Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance.

OBJECTIVE: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment. METHOD: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program. RESULTS: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype. CONCLUSIONS: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.

Marked elevations of serum creatine kinase activity associated with antipsychotic drug treatment.

Serum creatine kinase (SCK) activity of the skeletal muscle (MM) form is sometimes moderately increased in acutely psychotic patients and may be massively increased as a result of muscle damage. The objective of this study was to characterize the SCK increases in patients treated with novel antipsychotic drugs. SCK activity and myoglobinuria, an index of gross muscle damage, were monitored at varying intervals in schizophrenic or schizoaffective patients treated with antipsychotic drugs. Possible causes of increases in SCK activity, such as trauma, excessive physical activity, exacerbation of psychosis, were assessed. Fifteen instances of massive increases in SCK activity were observed in 11 out of 121 patients (10%) treated with the following antipsychotic drugs: clozapine, loxapine, haloperidol, melperone, risperidone, or olanzapine. These increases in SCK activity were of the MM type and ranged from 1,206 to 177,363 IU/L (median, 9,600 IU/L). Thus, they were much larger than the increases usually found in acutely psychotic patients or patients with neuroleptic malignant syndrome (range, 500-3,000 IU/L). Only the patient with SCK activity of 177,363 IU/L had rhabdomyolysis as evidenced by myoglobinuria. The onset of the increases was from 5 days to 2 years after initiating treatment, and the increases lasted 4 to 28 days (median, 8 days). Flulike symptoms were present in two of the patients, but the others were asymptomatic. The increases were self-limiting in three cases, despite continuing treatment. Two of three cases rechallenged with the same drug again developed large increases in SCK activity within a week. It is unlikely these increases in SCK activity are related to acute psychosis, trauma, or the neuroleptic malignant syndrome. The increase in SCK activity may reflect the ability of the drugs to increase intermittently cell membrane permeability, especially in skeletal muscle, in some vulnerable subjects. A possible role of serotonin in this process is suggested by the pharmacology of most of the offending drugs. However, in some instances, the increases may have been unrelated to drug treatment. There was no evidence that these increases in SCK activity, despite their magnitude, compromised renal function. Routine monitoring of SCK activity of myoglobinuria during treatment with the antipsychotic drugs studied here is probably not necessary.

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

The pharmacoeconomics of clozapine: a review.

BACKGROUND: A pharmacoeconomic analysis of clozapine is of particular importance because clozapine has a unique profile of benefits, risks, and costs relative to typical neuroleptic drugs and because it is currently approved for use in only two populations, i.e., neuroleptic-resistant and neuroleptic-intolerant schizophrenic patients, although it has also been found to be useful in a variety of other indications, e.g., refractory bipolar patients. METHODS: The three studies of the primary data relevant to a pharmacoeconomic analysis of clozapine in the treatment of schizophrenia were reviewed. RESULTS: The results suggest that clozapine as a treatment of neuroleptic-resistant schizophrenia leads to better outcome and lower costs in treatment-resistant patients compared with typical neuroleptic drugs because of decreased hospitalization, even when the costs associated with dropouts from clozapine are included. No pharmacoeconomic data are available for other indications of clozapine. CONCLUSION: Clozapine has been found to produce superior outcome compared with prior treatment with typical neuroleptic drugs in neuroleptic-resistant patients in dimensions that can be readily transformed into cost-utility measures such as decreased psychopathology, improved cognition, decreased rehospitalization, decreased suicide attempts, and better work function. If the frequency of hospitalization of patients has been appreciable, and dropouts from clozapine are in the range of 30% to 50% and occur within 1 to 4 months of starting treatment, it is likely that clozapine will be a cost-effective treatment. Cost-effectiveness studies comparing clozapine with standard treatments are needed for each application of clozapine, including use in neuroleptic-intolerant patients.

Plasma clozapine and desmethylclozapine levels in clozapine-induced agranulocytosis.

Clozapine may produce agranulocytosis in 1-2% of patients treated with it for 4 weeks or longer. Three mechanisms have been suggested: a direct toxic effect of metabolite of clozapine, an immunologic mechanism or a combination of both. N-desmethylclozapine, the major metabolite of clozapine, has been reported to be more toxic than clozapine itself (Gerson et al., 1994). In this study, plasma levels of clozapine and desmethylclozapine were measured in five patients who developed agranulocytosis. The levels of both parent compound and metabolite were within the range found in other patients and below the toxic range. If a toxic mechanism is involved in clozapine-induced agranulocytosis, an additional vulnerability factor must be important.