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CLOZAPINE-AN ATYPICAL NEUROLEPTIC STATUS OF TODAY |
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Tommie Lundberg MD PhD Upsala University, Department of Psychiatric research, Västerås Central Hospital |
| In the 1950’s clozapine
was regarded as a potential antidepressant because of the structure of
the molecule. When is showed to have antipsychotic effect the manufacturer
hesitated to develop the compound further because its lack of extrapyramidal
side effects (EPS). It was a dogma at that time of a correlation between
EPS and antipsychotic effect. In the mid 70’s several clinical trials proved
the superiority of clozapine compared to classical neuroleptics in the
treatment of psychotic patients. The eight deaths of agranulocytoses reported
from Finland in 1975 was a Major drawback for the manufacturer, clinicians
and patients. The compound was withdrawn from most countries due to these
fatal cases. Clozapine was reintroduced for restricted use in the late
80’s in USA and Europe after pressure from several clinicians experience
of a superior antipsychotic effect without EPS.
The new concept of an antipsychotic compound with the pharmacological properties of clozapine challenged three major hypothesis of antipsychotic drugs. The first hypothesis was the anticipated correlation between the chemical structure and the clinical effect. Secondly it became obvious that it was not a necessity for an antipsychotic drug to cause EPS. Thirdly it was shown in the 90’s that a selective D2 blockade was not an optimal treatment for psychoses. Accordingly all new potential antipsychotic compounds under development are multireceptor drugs trying to combine the effect of clozapine without causing EPS or agranulocytoses. The Pharmacokinetic properties of x\clozapine are crucial both for the antipsychotic properties and its side effect profile. The latter contributes to a good compliance. Equal half lives in plasma and at the receptors in the brain and low affinity for D2 receptors in striatum are major properties contributing to the lack of EPS and rapid relapse after withdrawal of the compound. Clozapine also binds to D1, 5HT2, a and muscarinic-cholinergic receptors. Clozapine is the only antipsychotic proved to be atypical. The lack of EPS corresponds well to the low D2 receptors occupancy value demonstrated with Positron Emission Tomography (PET) in contrast to higher D2 occupancies for classical neuroleptics. A world wide review of scientific articles performed during the early 90’s demonstrate that clozapine is the only antipsychotic proved to be effective in the treatment of therapy refractory psychotic patients. three controlled randomized double blind trials of high scientific standard all show clozapines superiority compared to the three comparative classical neuroleptics. A retrospective long term follow up study up to 18 years reveal that 50% of the chronic psychotic inpatients were very much improved after clozapine treatment compared to previous treatment. The improvement of the social function was even more impressing and continued over time up to 10 years of treatment. After 2 years of clozapine treatment 40% of the patients were able to keep jobs compared to 4% with the previous treatment. The risk of agranulocytoses (0,8%) has led to a strict blood monitoring scheme with blood samples and white cell blood counts (WBC) once a week during the first 18 treatment weeks and thereafter once a month. If granulocytopenia (<1,5x109) appears clozapine has to be withdrawn. After 7-4 days the WBC is normalized. Clozapine can be regarded as a safe antipsychotic provided that the monitoring scheme id performed as outlined. |