Therapeutic drug monitoring of clozapine treatment. Therapeutic threshold value for serum clozapine concentrations.

It has been suggested that the minimum effective serum clozapine concentration for an acceptable clinical response (threshold value) is about 400 micrograms/L. This article argues against the use of therapeutic drug monitoring (TDM) as a tool to obtain clozapine concentrations of > or = 400 micrograms/L in the individual patient from the start of clozapine treatment. The following arguments are presented: (i) because of a great interindividual variability of the clozapine concentration to dose ratio (C/D) it can be calculated that extremely high daily doses (900 to 1800 mg/day) would be necessary in 15% of patients to obtain a clozapine concentration of 400 micrograms/L; (ii) doses of 200 to 300 mg/day are commonly used in Central Europe. although about 80% of the patients can be expected to have clozapine concentration < 400 micrograms/L; (iii) in a double-blind study, no difference in clinical response was found between patients treated with clozapine in the concentration range of 200 to 300 micrograms/L, and a group with higher clozapine concentrations; (iv) positron emission topography (PET) studies indicate that maximum receptor occupancy is obtained at clozapine concentrations of about 200 micrograms/L and no further receptor occupancy is obtained by increasing clozapine concentrations to > or = 400 micrograms/L; (v) the frequency of both severe clozapine-induced adverse effects (seizure and confusion) and more common adverse effects increases with increasing doses/clozapine concentrations. It is concluded that the antipsychotic effects and adverse effects of clozapine occur over a very broad range of serum concentrations. In most countries the majority of patients are treated with clozapine concentrations well below the 400 micrograms/L suggested as threshold concentration for optimum response. Therefore clinical judgement should always be primarily used for dose adjustments. TDM is useful to follow compliance and to adjust for extreme serum concentrations and revealing drug interactions.