Unraveling the Heterogeneity of Schizophrenia

Psychiatrists at NYU Langone Seek New Ways to Approach Psychosis

The NYU Langone Medical Center Department of Psychiatry recently published research on the effects of folate supplementation in schizophrenia, marking one of the first successful uses of personalized medicine in psychiatry. Ongoing work in this area may change the way the medical profession views psychosis.

“NYU Langone is in the forefront of the study of biomarkers, early intervention, and personalized medicine in psychosis,” says Donald Goff, MD, the Marvin Stern Professor of Psychiatry and vice chair for research in the Department of Psychiatry at NYU Langone.

According to Dr. Goff’s newest study, published in JAMA Psychiatry, supplementation with folate and vitamin B12 improved the prominent negative symptoms of schizophrenia in individuals, but only those with low folate levels who also had genes for less active forms of folate hydrolase and methylene tetrahydrofolatereductase enzyme at baseline.

“One genotype that achieved statistical significance on its own was folate hydrolase, which is a rate-limiting step in absorption of folate from the gut,” Dr. Goff says. “Subjects with the most active form of folate hydrolase were the most likely to benefit—possibly because they were better able to absorb the supplemental folate.”
Dr. Goff’s earlier work, with his collaborator Joshua Roffman, MD, identified the link between folate deficiency and negative schizophrenia symptoms, and this new study takes this work a step further by showing who is most likely to respond to folate supplementation.

Dr. Goff and his team are now using molecular imaging to identify biomarkers and biochemical changes that are indicative of treatment response in patients with newly diagnosed, first episode psychosis. In this randomized study, participants will receive standard care with an antidepressant or standard care plus placebo. “The hope is if we intervene early enough with antidepressants in the right patients, we may have a major impact on the long-term course of psychosis,” Dr. Goff says.

Prenatal Adversity Linked to Psychosis

Part of the complexity involved in the diagnosis and treatment of psychosis is that its exact cause is not fully understood. Current research points toward inflammation, oxidative stress, emotional stress, marijuana use, and low folate levels as possible risk factors. Some of these risks may accrue in utero as responses to infection, stress, or malnutrition.

Dolores Malaspina, MD, MSPH, the Anita and Joseph Steckler Professor of Psychiatry at NYU Langone, was the first to link a mutation in the paternal germ cell line to risk for schizophrenia. “Schizophrenia and other psychiatric diseases do run in families, but the vast majority of people have no family history,” she says. This led Dr. Malaspina to dig deeper and consider that the heritability of psychosis may lie in genetic mutations. “We are actively trying to understand how psychosis develops in the brain,” she says. “The hope is that a better understanding of the neurochemical pathways involved in the prodromal period will allow unique opportunities to stop the cascade.”

Dr. Malaspina’s work is also helping to broaden the context in which the medical profession sees psychosis. Research has shown that psychosis increases risk for metabolic syndrome, cardiovascular disease, and diabetes. These risks cannot be explained by unhealthy behaviors such as smoking. “These contribute to the additional risk, but the earlier mortality is not explained by these behaviors. It just transcends them,” she says.

The new theory is that psychiatric disease may be the earlier manifestation of compromised microvasculature and that it is likely a whole body disorder, Dr. Malaspina explains. “Psychosis may be the first presentation of systemic illness, not only a brain disease.” The work, if validated, will help remove the stigma associated with mental illness.

Dr. Malaspina discusses this research in the December 2013 issue of the Journal of the American Psychiatric Association.