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Robert M. Cohen, PhD, MD; Thomas E. Nordahl, PhD, MD; William E. Semple, PhD; Paul Andreason, MD; Robert E. Litman, MD; David Pickar, MD

Arch Gen Psychiatry. 1997;54(5):481-486.

Abstract
Background
The comparison of the effects of 2 classes of neuroleptic drugs on regional brain functional activities may reveal common mechanisms of antipsychotic drug efficacy.

Methods
The regional cerebral glucose metabolic rates of patients with schizophrenia who were and were not receiving neuroleptic drugs and normal control subjects were obtained by positron emission tomography using fludeoxyglucose F 18 as the tracer.

Results
Compared with normal controls and patients not receiving medication, fluphenazine hydrochloride—and clozapine-treated patients had lower global gray matter absolute metabolic rates throughout the cortex. When normalized regional glucose metabolic rates were examined, both medications lowered rates in the superior prefrontal cortex and increased rates in the limbic cortex. Fluphenazine, but not clozapine, increased metabolic rates in the subcortical and lateral temporal lobes, whereas clozapine, but not fluphenazine, decreased inferior prefrontal cortex activity.

Conclusions
These changes are consistent with the idea that neuroleptic drugs lead to "compensation" and "adaptation" rather than "normalization" of the functional activities of brain structures in schizophrenia. The overall similarity of their global and regional metabolic effects suggests that both classes of antipsychotic drugs share some common mechanisms of action. One possibility is that of inducing a shift in the balance of cortical to limbic cortex activity. Differential effects in the inferior prefrontal cortex and the basal ganglia might underlie differences in the therapeutic efficacy and side effect profile of clozapine and fluphenazine.

Author Affiliations
From the Section on Clinical Brain Imaging, Laboratory of Cerebral Metabolism, National Institute of Mental Health and Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Md. Dr Nordahl is now affiliated with the Department of Psychiatry, University of California Medical Center, Davis. Dr Semple is now affiliated with the Cleveland Veterans Administration Medical Center and the Department of Psychiatry, Case Western Reserve Medical School, Cleveland, Ohio. Dr Andreason is now with the Food and Drug Administration, Bethesda.

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