***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: STUDY OBJECTIVE To investigate the relationships between cytochrome P450 ( CYP ) 2D6 genotype ,  antipsychotic drug  exposure , abnormal movements and tardive dyskinesia , and cigarette smoking . DESIGN Prospect i ve , longitudinal study . SETTING University mental health research center . PATIENTS Thirty-seven patients with schizophrenia . INTERVENTION Patients were genotyped for CYP2D6 * 1 , * 3 , and * 4 alleles , and data were collected on their psychiatric symptoms , cigarette smoking status , and antipsychotic drug exposure .  Abnormal movements were measured using the Abnormal Involuntary Movement Scale ( AIMS ) . Presence of tardive dyskinesia was also evaluated . MEASUREMENTS AND MAIN RESULTS A linear regression model used the AIMS scores as the dependent variable , and genotype , sex , smoking status , and antipsychotic drug exposure as independent variables .  Antipsychotic drug exposure , genotype , and cigarette smoking interaction was significant ( p<0.0212 ) for patients with the CYP2D6 * 1/*3 , * 4 genotype . Seventy-eight percent of smokers with the CYP2D6 * 1/*3 , * 4 genotype had tardive dyskinesia compared with 20 - 33 % of patients in other groups . CONCLUSION Patients with a CYP2D6 * 3 or * 4 allele may shunt antipsychotic metabolism through other pathways that are induced by cigarette smoke . This induction may result in formation of neurotoxic metabolites , leading to increased AIMS scores and a higher frequency of tardive dyskinesia compared with patients without these alleles Cytochrome P450 ( CYP ) genotyping can be used to prospect ively identify individuals at risk for adverse drug reactions or therapeutic failure due to altered drug metabolism . Based on the specific CYP(s ) affected , individuals may require less or more of a particular drug than people with unaffected CYP-mediated metabolism , or may be best managed by avoiding certain drugs entirely . Here we evaluated the Tag-It ™ CYP mutation detection reagents ( Tm Bioscience Corp. ) . As these reagents , based on a universal bead array , detect more than 20 clinical ly significant variants common to different ancestries , it was important to consider DNA from genetically diverse population s. Thus , we also report CYP2D6 , CYP2C9 and CYP2C19 genotypes for DNA available through the Coriell Institute for Medical Research ( NJ , USA ) . These sample s represent individuals from Caucasian , Japanese , Chinese , Southeast Asian , African – American and Middle Eastern ancestry , and provide an excellent re source for evaluating and validating CYP genotyping methods . Using these sample s , the Tag-It mutation detections assays reliably provided genotypes for CYP2D6 , CYP2C9 and CYP2C19 . The CYP2C9 and CYP2C19 assays were particularly robust and were easily implemented in our clinical laboratory . The CYP2D6 assay was somewhat less robust and could be improved by associating the 2850C > T variant with a specific allele , as well as by discriminating the allele affected when gene duplication is detected Abstract . