J.A. Lieberman

OBJECTIVE: This study examined the pathomorphology of the caudate nuclei in first-episode schizophrenic patients with minimal previous neuroleptic exposure. METHOD: Magnetic resonance imaging (MRI) of the brain was used to examine longitudinally the caudate pathomorphology in 29 first-episode schizophrenic patients and 10 healthy comparison subjects. MRI scans were obtained after the subjects entered the study and at 18-month follow-up. The patients were treated with standardized neuroleptic regimens during the 18-month period. Volumetric assessments of the cerebral cortex, lateral ventricles, and caudate nuclei were performed on T1-weighted coronal brain sections. In addition, the patients were systematically evaluated for psychopathology at baseline and during treatment. RESULTS: Caudate volumes increased 5.7% in the patients during the 18-month treatment interval, whereas they decreased 1.6% in the comparison subjects over the same time period. Greater amounts of antipsychotic medication received by patients before the first scan and younger age at the time of the first scan were associated with larger increases in caudate volume. CONCLUSIONS: Caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.

OBJECTIVE: This study addressed the unique clinical properties attributed to the atypical antipsychotic clozapine, including its efficacy in patients with treatment-refractory psychosis and against negative symptoms, its lack of acute extrapyramidal side effects, and the longer time course of its therapeutic effects. METHOD: The clinical responses of 84 schizophrenic inpatients (66 with treatment-refractory illness and 18 who were intolerant of antipsychotic treatment) were examined. After all previous antipsychotic medications had been withdrawn, the patients were treated with clozapine according to a standardized titration and dosage schedule. Patients who tolerated and responded to treatment were discharged and maintained on a regimen of clozapine for up to 52 weeks. Patients were evaluated for behavioral response and side effects after weeks 3, 6, 12, 26, 39, and 52 of treatment. RESULTS: Fifty percent of the patients with treatment-refractory illness and 76% of the treatment-intolerant patients responded to clozapine in up to 52 weeks. The optimal period for a trial of clozapine appeared to be 12-24 weeks. Clozapine exhibited therapeutic effects on negative symptoms, but these were not clearly independent of its effects on positive symptoms and extrapyramidal side effects. Several variables, including early age at onset of illness and female gender, were found to be predictors of poor response to treatment. Predictors of good response included the presence of extrapyramidal side effects during previous treatment with classic neuroleptics and a diagnosis of paranoid schizophrenia. CONCLUSIONS: These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.

OBJECTIVE: The purpose of this study was to determine if plasma clozapine levels were associated with treatment response. METHOD: To examine this question, neuroleptic nonresponsive patients with schizophrenia or schizoaffective disorder were given clozapine, which was titrated to 500 mg/day by day 14 of treatment, and the dose was held fixed at least through day 21. Subsequently, clozapine doses were adjusted as clinically indicated, up to a maximum of 900 mg/day. Plasma clozapine levels were obtained at weeks 3 and 6, and standard clinical ratings (Brief Psychiatric Rating Scale [BPRS] and Clinical Global Impression) were done at baseline and at weeks 3 and 6. RESULTS: Data from 45 subjects were analyzed. There were no correlations between plasma clozapine levels and change in BPRS scores at treatment weeks 3 and 6. However, when the subjects were classified as responders or nonresponders, therapeutic response was associated with clozapine blood levels above 350 ng/ml. CONCLUSIONS: This study suggest that clozapine blood levels are correlated with clinical response.

Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.