Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement

Rationale: The study of the different effects on brain metabolism between typical and atypical antipsychotics would aid in understanding their mechanisms of action. Clozapine is of special interest, since it is one of the most effective antipsychotic drugs and demonstrates a distinctive mechanism of action in pre-clinical studies with respect to typical neuroleptics. Objective: To study the differences in cerebral activity induced by clozapine as compared to those produced by haloperidol. Methods: [F-18]Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) scans were obtained in the resting condition before and after 6 months of treatment with clozapine in 22 treatment-resistant patients with schizophrenia. Before inclusion, patients had been chronically treated with classical drugs, and all of them received haloperidol during the last month. Data were analyzed with statistical parametric mapping (SPM'99) methods, comparing pre-treatment and post-treatment conditions. The association between the changes in symptom scores and metabolism was also assessed to corroborate the functional relevance of possible metabolic changes. Results: Clozapine decreased prefrontal and basal ganglia activity, and increased occipital metabolism, including primary and association visual areas. The change in negative symptoms was related with the decrease of basal ganglia activity; the improvement in disorganization related to the metabolic decrease in the motor area, and the change in positive symptoms was associated to the increase of activity in the visual area. Conclusions: These results show that haloperidol and clozapine produce different patterns of metabolic changes in schizophrenia. Compared to the haloperidol baseline, clozapine inhibited the metabolic activity of the prefrontal and motor cortical regions and basal ganglia and induced a higher activation of the visual cortex. The improvement in disorganization, negative and positive syndromes with clozapine may be respectively associated with metabolic changes in the motor area, basal ganglia, and visual cortex.