Therapeutic drug monitoring of clozapine in relapse prevention: A five-year prospective study

Twenty-three outpatients with schizophrenia (ICD-10 F20,xx) treated with cl ozapine (CZ) as monotherapy entered a prospective study on relapse preventi on. Every 4 weeks, psychopathology was assessed by the Brief Psychiatric Ra ting Scale (BPRS), and plasma CZ and norclozapine levels were measured. Pat ients were enrolled after complete remission of positive symptoms for at le ast 4 months according to the psychosis cluster of the BPRS and at a mean o f 3.3 years after their last hospitalization. At the time of enrollment, th e median BPRS total score was 29 points (range, 19-48), Within 4 months, th e baseline CZ plasma level was established as the mean of CZ levels from at least four subsequent measurements. These baseline plasma levels were cons idered as the optimal relapse-preventing plasma CZ levels in the individual patients. When the patients were enrolled, they were considered to be pron e to relapse. Relapse was defined as clinical deterioration, hospitalizatio n, or both. Plasma levels were considered a prognostic factor, and patients were defined as at increased risk if plasma levels decreased by more than 40% from baseline CZ plasma level. The effect of plasma CZ levels on clinic al outcome was evaluated by a Cox regression with plasma level as a time-de pendent covariate, Within 46 months of enrollment, 32 episodes of relapse e vents in 10 patients were available for evaluation. Seventeen patients had a plasma level decrease of more than 40% at some point. In 12 of these, the decrease was present for more than 12% of the observation period. Eight pa tients of this group relapsed, and three of these had to be rehospitalized. Two patients relapsed, although their plasma levels decreased by more than 40% for less than 12% of the observation period. Within the first 2 years, relapse-free survival curves illustrate that both groups (episodes under e levated risk and episodes not under elevated risk) had identical relapse pa tterns, but from then on the relapse risk increased rapidly in the group wi th longer exposure to elevated risk. In a Cox model with a 40% decrease of plasma CZ levels as a dichotomous time-varying explanatory covariate, the r isk ratio is 6 (95% confidence interval = 2-19,p = 0.003), The 10 patients who relapsed exhibited safe plasma levels (less than a 40% decrease from th eir baseline levels) for only 210 months, and 13 nonrelapsing patients had plasma levels defined as safe for 426 months.