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
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
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
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
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