NONFUNCTIONAL CYP2D6 ALLELES AND RISK FOR NEUROLEPTICS-INDUCED MOVEMENT-DISORDERS IN SCHIZOPHRENIC-PATIENTS

The use of classic anti-psychotic drugs in the long-term treatment of schizophrenia is associated with risk for extrapyramidal side-effects, such as akathisia, parkinsonism and tardive dyskinesia (TD). Approxim ately 5-10% of European Caucasians lack the cytochrome P450 enzyme CYP 2D6 (so-called poor metabolizers; PM), which normally metabolizes seve ral drugs including many neuroleptics. PM subjects may achieve high or toxic plasma levels upon standard drug therapy. In this study we have examined 100 subjects from the Nithsdale cohort of schizophrenic pati ents in South-west Scotland receiving long-term neuroleptic medication , which enabled us to perform both a cross-sectional and longitudinal evaluation of extrapyramidal side-effects in relation to the genetical ly impaired CYP2D6 metabolism. We identified ten (10%) schizophrenic s ubjects with the PM genotype. In the cross-sectional study, the preval ence of TD, parkinsonism and akathisia was 51%, 38% and 15%, respectiv ely. Patients with TD or parkinsonism were significantly older than pa tients without these side-effects. In contrast, patients with akathisi a were significantly younger than patients without akathisia. There wa s a nonsignificant tendency for PM subjects to have more severe rating s for TD and parkinsonism. In the longterm evaluation based on repeate d ratings since 1981, there was a non-significant 3-fold higher freque ncy of PM subjects among schizophrenic patients with longitudinal TD, as compared with the group of patients with fluctuating or no TD. Thes e results indicate that genetically impaired CYP2D6 metabolism may be a contributing factor for the development of persistent TD.