NEUROLEPTIC-RESISTANT SCHIZOPHRENIC-PATIENTS TREATED BY CLOZAPINE - CLINICAL EVOLUTION, PLASMA AND RED-BLOOD-CELL CLOZAPINE AND DESMETHYLCLOZAPINE LEVELS

The aim of this open study was to determine a more rational therapeuti c approach for psychotic patients treated with clozapine for several m onths, using measurement of plasma and red blood cell levels (P, RBC) of clozapine (cloza) and N-desmethylclozapine (descloza), the major me tabolite of clozapine, which has been reported to be less active hut m ore toxic (agranulocytosis) than clozapine itself. The RBC concentrati on may be considered as more representative of the free fraction drug. The study concerned 7 patients suffering from chronic paranoid schizo phrenia according to the DSM-IV criteria. All of them were treatment-r efractory schizophrenic inpatients (4 men, 3 women; mean age +/- SD : 38.2 +/- 8.4 years; mean duration of illness +/- SD : 14.4 +/- 5.1 yea rs). They had received at least two different neuroleptics, for 6 week s, before entering the study. Treatment started in our hospitalization unit with clozapine 25 mg up to a maximum of 900 mg/d (mean stabilize d daily dose +/- SD : 507 +/- 211 mg and mean daily dose per kg: 6.91 +/- 3.08 mg). Clinical evaluations (Quality of Life Scale : QLS), regu lar blood monitoring and biological samples were conducted at the same time, weekly for 18 weeks and then monthly (duration of the study : 4 to 38 months; mean +/- SD : 12.9 +/- 11.5 months). Plasma and RBC (al ter lysis) levels were determined by reversed phase HPLC and UV detect ion after extraction with hexane. All the patients improved very quick ly after the first week of treatment and six were able to leave the ho spitalization unit and start outpatient care such as daily hospitaliza tion, returning home or in sheltered accommodation. With the following plasma (P) and RBC levels: mean cloza +/- SD : (P = 294 +/- 146 ng/ml ; RBC = 110 +/- 82 ng/ml) and mcan descloza +/- SD : (P = 173 +/- 106 ng/ml; RBC = 76 +/- 54 ng/ml); none of the seven patients developed ag ranulocytosis. The blood levels, ensuring better surveillance, have a predictive value for clinical improvement. A linear pharmacoclinical c orrelation was only found between RBC cloza concentrations and the evo lution of the QLS scores. Clozapine fulfils the criteria for therapeut ic drug monitoring, and determination of plasma, and more particularly RBC, cloza and descloza levels may help to find the lowest effective dose with the fewest side effects.