Inside Out: Looking at schizophrenia’s inner chaos  pg. 3

Dr. Herbert Y. Meltzer, who has helped pioneer the development of "atypical" antipsychotic drugs at Vanderbilt, is using positron emission tomography (picutred here) to study the effect of these medications on cognitive function in patients with schizophrenia.
Photo by Dean Dixon
To everyone’s surprise, the drug not only sedated, it also diminished delusions and hallucinations. As doctors pushed the dose, however, patients developed Parkinson’s-like conditions: rigidity, loss of movement, drooling. The story led Swedish scientist Arvid Carlsson, who would later win a Nobel Prize for his work, to discover dopamine and its role as a neurotransmitter in communicating instructions between the brain’s nerve cells.

Studies showed that many antipsychotic agents block dopamine receptors, suggesting that an excess of dopamine in the brain may be part of schizophrenia’s pathophysiology. Dopamine’s role in schizophrenia dominated the field for some time, and though other neurotransmitters—glutamate, GABA, acetylcholine, and serotonin, for example—have since been implicated in the disease process, the “dopamine hypothesis” continues to be a central focus.

“The evidence is that multiple brain chemical systems all come to bear on the synthesis, release, and inactivation of dopamine in various areas of the brain — too much in some, too little in others,” says Dr. Herbert Y. Meltzer, Bixler/Johnson/Mays Professor of Psychiatry and director of the Division of Psychopharmacology at Vanderbilt.

“It’s like the ‘six degrees of separation’ concept,” he says. “You might start over here with glutamate or GABA, but sooner or later it’s going to link up with dopamine as a key element in the final common pathway of the disordered brain function.”

Meltzer has a history of contributions to the field of schizophrenia drug development, beginning with his efforts showing that clozapine—the first of the second-generation “atypical” antipsychotic drugs—effectively treats psychosis without producing Parkinsonism. Late last year, the FDA named clozapine the drug of choice to reduce suicidal behavior in schizophrenia, an endorsement due in large part to an international clinical trial led by Meltzer.

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