Microvascular abnormalities on retinal imaging may help distinguish patients with schizophrenia from healthy individuals as well as those suffering from other disorders, including depression, new research suggests.

A population cohort study of nearly 1000 participants showed that those diagnosed with schizophrenia had significantly wider retinal venules, reflecting insufficient brain oxygen supply, compared with patients suffering from depression or with healthy control participants.

Retinal imaging also showed a significant vascular distinction between those with schizophrenia and those with hypertension, a condition commonly found in individuals with the disorder.

"This imaging process allowed us to look at the quality of the blood vessels in the back of the eye, which gives a window into what's probably going on with the blood vessels in the brain," coinvestigator Terrie E. Moffitt, PhD, professor of psychology and neuroscience at Duke University in Durham, North Carolina, told Medscape Medical News.

Dr. Moffitt noted that although more research now needs to be done, it is exciting to hypothesize about how this technology could be used in the future.

"These findings highlight the promise of retinal imaging as a tool for understanding the pathogenesis of schizophrenia," write the investigators. "The noninvasive nature, its relative cost- effectiveness, and the availability of the technology in primary care, optometry, and ophthalmology centers all suggest the value of retinal imaging analysis as an exciting tool for schizophrenia research."

The study was published in the December issue of the American Journal of Psychiatry.

Measuring Microvessels

As reported by Medscape Medical News, a small study from researchers from the University of Aberdeen, United Kingdom, showed that simple tests focusing on viewing patterns could detect eye-movement abnormalities associated with schizophrenia from healthy controls with up to 98.3% accuracy.

Those investigators are now working to determine whether the eye tests can distinguish patients with schizophrenia from those with bipolar disorder.

Dr. Terrie Moffitt

In the current study, Dr. Moffitt and colleagues sought to measure retinal microvessels, using noninvasive retinal imaging, to assess their effectiveness as a biomarker of schizophrenia.

The original Dunedin Multidisciplinary Health and Development Study was created to assess health and behaviors in a cohort of 1037 individuals born in the New Zealand city between April 1972 and March 1973; the participants were followed periodically throughout their lives.

For the current analysis, the researchers assessed the participants who underwent measurements at the age of 38 years (95% of the original study), including retinal scanning.

The Diagnostic Interview Schedule (DIS) was used, starting at age 21, to assess schizophrenia. A diagnosis of the disorder required the presence of non–substance use–related hallucinations and at least 2 other positive symptoms.

The DIS was also used to assess psychosis symptoms in the adults, and the DIS for Children was used to assess childhood psychosis symptoms starting at the age of 11 years.

Results showed that 20 of the overall participants (2%) met the study criteria for schizophrenia and had been hospitalized for the disorder by the time they were age 38, with an additional 17 (1.7%) meeting all criteria but never receiving treatment. However, only 27 of these 37 were able to undergo retinal imaging.

In addition, 188 of the cohort members had a clinical diagnosis of persistent depression, and 412 were characterized as "healthy controls." The remaining members were classified as having hypertension, prediabetes/diabetes, or persistent tobacco dependence. These last 3 subgroups were chosen because the conditions "have been associated with vessel calibre in previous retinal imaging studies."

Distinguishing Feature

All of the subgroups were found to have wider venules than healthy control participants. However, the venules were much wider for those with schizophrenia than for those with persistent depression, prediabetes/diabetes, and tobacco dependence.

Although the schizophrenia group's venules were not significantly wider than those in the hypertension group, the latter group had significantly narrower arterioles (tiny branches off the arteries) than the other subgroups.

"This is consistent with previous research linking narrower arterioles specifically to hypertension and suggests that hypertension cannot explain the wider venules in the schizophrenia group," note the investigators.

After adjusting for arteriolar caliber and sex, the association between schizophrenia and wider venular caliber remained statistically significant (P = .002) and continued to remain so after the researchers controlled for systolic and diastolic blood pressure, persistent tobacco dependence and depression, and hemoglobin A 1c level (P = .01).

"Wider venules among individuals diagnosed with schizophrenia could also not be explained by current use of antipsychotic medication," report the researchers.

Finally, after adjusting for arteriolar caliber and sex, venular caliber at age 38 was significantly associated with psychotic symptoms in adulthood (P < .001) and in childhood (P = .015), suggesting that pathologic vascular mechanisms start in early life.

Although these mechanisms are not yet entirely understood, "our analyses…suggest the possibility that wider venules are a distinguishing feature of schizophrenia and not simply an artifact of co-occurring health problems," the investigators write.

Dr. Moffitt added that the implication for clinicians is that "there's something wrong with either the oxygen delivery to the brain or removal of toxins from the brain." She also reported that some investigators are currently assessing whether administering oxygen to people with mental illness while they are sleeping can alter their symptoms.

"It's possible that our research on retinal vasculature will feed into that kind of treatment. But it's very early days. So the first step is to just see if it's true," she said.

Schizophrenia Biomarker?

In an accompanying editorial, Dolores Malaspina, MD, MSPH, from the Department of Psychiatry at New York University School of Medicine in New York City, calls the study interesting.

"Retinal imaging is an intriguing tool for understanding the etiopathophysiology of schizophrenia, but these findings using the newest tools for in vivo imaging of the vasculature to find a biomarker for schizophrenia have other implications as well," writes Dr. Malaspina.

She notes that previous research suggests an association between inflammatory conditions and widened venules.

"Although endothelial dysfunction and inflammation are acknowledged to be associated with schizophrenia, this latest finding advances the field by confirming that…microvenule dilation was even present in cohort members who only had some childhood psychotic symptoms," she writes.

"This suggests that the pathophysiology of the vascular abnormality is related to the initiating vulnerability for the disease itself and is not a consequence of the lifestyle related to the illness or of having received treatment for it."

The study was funded by grants from the National Institute on Aging, the United Kingdom Medical Research Council, the National Institute on Drug Abuse, and the National Institute of Child Health and Human Development and by the New Zealand Health Research Council and the Jacobs Foundation. Dr. Moffitt and 9 of the other 11 study authors report no relevant financial relationships. A full list of disclosures for the other study authors is available in the original article. Dr. Malaspina reports no relevant financial relationships.

Am J Psychiatry. 2013;170:1451-1459, 1382-1384. Abstract, Editorial