Building A Better Antipsychotic Drug By Treating Schizophrenia's Cause

The classic symptoms of schizophrenia -- paranoia, hallucinations, the inability to function socially -- can be managed with antipsychotic drugs. But exactly how these drugs work has long been a mystery. Now, researchers at Pitt have discovered that antipsychotic drugs work akin to a Rube Goldberg machine -- that is, they suppress something that in turn suppresses the bad effects of schizophrenia, but not the exact cause itself. In a paper published in the Journal of Neuroscience, they say that pinpointing what's actually causing the problem could lead to better avenues of schizophrenia treatment that more directly and efficiently target the disease.

"In the past five years or so, we've really started to understand what may be going wrong with the schizophrenic brain," says Anthony Grace, Distinguished Professor of Neuroscience and professor of psychology in Pitt's School of Arts and Sciences and professor of psychiatry in the Pitt School of Medicine, who is senior author of the paper.

Schizophrenia is made up of three different types of symptoms. Positive symptoms, which are added onto a "normal" personality, include hallucinations and delusions, such as hearing voices, thinking people are after you, or thinking you're being targeted by aliens. Those are the classic symptoms of schizophrenia and the ones antipsychotic medications work on best. Grace says these are the symptoms most likely related to a neurotransmitter called dopamine.

The other two categories of symptoms are negative (what's missing from the normal personality -- the ability to interact socially or hold down a job; some emotional flattening) and cognitive (the ability to think linearly or concentrate on one thing at a time). These two really aren't addressed well by antipsychotic drugs. "Blocking the dopamine system seems to fix classic hallucinations and delusions a whole lot better than it fixes the other problems," says Grace.

Grace has been studying the role dopamine plays in the schizophrenic brain since 1978. It's long been known that after several weeks of treatment with antipsychotic drugs, dopamine-producing neurons are inactivated. "It would suggest to us that in schizophrenia there is not too much dopamine, but rather the dopamine system is too responsive," says Grace.

Therefore, by inactivating the neurons, this overresponsivity should be able to be treated. "If there were just too much dopamine in the brain, one would expect the biggest treatment effect would be at the beginning and then it would diminish," Grace says.