Oct-6 was shown to be expressed in the brain of patients diagnosed with schizophrenia, but not in the brain of healthy individuals, in a study led by Jack Price and published in the July 2002 issue of The American Journal of Psychiatry. Kirenjeet Ubhi and Jack Price, from Kings College London, UK have now replicated Price's original study and extended it. Their findings contradict Price's earlier study.
Events affecting brain development are thought to underlie the occurrence of schizophrenia in later life. Oct-6 plays a crucial role in neurodevelopment, and a genetic variation within the Oct-6 gene has been linked to a subset of patients with schizophrenia and bipolar disorder; therefore, Oct-6 seemed like a good candidate for a biological marker for these disorders.
Ubhi and Price extended Price's original study to include patients with bipolar disorder and major depression “ it has been suggested that schizophrenia shares a common pathology with these disorders. They analysed post-mortem brain samples from 3 groups of 15 patients. The first group had been diagnosed with schizophrenia, the second group with bipolar disorder and the third group with major depressive disorder. They used 15 brain samples of matched healthy individuals as controls. Oct-6 mRNA and protein expression were determined by in-situ hybridization and immunostaining respectively.
Contrary to their previous results, Ubhi and Price found no difference in Oct-6 protein or mRNA expression between patients and controls.
biomedcentral/bmcpsychiatry/
The researchers matched the age, gender, ethnicity and IQ of the 24 children with the deletion with 23 children with developmental disabilities of unknown causes. They then tested their subjects' verbal IQ and cognitive abilities. None of the children in either group had yet experienced any psychotic symptoms. They also measured the size of the children's prefrontal cortex - an area of the brain where COMT activity is particularly important and that is strongly associated with schizophrenia. They repeated the same tests after about five years, when their subjects reached late adolescence or early adulthood.
As expected, about 29 percent, or seven, of the children with the deletion had developed a psychotic disorder by the second round of testing, compared with only one child in the control group. Of these seven, those with the low-activity version of COMT had experienced a significantly greater drop in their verbal IQ and expressive language skills and a markedly greater decrease in the volume of their prefrontal cortex than did their peers with the more highly active version of COMT. The psychotic symptoms of the low-activity subset were also significantly more severe.
In contrast, members of the control group experienced no significant differences in any of these categories, regardless of their COMT profiles.
"What's interesting about this finding is that the disease course in the individuals with low-activity COMT looked remarkably like idiopathic schizophrenia," said Reiss, who hopes to use this and future data to develop a model for other causes of schizophrenia.
"Although this deletion probably causes less than 5 percent of schizophrenia cases, it's the only well-defined genetic risk factor we have right now," said Reiss. "In the future, researchers will likely discover multiple causes of this disorder, with complex interactions between genetic and environmental risk factors. But COMT activity appears to be an important contributory factor for the development of psychosis in the chromosome 22 deletion syndrome."
The researchers next plan to extend their studies to younger children, and to repeat the above study using multiple time points to more precisely catch the ongoing development of the disorder.
med.stanford/