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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 After all previous antipsychotic medications had been withdrawn, the patients were treated with clozapine according to a standardized titration and dosage schedule.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.

Objective: The prevalence, clinical correlates, and outcome of the deficit syndrome were determined for 70 patients ascertained in their first episode of schizophrenia and then followed through their recovery. Method: Patients were treated in a standardized manner and underwent baseline assessments of symptoms and adverse effects that were repeated at intervals throughout their inpatient and subsequent outpatient course. Forty-seven patients were followed for a minimum of 6 months after remission of their positive symptoms, allowing for an assessment of their deficit syndrome status. Results: Using modified criteria of Carpenter et al. for the deficit syndrome, the authors found that two patients (4%) met all criteria for the deficit syndrome, nine (19%) had deficit symptoms (questionable deficit state), and 36 (77%) had no deficit symptoms. When patients who had not fully remitted or had remitted for less than 6 months were included, seven (10%) met deficit syndrome criteria, 11 (16%) had deficit symptoms, and 52 (74%) had no deficit symptoms. Conclusions: The prevalence of the deficit syndrome in first-episode schizophrenia varies depending on the criteria used and is lower than that previously described in more chronic patient samples. Patients without deficit symptoms had better premorbid functioning and a better global outcome than patients with deficit symptoms.

Objective: This study was undertaken to assess the potential effect of duration of untreated illness on outcome in a group of first-episode schizophrenic patients. Method. Seventy patients with schizophrenia diagnosed according to the Research Diagnostic Criteria entered the study and were followed for up to 3 years. All patients received standardized treatment and uniform assessments both during the acute phase of their illness and throughout the follow-up period. Outcome was measured in terms of time to remission of acute psychotic symptoms as well as degree of symptom remission. Results: The mean duration of psychotic symptoms before initial treatment was 52 weeks, preceded by a substantial prepsychotic period. According to survival analysis, duration of illness before treatment was found to be significantly associated with time to remission as well as with level of remission. The effect of duration of illness on outcome remained significant when diagnosis and gender variables, themselves associated with outcome, were controlled in a regression analysis. Duration of illness was not correlated with age at onset, mode of onset, premorbid adjustment, or severity of illness at entry into the study. Conclusions: Duration of psychosis before treatment may be an important predictor of outcome in first-episode schizophrenia. Acute psychotic symptoms could reflect an active morbid process which, if not ameliorated by neuroleptic drug treatment, may result in lasting morbidity. Further implications of these findings are discussed.

MDL 100,907 is a potent and selective antagonist of 5-HT2Aserotonin receptors. Animal studies suggest that MDL 100,907 may behave as an atypical antipsychotic drug. Positron emission tomograph (PET) using [11C]NMSP as the radiotracer was used to define the time course of 5-HT2receptor occupancy in the human frontal cerebral cortex after a single oral dose of MDL 100,907 (10 or 20 mg) in nine healthy subjects. After the baseline scan each subject was studied three times post dosing at various time points. 5-HT2occupancies were in the range of 70 and 90% after each dose. While the occupancy remains in this range over 24 hours after 20 mg MDL 100,907, it decreases by about 20% at 24 hours compared to the timepoint at 8 hours, when only 10 mg are administered (p< 0.05). Our results should allow determination of the appropriate dosing regimen for future trials in schizophrenic patients. [