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Background: Cytochrome P450 2D6 enzyme (CYP2D6) is an important metabolic pathway for many antipsychotics. Its genetic polymorphism causes pharmacokinetic variability that might lead to adverse drug reactions or treatment failure unless countered by appropriate dose adjustments or shift to CYP2D6-independent antipsychotics., Purpose: To investigate the clinical impact of CYP2D6 genotype in patients with a diagnosis within the schizophrenic spectrum using medication pattern as proxy for therapeutic and side effect., Methods: The study was conducted in patients genotyped during an inpatient stay (N = 576). Continuous antipsychotic, adjuvant, and anticholinergic drug regimens were registered retrospectively in a cross-sectional manner before genotyping. Antipsychotics were divided into CYP2D6 dependent and independent, and dose equivalents were calculated as chlorpromazine equivalents (CPZEq)., Results: Poor metabolizers and ultrarapid metabolizers were treated with significantly higher median CPZEq doses (625.8; inter quartile range [IQR], 460.4-926.7; and 550; IQR, 199.8-1049) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (384; IQR, 150-698; and 446; IQR, 150-800) (P = 0.018). Logistic regression showed no association between anticholinergic treatment and CYP2D6 genotype or concomitant treatment with CYP2D6 inhibitors (P = 0.79 and P = 0.46, respectively)., Conclusions: Our results indicate that CYP2D6 genotype has no sufficient clinical impact that poor metabolizers and ultrarapid metabolizers are easily clinically identified with.

Classic chlorpromazine (CPZ) equivalents can be used to chart relative antipsychotic potencies of antipsychotic drugs. Values of CPZ equivalents per drug are ambiguous in literature. In drug use evaluation studies, antipsychotic doses are frequently compared by use of the defined daily dose (DDD). The DDD is the assumed average maintenance dose per day for a drug if used for its main indication in adults. The DDD is based on review of the available older and recent literature. In this report, we evaluated discrepancy between CPZ-equivalent values and DDD-equivalent values. We plotted CPZ-equivalent values against DDD-equivalent values and performed linear regression to determine the mean relationship between the 2 methods. About 67% of the DDD-equivalent values demonstrated lower potencies for antipsychotic drug compared with CPZ-equivalent values. The slope of the regression line was 0.68 (r2 = 0.81). Because we found a great discrepancy between these 2 methods of comparing antipsychotic drug doses, we think further research is necessary to develop a standardized way of antipsychotic drug comparison.

Serum neuroleptic activity by radioreceptor assay and prolactin concentration were measured every 6 months for 2 years in 105 male schizophrenic outpatients. The patients took a variety of neuroleptics at clinically determined doses. As expected, when four dissimilar neuroleptics were examined together, there was no significant correlation between serum neuroleptic activity and either equivalent neuroleptic dose or serum prolactin concentration. Moderate correlations were seen, however, when neuroleptic activity was standardized between neuroleptic drugs. Similar moderate correlations were seen when neuroleptic activity was corrected for the blood-to-brain distribution of each neuroleptic. These two correction techniques ranked corrected neuroleptic activity in very similar orders. Correction for blood-to-brain distribution may be a practical way to compare serum neuroleptic activity from different neuroleptics.

Interpatient variation in response to therapy with antipsychotic drugs is a major problem. This study was designed to assess the extent of variation in disease-free subjects in whom known sources of variance were controlled as much as possible. The subjects were 32 healthy, nonsmoking males of European origin, aged 18-25 years, and weighing no more than +/- 15% from the ideal weight for height. After an overnight fast, each subject ingested 50 mg of chlorpromazine. Plasma samples were harvested over a 24-hour period during which the subjects were on a standardized, caffeine-free diet. Plasma levels of chlorpromazine were measured by gas-liquid chromatography-mass spectrometry. The results showed wide intersubject variation in all pharmacokinetic parameters including maximum concentration, area under the curve, and oral clearance. Furthermore, none of the data were normally distributed. For each pharmacokinetic parameter, the distribution was leptokurtotic and skewed. As a consequence, the geometric means provided better estimates of central tendency than the arithmetic means. It seems that a major proportion of intersubject variation is an inherent problem that cannot be accounted for by differences in race, diet, smoking habits, or concomitant drug ingestion.