Are the Eyes a Window Into the Mind of Schizophrenia?


Recently, the use of spectral-domain optical coherence tomography has contributed to our understanding of retinal abnormalities in schizophrenia.


The strongest risk factor for schizophrenia is the presence of an affected first-degree relative.1 One approach to investigate the effects of genetics on schizophrenia pathophysiology is the study of endophenotyes.  Endophenotypes are measurable, heritable traits that are intermediate between genotypes and phenotypes, and they are more likely to be expressed in unaffected relatives of patients than in the general population.

The retina is embryologically related to and considered a “window” to the brain. There is evidence for retinal abnormalities in schizophrenia.2 Recently, the use of spectral-domain optical coherence tomography (OCT), a non-invasive imaging technique, has contributed to increased understanding of retinal abnormalities in schizophrenia.

OCT uses infrared light to create an optic “ultrasound,” providing information on the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) of the retina. Given the potential confounding of retinal imaging findings by metabolic dysfunction and antipsychotic medications in schizophrenia, the use of OCT in first-degree relatives represents an important new area of investigation.

Kurtulmus and colleagues3 performed a study of retinal layer thicknesses between patients with DSM-IV schizophrenia, their unaffected first-degree relatives, and healthy controls. The authors recruited 38 chronic, stable patients with schizophrenia; 38 unaffected first-degree relatives (parents [n=13], siblings [n=14], adult children [n=11]); and 38 controls without a family history of psychotic or bipolar disorder.

Exclusion criteria were history of systemic disease that may involve the eyes (including diabetes, hyperlipidemia, hypertension, and cardiovascular disease); pre-existing retinal or other ocular pathology; history of ocular surgery/trauma; any neurological condition affecting the visual pathway; severe refractive error; and alcohol or other substance use in the past year. In patients with schizophrenia, comorbid psychiatric diagnoses were excluded, and relatives and controls did not have a history of any psychiatric diagnoses.

OCT was performed without pupil dilation using a Spectralis OCT device, with all scans performed by the same operator. There were no significant differences in measurements between the right and left eyes, and so only the data from the right eye was analyzed. Between-group differences on OCT measurers were examined using analysis of variance, and significant findings were confirmed using linear regression models controlling for potential confounding factors.

Mean age in the study sample was 41; 55% were female; and the mean body mass index (BMI) was 27. In patients with schizophrenia, mean illness duration was 18 years and the mean total Positive and Negative Syndrome Scale (PANSS) score was 66. Of 38 patients, 26 were prescribed atypical antipsychotics, with a mean daily dose of 781 chlorpromazine units.

There was no significant difference between study groups in overall RNFL, GCL, and macular thickness. However, both patients and unaffected relatives had significantly lower IPL thickness compared with controls (the magnitude of this difference was about 5%). Increased BMI was associated with IPL thinning; however, the between-group differences remained significant after controlling for BMI and other potential confounding factors (eg, age, sex, smoking, medical comorbidity).

The IPL consists of the ganglion cell dendrites and synaptic connections in the retina, also termed the “inner synaptic layer.” This finding may reflect abnormal synaptic/dendritic organization in schizophrenia.

The authors note that limitations of the study include the relative small sample size, and differences in shared genetics across the various types of relatives included.

The bottom line

The authors performed what is believed to be the first study of OCT in unaffected relatives of patients with schizophrenia. Findings raise the possibility of IPL thinking as a potential endophenotype for schizophrenia.


Dr Miller is Associate Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.


1. Waddington JL, Corvin AP, Donohoe G, et al. Functional genomics and schizophrenia: endophenotypes and mutant models. Psychiatr Clin North Am. 2007;30:365-399.

2. Adams SA, Nasrallah HA. Multiple retinal anomalies in schizophrenia. Schizophr Res. 2018;195:3-12.

3. Kurtulmus A, Elbay A, Parlakkaya FB, et al. An investigation of retinal layer thicknesses in unaffected first-degree relatives of schizophrenia patients. Schizophr Res. 2020 Jan [Epub ahead of print].

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