by the retina in response to light are recorded. First, hyperpolarization of photoreceptors (light-receiving cells) occurs, generating the “a-wave”, followed by depolarization of bipolar cells that transmit the signal to the brain, producing the “b-wave” (Wójciak et al. 2020; Gagné et al. 2015).
Studies have shown that schizophrenic patients experience a decrease in the amplitude of the a-wave regardless of the dose of neuroleptics, which is associated with a deficiency of membrane omega-3 fatty acids. A similar deficit is observed in the brain of these patients (Wójciak et al. 2020; Warner et al. 1999; Ohara 2007). In addition, abnormalities in the ERG may be influenced by neurotransmission and metabolic abnormalities of serotonin and dopamine, so that ERG abnormalities in mentally ill patients may serve as biomarkers of monoaminergic dysfunction (Wójciak et al. 2020; Lavoie et al. 2014). An example of this is the change in activity in short-wavelength (S) cones, which changes under the influence of dopamine deficiency in the brain. Therefore, ERG can be used to assess response to treatment or predict relapse in schizophrenia (Silverstein et al. 2022). There are also functional methods for assessing dopaminergic activity, such as pattern-generated electroretinography (PERG) (Wójciak et al. 2020; Schwitzer et al. 2016).
According to some researchers, changes in retinal function are limited to the acute phase of the illness and are characteristic of schizophrenia (compared to bipolar disorder) (Hosak et al. 2018; Balogh et al. 2008). In contrast, other studies have shown that retinal examination can be a specific early biomarker of risk as early as in the pre-onset period (Hosak et al. 2018; Hébert et al. 2010).
With its ability to assess retinal function, ERG may become a good tool for diagnosis and monitoring of treatment in schizophrenia patients, including supplementation with omega-3 fatty acids, after which patients’ clinical condition has been reported to improve (Wójciak et al. 2020; McNamara and Strawn 2013). Also important in the context of schizophrenia is the ability to measure the activity of specific cell types using ERG (Silverstein et al. 2022). Table 2 presents a summary of ERG findings in patients with schizophrenia.
Negative symptoms and changes in the retina
In addition to the positive symptoms, schizophrenia is also characterized by the presence of negative symptoms, which include flattering of affect, anhedonia, alogia, avolition, and social withdrawal. These are divided into primary symptoms, which are part of the schizophrenic process, and secondary symptoms, which are a consequence of factors accompanying the disease process (Wójciak et al. 2017).
In schizophrenic patients with predominantly negative symptoms, changes in brain structure and function are observed. Among other things, a reduction in the volume of certain structures has been described, including the prefrontal cortex, temporal cortex, caudate nucleus, limbic system, right parietal lobe cortex, and corpus callosum (Wójciak et al. 2020; Galderisi et al. 2015). An association of the severity of negative symptoms with white matter disorders is also observed (Wójciak et al. 2020; Galderisi et al. 2015; Rowland et al. 2009). In addition, it has been suggested that negative symptoms are associated with deficits in dopaminergic neurotransmission and a reduction in the number of D1, D3, and D4 dopamine receptors in the prefrontal cortex (Wójciak et al. 2020; Galderisi et al. 2015; Abi-Dargham et al. 2000).
One study showed thinning of the central foveal thickness (CFT) and central macular thickness (CMT) in patients with schizophrenia and its association with the severity of negative symptoms (Zhu et al. 2025). Another study observed that thinning of the photoreceptor complex, particularly the outer nuclear layer and inner segment layer, was pronounced and significantly associated with the severity of negative symptoms assessed using the Positive and Negative Syndrome Scale (PANSS; Samani et al. 2018).
The classic theory of dopamine excess in schizophrenia has been expanded to include a newer model of glutamatergic dysfunction, which may significantly contribute to negative symptoms. NMDA glutamatergic receptor hypofunction also involves photoreceptor-bipolar cell pathways in the retinal fovea. Therefore, photoreceptor thinning may reflect NMDA dysfunction. Interestingly, NMDA hypofunction has also been associated with positive symptoms, for which, however, no correlation with retinal disorders has been found (Samani et al. 2018).
Cognitive function in schizophrenia and its relation to retinal parameters
In addition to the positive (delusions, hallucinations) and negative symptoms, schizophrenia is also characterized by cognitive deficits, including impairments of memory, executive functions, or attention. These are the factors that mainly determine the patients’ reduced quality of life, hindering daily functioning both at work and in society. Unfortunately, they are difficult to treat and usually do not improve after antipsychotic treatment (Molho et al. 2024; McCleery and Nuechterlein 2019).
