POLYMORPHIC DRUG-METABOLISM IN SCHIZOPHRENIC-PATIENTS WITH TARDIVE-DYSKINESIA

The metabolism of many neuroleptics cosegregates with the capacity to 4-hydroxylate debrisoquine, catalyzed by the polymorphic cytochrome P4 50 CYP2D6. The population can be phenotyped into extensive metabolizer s (EM) and poor metabolizers (PM) with respect to this enzyme's activi ty. PM: are likely to achieve higher than average concentrations of ne uroleptic drugs in plasma, with an increased risk of extrapyramidal si de effects, possibly including tardive dyskinesia. Sixteen white schiz ophrenic patients who had developed tardive dyskinesia during long-ter m neuroleptic treatment were phenotyped with debrisoquine and genotype d by CYP2D6-specific DNA amplification and EcoRI restriction fragment length polymorphism analysis, Only 1 (6%) of the 16 patients had a PM genotype, 8 (50%) were homozygous, and 7 (44%) were heterozygous EM, N one had a CYP2D6 genotype indicative of ultrarapid debrisoquine hydrox ylation capacity. The patients were also phenotyped with mephenytoin, a probe drug for another polymorphic cytochrome P450, CYP2C19. One pat ient was a PM of S-mephenytoin, which corresponds to the frequency fou nd in healthy white volunteers. In conclusion, there was no overrepres entation of PM of debrisoquine or of S-mephenytoin among the 16 patien ts with neuroleptic-induced tardive dyskinesia, However, the PM of deb risoquine had the highest score on the Simpson-Angus Rating Scale and the second highest on the Abnormal Involuntary Movement Scale, despite a very low neuroleptic dose, Also, the debrisoquine MR correlated sig nificantly with the SAPS score (r(s) = 0.685, p < 0.05, N = 10), indic ating a relationship between the degree of impaired CYP2D6 activity an d the severity of extrapyramidal side effects during neuroleptic treat ment.