THE RELATIONSHIP BETWEEN SERUM CONCENTRATION AND THERAPEUTIC EFFECT OF HALOPERIDOL IN PATIENTS

Haloperidol is the most commonly used antipsychotic drug in the therap y of acute schizophrenia. Clinicians have been using therapeutic drug monitoring in an attempt to improve clinical application of this drug. The scale of interest in this area is emphasised by the large number of studies (about 50) concerning the serum concentration-therapeutic e ffect relationship (SCTER) of haloperidol, including 35 studies on pat ients with acute schizophrenia However, conflicting results concerning the existence and position of a therapeutic window have emerged. This article aims to provide a comprehensive review of the study design of studies in patients with acute schizophrenia before the study data ar e used for decision-making. For this purpose, a reproducible system fo r the evaluation of studies in this special area, a so-called total st udy score (TSS), was developed on an empirical basis. Thus, insufficie nt study design was found to be a reason for negative results. On the ether hand, in spite of a great variability, the majority of studies w ith good design provided evidence for a significant SCTER: a bisigmoid al dependence of clinical effect on haloperidol serum concentration. T he therapeutic effects of haloperidol increase at low concentrations, and the concentration has a maximum effect at about 10 mu g/L, and aga in decreasing at higher concentrations. The data of 552 patients also fit to this model in a single scatter plot (pseudo-r(2) = 0.076, p < 0 .001). The position of the therapeutic window was determined at about 5.6 to 16.9 mu g/L. Patients treated with serum concentrations within this optimal range had a significantly better response compared with o utside this range (p < 0.001, Student t-test). Therefore, a quantitati ve synthesis of all available data by means of effect-size analysis pr ovides a mean effect-size (g)over dot = 0.499 +/- 0.182 (standard devi ation) for the comparison of haloperidol-treatment with serum concentr ations within versus outside the therapeutic window. Thus, because of this moderate positive effect, serum concentration assay of haloperido l is recommended for patients with acute schizophrenia in a therapeuti c drug monitoring programme. The modalities of haloperidol therapeutic drug monitoring in clinical practice are discussed, e.g. patient sele ction, method and time for serum concentration measurement, influence of premedication and comedication, interpretation of results and dose adjustment. Clinical investigations into this subject should focus on covariates which are responsible for the variability of the SCTER. Ser um concentration assay is advised for investigations of nonresponse to exclude patients with pseudo-drug resistance.