[Clozapine treatment: possibilities and limitations]. / Klozapina: mozliwosci i ograniczenia stosowania.

The purpose of this article--based on the recent years literature--is discussing the principles of the use of clozapine in schizophrenia, with the special attention to treatment-resistance as a main indication, dose selection and duration of the trial. In spite of dynamic development of pharmacotherapy of schizophrenia, clozapine, registered in Europe 25 years ago, still remains a drug of choice in treatment-resistant schizophrenia, that is in 5-25% of patients, bringing a substantial clinical improvement in 30-50% of the group. The main factor limiting the possibility of the use of clozapine is the increased risk of neutropenia and agranulocytosis, what demands the WBC monitoring. Old age and female sex are considered to be potential risk factors. In both classical neuroleptics and clozapine, no clear linear correlation was noticed between the dose and clinical effect. It seems, however, that only in case of clozapine a noticeable correlation exists between the plasma level and clinical improvement. Many authors try to define a threshold level sufficient/necessary to achieve improvement. Suggested amounts are between 250-420 ng/ml. With fixed doses used, extremely different levels of clozapine are observed (from a few, to thousands ng/ml), so measuring plasma level is suggested as a routine procedure in cases of clozapine-resistance. The duration of the trial creates real controversy. Most authors agree that six weeks time, sufficient to diagnose treatment resistance in case of typical neuroleptics, may be too short for clozapine. At the same time, the postulated prolongation of the trial to a few months or even one year, explained by the presence of late improvements, is not well and generally accepted. It seems that time of 2-4 months is in most cases sufficient to notice the potential advantage. The problem of clozapine-resistance still remains open. Many strategies are being proposed (augmentation with lithium, valproate, sulpiride and benzodiazepines), but they demand further examination.

[Clozapine withdrawal. A review]. / Odstawienie klozapiny. Przeglad pismiennictwa.

The article describes the symptoms of withdrawal of clozapine and their possible causes as well as research on switching from clozapine to another antipsychotic drug. A computerised search was conducted using MEDLINE (1966-1997) to retrieve reports of clozapine withdrawal. Fifteen case reports and sixteen withdrawal studies (only one of them double-blind and two single-blind) were identified. Clozapine multi-receptors profile seems to be responsible for withdrawal symptoms--several specific mechanisms are suggested: cholinergic supersensitivity, dopaminergic supersensivity, special role of D4 receptors, possibilities of serotonergic, noradrenergic and GABA-ergic involvement. Risk of relapse after withdrawal of clozapine seems to be greater than after withdrawal of classical neuroleptics. Some patients might become de novo neuroleptic resistant for at least several weeks after withdrawal. Therefore, clozapine should be stopped only due to strong clinical indications, and if only possible, the withdrawal should be slow (50 mg/week). To prevent relapse of psychosis some experts advocate starting new antipsychotic drugs in therapeutic dosage before withdrawal of clozapine is completed. In case of emergency, when clozapine (high dosage) must be withdrawn immediately, patient must be hospitalised and cholinergics might be considered to prevent, cholinergic rebound". There are no established guidelines which antipsychotic to choose after withdrawal of clozapine. In general, classical antipsychotics are ineffective. Thioridazine is suggested because of its prominent anticholinergic activity, but there is no clinical evidence of advantage of this treatment in comparison to classical drugs. Risperidon and especially olanzapine are promising possibilities, but initial data are disappointing. Benzamides might be another possibility but clinical data are scarce. These important issues require further studies.