GABA Targeted For Study In Schizophrenia

One of the most exciting and provocative areas of schizophrenia science these days is to try to find a way of delaying, or even preventing, the development of schizophrenia in individuals at high risk for it.

For example, Thomas McGlashan, M.D., a professor of psychiatry at Yale University, and colleagues have been attempting to see whether an antipsychotic medication might do the trick (Psychiatric News, June 21, 2002). “We are analyzing the data” and plan to submit results to a psychiatric journal, McGlashan said in a recent interview with Psychiatric News.

Patrick McGorry, M.D., Ph.D., a professor of psychiatry at Australia's University of Melbourne, and coworkers have been exploring whether an antipsychotic medication and cognitive-behavioral therapy might do it (Psychiatric News, November 15, 2002). They have followed up most of their subjects, McGorry told Psychiatric News, but have not yet published the results.

And now T.-U. Wilson Woo, M.D., Ph.D., an assistant professor of psychiatry at Harvard University, and colleagues want to find out whether a medication that increases levels of the neurotransmitter gamma-amino butyric acid (GABA) in the brain might be effective in delaying or preventing schizophrenia.

It has been postulated that excessive pruning of nerve synapses in the brain during adolescence and early adulthood may result in the onset of schizophrenia. This excessive pruning in turn may be influenced by the maturation of nerves in the prefrontal cortex that use GABA as their neurotransmitter. The antiepilepsy medication tiagabine (Gabitril) is known to enhance GABA availability. So Woo and his team speculated that if tiagabine were given to young people at high risk for schizophrenia, it might enhance GABA availability in the prefrontal cortex region of their brains. Enhanced GABA availability might in turn halt the excessive pruning of nerve synapses in the prefrontal cortex, and a halt of excessive pruning in the prefrontal cortex might delay or prevent the development of schizophrenia.

Their first step is to conduct a small pilot trial to see whether tiagabine might be able to alter late-development prefrontal nerve circuitry in 30 teens who have recently developed schizophrenia. They will use fMRI scans to visualize the prefrontal nerve-activation patterns of their subjects during working memory, that is, when the prefrontal cortex is functionally challenged. Then they will give the subjects tiagabine. After that, they will use fMRI scans to again visualize the subjects' prefrontal nerve-activation patterns during working memory. Finally, they will compare the subjects' prefrontal nerve-activation patterns before getting the medication with their prefrontal nerve-activation patterns after taking it.

“Very preliminary findings” from the first three subjects recruited for the trial suggest that the patterns are “significantly different before and after treatment,” Woo told Psychiatric News. In other words, it looks as if tiagabine “may be effective in modifying the late development of prefrontal circuitry in young patients with recent-onset schizophrenia.”

Several questions remain to be answered: Will more subjects from the pilot trial also demonstrate tiagabine-induced prefrontal nerve-activation changes? If so, can tiagabine do the same for teens at high risk for schizophrenia? And if tiagabine can do the same for teens at high schizophrenia risk, will it in turn delay, or even prevent, illness development?

“We are hoping,” Woo said, “that positive findings from this study will eventually justify a clinical trial in clinically high-risk prodromal patients.”

Their research is being funded by the Stanley Medical Research Institute and the National Institute of Mental Health. More information about the scientific rationale underlying it can be found in a review paper published in the March Schizophrenia Research.

An abstract of “Targeting Synapses and Myelin in the Prevention of Schizophrenia” can be accessed online at<www.sciencedirect.com> by clicking on “Browse A-Z of journals,” then “S,” then “Schizophrenia Research.” ▪