Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients

Abstract

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). Approximately 5-10% of European Caucasians lack the cytochrome P450 enzyme CYP2D6 (so-called poor metabolizers; PM), which normally metabolizes several 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 patients 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 genetically impaired CYP2D6 metabolism. We identified ten (10%) schizophrenic subjects with the PM genotype. In the cross-sectional study, the prevalence of TD, parkinsonism and akathisia was 51%, 38% and 15%, respectively. Patients with TD or parkinsonism were significantly older than patients without these side-effects. In contrast, patients with akathisia were significantly younger than patients without akathisia. There was a non-significant tendency for PM subjects to have more severe ratings for TD and parkinsonism. In the long-term evaluation based on repeated ratings since 1981, there was a non-significant 3-fold higher frequency of PM subjects among schizophrenic patients with longitudinal TD, as compared with the group of patients with fluctuating or no TD. These results indicate that genetically impaired CYP2D6 metabolism may be a contributing factor for the development of persistent TD.

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

“…Nine studies 58,60,70,76,78,88,89,96,97 clearly specified the number of missing genotypes and six of these provided reasons for the missing data. 58,60,70,76,78,96 In the remaining 42/51 studies, it was unclear whether the number contributing to each analysis was equal to the sample size.…”

“…Nine studies 58,60,70,76,78,88,89,96,97 clearly specified the number of missing genotypes and six of these provided reasons for the missing data. 58,60,70,76,78,96 In the remaining 42/51 studies, it was unclear whether the number contributing to each analysis was equal to the sample size. No study mentioned conducting specific tests for population stratification even though six 57,60,87,96,102,103 were known to include patients with different ethnic backgrounds.…”

Support for association of HSPG2 with tardive dyskinesia in Caucasian populations

“…As patients were assessed only once, the TD diagnosis in our sample corresponds to the category of 'cross-sectional TD'. [36][37][38] Association of HSPG2 with TD in Caucasians…”

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

“…Therefore, it is unclear what range of effect sizes the studies were powered to detect. 126 Andreassen 1997, 127 Armstrong 1997, 128 Arranz 1995, 129 Arthur 1995, 130 Brockmoller 2002, 131 Culav-Sumic 2001, 132 de Leon 2004, 133b Dettling 2000, 134 Ellingrod 2000, 135 Ellingrod 2002, 136 Ellingrod 2002, 137 173 However, when studies reporting significant outcomes were subsequently analysed, around half had adequately given reasons for the specific alleles tested.…”

“…In terms of the included studies, it was not always apparent from the manner in which data were reported whether any genotype data were missing. Some studies (n = 9) 127,139,145,146,148,152,153,162,164 clearly specified the number of missing genotypes and two-thirds of these 127,139,146,152,153,164 provided reasons for the missing data. All but two studies 142,171 gave the number of patients contributing to each analysis.…”