Can Meds Halt Schizophrenia's Gray-Matter Decline?

The second-generation antipsychotic olanzapine (Zyprexa) appears to protect the brain from the loss of gray matter known to occur as schizophrenia progresses, according to a new study. However, the first-generation antipsychotic haloperidol did not have this effect.

The study also confirmed earlier findings that patients who experience less gray-matter loss fare better clinically.

Eli Lilly and Co., which markets olanzapine under the brand name Zyprexa, funded the study.

The study, which gathered data from 14 sites in North America and Europe, was led by Jeffrey Lieberman, M.D., while he was a professor of psychiatry at the University of North Carolina. He is now director of the New York State Psychiatric Institute and chair of the psychiatry department at Columbia University Medical Center. The report appears in the April Archives of General Psychiatry.

Structural brain abnormalities have been extensively studied and consistently described in patients with schizophrenia, Lieberman explained. Compared with healthy controls, people with schizophrenia generally experience decreases in brain volume involving the cortical and subcortical gray matter, along with corresponding increases in the volume of the lateral ventricles.

The reductions in gray matter have been shown to be progressive and occur most significantly in the early stages of the illness, corresponding to the period during which patients typically show the most clinical deterioration.

More recently, Lieberman added, imaging studies of patients taking older, conventional antipsychotics showed what appeared to be a treatment effect of the drugs: a potentially compensatory increase in the size of the caudate nucleus and the putamen.

To see whether antipsychotic drugs could slow the initial brain changes in patients recently diagnosed with schizophrenia, Lieberman and his colleagues measured brain volume and cognitive changes in 263 patients with first-episode schizophrenia and 58 healthy volunteers over a two-year period. Half of the patients received olanzapine, and half received haloperidol.

The researchers found that, on average, haloperidol-treated patients lost about 2 percent of their gray matter, or about 12 cubic centimeters of brain tissue. No changes were detected in the olanzapine-treated patients or the normal volunteers. Patients who lost gray matter, particularly in the frontal lobe of the brain, also had greater problems with cognitive functioning, as measured by tests of verbal fluency, verbal learning, and memory.

Thus, with the data from the haloperidol group, the researchers replicated the finding of other studies that there is a subtle but significant progression of brain pathology reflected by decreases in gray-matter volume in a regionally specific manner. They also replicated the finding that the use of haloperidol is associated with increases in the caudate nucleus volume. What is new, said Lieberman, is the finding that olanzapine can prevent the gray-matter loss.

He speculated that olanzapine may not be the only second-generation drug with this benefit.

“What I like to call `the clozapine-like antipsychotic drugs' may also have a therapeutic effect that is protective against illness progression,” he said. Quetiapine, he continued, is structurally similar to clozapine, whereas risperidone and ziprasidone, while structurally similar to each other, are different from clozapine. He called for additional studies similar to the one he led to determine whether other second-generation antipsychotics might prevent the loss of gray matter.

When asked what role Lilly had played in the study, Lieberman said he designed the study protocol himself, put together the international team of experts that conducted the study, and then approached Lilly for the funding. Lilly provided medication and assisted in study and data management. The research team controlled the data, he continued, and University of North Carolina statisticians analyzed the data.

The final proof of any study outcome, Lieberman concluded, is in its replication. “I believe [our study results] are the first demonstration of this potential protective effect of treatment, and that this will be borne out by future studies.”

An abstract of “Antipsychotic Drug Effects on Brain Morphology in First-Episode Psychosis” is posted online at<http://archpsyc.ama-assn.org/cgi/content/abstract/62/4/361>.▪

Arch Gen Psychiatry 2005 62 361