Studies conducted through the use of optical OCT and electroretinography show changes in retinal structure and function that may correlate with the severity of patients’ cognitive deficits. For example, reductions in the thickness of retinal ganglion cells (GCL), inner plexiform layer (IPL), and macular volume (MV) have been observed in patients with schizophrenia, highlighting the correlation of neurocognitive test results with OCT findings. Based on these observations, it has been suggested that cognitive impairment may be caused by structural changes in the brain correlating with changes in retinal structure (Taşdelen et al. 2023). Another study described lower b-wave amplitudes on ERG in patients with early-onset psychosis, while finding no significant reduction in a-wave amplitudes. Changes in photoreceptor and bipolar cell responses have been linked to cognitive decline (Molho et al. 2024).
The retina is currently considered as a potential biomarker of cognitive impairment in schizophrenia due to being part of the central nervous system. Studies have shown that schizophrenia patients experience accelerated macular atrophy above 20, which is when white matter changes occur. The dynamics of changes in the macula and retinal ganglion cells increased linearly only in the subgroup of middle-aged patients, but did not progress with age in those over 50 years old or those with illnesses of duration over 30 years (Domagała et al. 2023). Moreover, according to the accelerated aging theory, there is an association between macular thickness and volume and cognitive impairment related to processing speed (Domagała et al. 2023).
Studies have revealed an association between structural changes in the retina and cognitive functions; for example, verbal fluency correlated with GCL-IPL thickness not only in schizophrenia patients, but also in their healthy first-degree relatives. Also, a population-based study showed an association of cognitive decline with RNFL thinning (Girbardt et al. 2021). Thus, both cognitive function tests and OCT can serve as predictors of cognitive impairment in patients with psychosis (Taşdelen et al. 2023).
In a study involving 485 schizophrenic patients evaluating the retina, patients with schizophrenia spectrum disorders showed changes in both retinal structure and function compared to healthy subjects; these changes were associated with cognitive impairment (Al-Mazidi 2024; Wagner et al. 2023; Silverstein et al. 2020). Reduction in macular thickness and volume has been described in patients with schizophrenia spectrum disorders compared to healthy individuals of the same age. This indicates faster retinal aging in patients with schizophrenic psychoses. Moreover, the severity of these changes was associated with increased cognitive impairment (Al-Mazidi 2024; Domagała et al. 2023).
Another population-based study showed that a reduction in GCL volume was more strongly associated with cognitive impairment, particularly in terms of verbal episodic memory processing, than RNFL thickness (Ward et al. 2020).
Lipids and their role in retinal function and schizophrenia
Recently, lipids, which are a much more diverse group than proteins (there are about 100,000 types of lipids in the human body), have attracted the interest of researchers (Zhuo et al. 2020; Shevchenko and Simons 2010; Brugger 2014). Changes in both lipid and glucose metabolism have been shown to correlate with the severity of schizophrenia symptoms (Yesilkaya et al. 2023). Lipidomics, which is the analysis of cellular lipids, opens a new field for studying the pathomechanisms of schizophrenia. The presence of lipid biomarkers in biofluids that could facilitate the diagnosis of the disorder seems promising (Zhuo et al. 2020).
It has been observed that in schizophrenia there are certain metabolic abnormalities and lipid deficiencies, which may result in changes in the structure and function of brain neurons and the retina leading to visual and cognitive dysfunction, among other things, by impairing the function of membrane proteins and disrupting neurotransmitter systems. Lipids, including polyunsaturated fatty acids (PUFAs) and phospholipids, are important for normal retinal function, and changes in their composition correlate with neurological abnormalities in schizophrenic patients (Zhuo et al. 2020). Studies have shown that patients in remission had significantly higher fasting blood levels of triglycerides, glucose, and low-density lipoprotein (LDL) relative to healthy subjects (Yesilkaya et al. 2023). A negative correlation of disease severity with LDL levels was observed, the reason being that lipids facilitate the penetration of drugs across the blood-brain barrier and serve as a reservoir for depot drugs (Yesilkaya et al. 2023). It is worth emphasizing the potential protective role for the central nervous system and retina shown by omega-3 fatty acids, which are one type of PUFA – as they reduce neuroinflammatory processes and thus the risk of neuronal damage, positively influencing cognitive functioning and having a protective effect in the course of schizophrenia (Zhuo et al. 2020).
