Long-term patient monitoring for clozapine-induced agranulocytosis and neutropenia in Korea: when is it safe to discontinue CPMS?

OBJECTIVES: This study documents the incidences of agranulocytosis and neutropenia, and the patterns of incidence of the side effects of long-term clozapine treatment in order to determine an appropriate time to stop the Clozaril Patient Monitoring System (CPMS). METHODS: Hematological, demographic, and other data from the CPMS for 6782 patients who took clozapine for the past 11 years in the Republic of Korea has been analyzed. RESULTS: Twenty-nine (53.7%) of fifty-four agranulocytosis cases occurred within the first 18 weeks. The cumulative incidence of agranulocytosis was 1.64% between 6 and 11 years and the crude incidence was 0.8%. Neutropenia occurred in 697 patients, and 365 (52.4%) of these cases occurred within the first 18 weeks. The cumulative incidence of neutropenia was 19.8% between 8 and 11 years, and the crude incidence was 10.3%. There were no cases of agranulocytosis or neutropenia after the 9th year of clozapine treatment. CONCLUSIONS: The incidence of agranulocytosis in the Republic of Korea was similar to those in the rest of the world. While agranulocytosis began several years after clozapine treatment, long-term monitoring of white blood cells is necessary. We suggest that the CPMS should be stopped or less frequently after the 9th year of treatment.

A preliminary study of the comparative effects of olanzapine and risperidone on cognition in schizophrenia.

The aim of this study was to compare the effects of olanzapine and risperidone on cognitive functions in patients with schizophrenia. The subjects were schizophrenic outpatients, all meeting DSM-IV diagnostic criteria for schizophrenia and already treated with risperidone. In the experimental group (15), risperidone was changed to olanzapine to be administered for 8 weeks. Risperidone was maintained without a change in the daily dose in the control group (13). The assessment of clinical symptoms and cognitive functions in both groups was made at baseline and at 8 weeks. The experimental group relative to the control group showed significant improvement in five items such as immediate and delayed recall of verbal memory, verbal fluency, visual memory and total error of executive function. Although these data are preliminary, they could suggest the possibility of cognitive benefits from treatment with olanzapine relative to risperidone. These findings did not appear to be mediated by changes in clinical symptoms and side effects.

Potentiated modulation of pregnolone on GABAA receptors in behaviorally stressed borderline-hypertensive rats.

The modulatory effects of behavioral stress on [(3)H]flunitrazepam, an agonist for the central-type benzodiazepine receptor binding to the GABA(A)-benzodiazepine receptor complex, in borderline hypertensive rats (BHR) were examined. In repeatedly immobilized (for 2 weeks, for 2 h/d) BHR, enhancement of [(3)H]flunitrazepam binding to the receptor was observed to be potentiated. The percent enhancement of [(3)H]flunitrazepam binding in BHR was higher than that in normotensive control Wistar-Kyoto rats. Pregnanolone, a neuroactive steroid that has been reported to be a putative endogenous modulator in the stress response, concentration dependently enhanced [(3)H]flunitrazepam binding to the receptor. Enhancement of [(3)H]flunitrazepam binding was observed to be potentiated by the same immobilized stress, and the EC(50) values of pregnanolone in BHR was significantly lower than those in controls and E(max) values were higher. From the above results, it can be concluded that neural modulation to behavioral stress, especially in GABAergic neurotransmission, is exaggerated in BHR. We propose strain-specific differences of stress reactivity as an important pathogenetic factor in psychosomatic disorders including stress-induced hypertension. This is supported by reports showing exaggerated cardiovascular and symathoadrenal responses to stress in BHR.

A placebo-controlled, double-blind trial of Ginkgo biloba for antidepressant-induced sexual dysfunction.

The aim of this study was to examine the effect of Ginkgo biloba on antidepressant-induced sexual dysfunction. The Ginkgo biloba (n=19) and the placebo groups (n=18) were divided; each to be administered with Ginkgo biloba and placebo respectively for 2 months by means of a randomized placebo-controlled, double-blind study. The results of this 2 month trial were: (1) there was no statistical significant difference from the placebo at weeks 2, 4 and 8 after medication; (2) in comparison with baseline, both the Ginkgo biloba group and the placebo group showed improvement in some part of the sexual function, which is suggestive of the importance of the placebo effect in assessing sexual function. This study did not replicate a prior positive finding supporting the use of Ginkgo biloba for antidepressant, especially SSRI, induced sexual dysfunction.

The effect of clozapine on blood glucose metabolism.

The aim of this prospective study was to examine the effect of clozapine on blood glucose metabolism compared with haloperidol. Oral glucose tolerance tests were taken every week for 8 weeks to assess the prevalence of diabetes mellitus, impaired glucose tolerance and glycemic peak delay in 19 patients of the clozapine group compared with 15 patients of the haloperidol group. There were two dropouts in the clozapine group and five in the haloperidol group. Finally 17 patients in the clozapine group and 10 patients in the haloperidol group participated in this study. In the clozapine group, six patients (35%) had impaired glucose tolerance, and seven patients (41%) had glycemic peak delay. In the haloperidol group, no patient (0%) had impaired glucose tolerance, and one patient (10%) had glycemic peak delay. None of either group developed diabetes mellitus. In conclusion, the clozapine group had more impaired glucose tolerance and glycemic peak delay than the haloperidol group. However, this difference did not achieve statistical significance (p = 0.056, p = 0.189). Copyright 2001 John Wiley & Sons, Ltd.