Mutation Implicated in Psychosis Points to Drug-Development Target

It's been 100 years since Swiss psychiatrist Eugen Bleuler coined the term "schizophrenia," renaming the symptoms German physician Emile Kraepelin in 1887 had initially called "dementia praecox." It was beginning to appear as if it might take another century to decipher the genetic basis of schizophrenia.

Efforts until now have suggested that the brain disorder that affects about 1 percent of adults might, in many cases, be rooted in different genetic causes in each affected individual, complicating prospects for elucidating the source of schizophrenia-spectrum disorders and delaying the search for cures.

But a recent National Institutes of Health–funded study published in the February 23 Nature may have yielded a tiny clue that has huge potential for furthering understanding of schizophrenia-spectrum disorders and possibly creating effective treatments. For the study, 30 investigators collaborated to analyze the genomic makeup of 15,721 individuals—8,290 of whom had been diagnosed with schizophrenia.

The size of the study is impressive: "Sample sizes like this are required in order to make progress. You really can't do this with a handful of families; you need thousands," said Jonathan Sebat, Ph.D., an assistant professor at the University of California, San Diego, chief of the Beyster Center of Molecular Genomics for Neuropsychiatric Diseases, and leader of the study team, in an interview with Psychiatric News.

The results of the study are equally impressive: Sebat and his colleagues found that patients with schizophrenia were 14 times more likely than controls to have mutations—specifically, mutations that are known as copy number variations (CNVs)—of the vasoactive intestinal peptide receptor gene VIPR2. The researchers say these findings implicate altered vasoactive intestinal peptide signaling in the pathogenesis of schizophrenia and point to the vasoactive intestinal peptide receptor VPAC2 as a potential target for the development of new antipsychotic drugs.

VIPR2 does a lot of exciting things in the brain, but it has been overlooked. That its name is misleading "is one reason why it hasn't already been on everyone's list of candidate genes," said Sebat. VIPR2 regulates patterns of activity in sleep, mediates important events during the development of the nervous system, and regulates learning and behavior. "It's been postulated to be involved in autism, Down syndrome, and fetal alcohol syndrome. But this is the first time it's been genetically linked to mental illness."

"In our previous smaller study (published in the April 2008 Science), we could see there was a contribution from rare mutations, but it wasn't clear which regions were the culprits," said Sebat. "At that time, it seemed that the mutations were often specific to single cases or families. Virtually every mutation we detected was different in a sample of 150 adults with schizophrenia and 268 healthy controls."

This larger study, however, has pointed the finger of responsibility, at least for a small percentage of patients with schizophrenia, at the VIPR2 gene, and that has exciting implications for the development of treatments for schizophrenia, with the VPAC2 receptor as a potential target.

"VIPR2 is a drop in the bucket in terms of genetic causes of schizophrenia, but it's a good one because it's a potential drug target. So it raises the possibility of a novel approach to drug development: Target a rare mutation the way you would develop an orphan drug, only expecting success with small markets," Sebat suggested. "Because some of these common neuropsychiatric disorders may be a constellation of rare genetic disorders, it may be feasible to establish efficacy in a small group of individuals, prove efficacy in small trials, then expand that drug to evaluate its applicability to a broader range of patients. Genomics is key to enabling this kind of treatment."

An abstract of "Duplications of the Neuropeptide Receptor Gene VIPR2 Confer Significant Risk for Schizophrenia" is posted at <www.nature.com/nature/journal/vaop/ncurrent/full/nature09884.html>.