Available antipsychotic medications treat some of the symptoms of schizophrenia, but are typically effective in only a subset of patients. Unfortunately, it is difficult to predict the effectiveness of a specific drug in any given individual with schizophrenia. John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, notes that in this era of medicine, the selection of particular antipsychotic medications for particular patients with schizophrenia is more art than science. We have been seeking objective guides, perhaps biological tests, which would inform this process. A new study published in the January 1st issue of Biological Psychiatry provides some interesting data to aid in that goal.

The authors report that differential effectiveness of antipsychotic treatment was predicted, in a subset of patients with schizophrenia, by variants of the gene encoding for the regulator of G-protein signaling 4 (RGS4), a protein that regulates the functional consequences of activating neurotransmitter receptors. Dr. Daniel Campbell, corresponding author for this article, explains these results: By applying genetic analysis to the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness, we show that variants in a specific gene, RGS4, predict the effectiveness of different antipsychotic treatments. Our results also indicate that the predictive power of the RGS4 genetic variants differed between patients of self-reported African and European ancestry, and thus emphasize the importance of including multiple ethnic groups in a study.

The authors importantly note that their results will require replication, but the findings indicate that RGS4 contributes to both the severity of schizophrenia symptoms and the response to antipsychotic treatment. Dr. Krystal adds, While this type of information is not yet ready to guide clinical practice, since the RGS4 variants explain only a small component of overall patterns of treatment response, these data provide an example of pharmacogenomics, the approach that will very likely ultimately guide treatment.

elsevier/

Yang said there is now reason to believe normal blood sugar levels can be maintained for long periods, suggesting that an infrequent Pdx1 injection might someday replace daily insulin injections. Even more importantly, the reprogrammed and regenerated cells should make and release insulin, automatically maintaining safe blood sugar levels, she said.

Right now, promoting beta cell regeneration has become such a hot topic, she added. The trick is to figure out how to trigger glucose-regulated insulin-producing cells to regenerate.

Still, the approach will have to be tested in studies that assess its safety before scientists could conduct patient trials to determine whether it works in people, studies that are still years away.

What's so innovative about UF's approach is the ability to normalize blood glucose levels in diabetic mice simply by delivering Pdx1 protein in the target cells, thus effectively eliminating the side effects associated with gene therapy, Yang said.

Dr. Joel Habener, a professor of medicine at Harvard Medical School whose research team was one of three groups that discovered Pdx1 and identified it as an important regulator of pancreas development, said using viruses as vectors for gene therapy in humans can pose problems because of the body's immune reaction to them. He heralded the UF findings and said the idea of using a protein to correct a condition like diabetes is appealing because it is naturally occurring, not a chemical compound that's been synthesized from the mind of a chemist that's a foreign substance.

What these findings teach is there is promise for a therapeutic approach to the treatment of diabetes, he said. I think one of the really major breakthroughs here is the demonstration of principle that the naked protein in and of itself can get into cells and cause changes that are remarkable in a mouse model of type 1 diabetes, the regeneration of the insulin-producing cells in the pancreas.

ufl/