Yesilkaya et al. (2023) did not find a correlation between retinal thickness and lipid levels, glucogenic proteins, or cholesterol and glucose metabolism parameters, despite the presence of areas of RNFL with lower thickness in patients with drug-resistant schizophrenia compared to healthy individuals.
Brain-derived neurotrophic factor versus retinal function and schizophrenia
Brain-derived neurotrophic factor is a widely distributed protein in the brain that plays a key role in the development and function of the nervous system, influencing the plasticity of synapses and thus the cognitive processes of the brain (Arabska et al. 2019; Ward et al. 2020). A growing number of studies show an association between BDNF and neuropsychiatric disorders, including a non-metabolic abnormality-related significant reduction in its levels in schizophrenia (Arabska et al. 2019; Tejeda and Diaz-Guerra 2017).
Schizophrenia is associated with abnormalities in the development of brain structures that may result from altered functioning of the neurotrophic system, including BDNF (Arabska et al. 2019; Weinberger 2017). A reduced amount of BDNF receptor mRNA has been found in schizophrenia patients (Arabska et al. 2019; Strzelecki et al. 2016). Koyya et al. (2024) observed reduced BDNF gene expression and decreased BDNF levels in people with long-term schizophrenia, supporting the potential role of BDNF in the pathogenesis of the disease. Shoshina et al. (2021) found reduced BDNF levels in patients with first-episode schizophrenia, while patients with schizophrenia of different durations had similar serum BDNF levels. However, differences in BDNF levels were found between men and women with illnesses longer than three months.
In the retina, BDNF plays a key role in promoting survival, particularly for retinal ganglion cells in vitro (Seki et al. 2003; Johnson et al. 1986) and in vivo (Seki et al. 2003; Mey and Thanos 1993; Mansour-Robaey et al. 1994). BDNF has been shown to increase the complexity of optic axons in Xenopus retina (Seki et al. 2003; Cohen-Cory and Fraser 1995), and the number of retinal dopaminergic synapses in rat retina (Seki et al. 2003; Cellerino et al. 1998).
In the rat, both BDNF mRNA (Perez and Caminos 1995) and BDNF protein itself (Vecino et al. 1998) localize to the ganglion cell layer (GCL) and inner nuclear layer (INL), suggesting local synthesis of BDNF in the retina. In addition to local synthesis, BDNF also undergoes retrograde transport from the tectum to the retina in amphibians (Cohen-Cory et al. 1996), birds (Herzog and Von Bartheld 1998), and rodents (Ma et al. 1998), possibly exerting an effect as a target neurotrophic factor (Seki et al. 2003).
Yang et al. (2025) observed a significant reduction in serum nerve growth factor β (NGF-β) and BDNF levels in patients with chronic schizophrenia compared to healthy subjects, which was associated with clinical symptoms and 1,25(OH)2D metabolism. In addition, NGF-β levels were positively correlated with vitamin D3 levels and negatively correlated with negative symptoms in PANSS, while serum BDNF levels were negatively correlated with language deficits. The above results indicate a significant role for the mentioned neurotrophic factors in the pathophysiology of schizophrenia.
Shi et al. (2024) observed an interesting association of cognitive improvement caused by playing video games with an increase in BDNF levels in patients with schizophrenia. They also highlighted the importance of serum BDNF as a relevant biomarker for predicting cognitive improvement in these patients. One review focused on the role of BDNF in autophagy as a protective factor against cognitive impairment (Koyya et al. 2024).
Summary and research perspectives
The results of the studies conducted so far are promising, pointing to the possibilities of using the assessment of retinal structure and function in the diagnosis and monitoring of the course of schizophrenia, and expanding our knowledge of the processes and mechanisms involved in the development of this disease. At the same time, they point to more challenges facing researchers, related both to the disease process itself (e.g., whether the changes present in the retina in schizophrenia precede the overt clinical process of the disease, or are rather an indicator of progressive neurodegenerative changes) and to the influence on the obtained results of many additional factors of a systemic nature, such as metabolic, endocrine, and inflammatory diseases. A particular challenge seems to be to link the observed structural retinal abnormalities with the aforementioned metabolic and biochemical abnormalities, especially in the context of their association with schizophrenic symptoms such as cognitive impairment and deficit symptoms.
Disclosures
This research received no external funding.
The study was approved by the Bioethics Committee of the Poznan University of Medical Sciences (Approval No. 474/25).
The authors declare no conflict of interest.
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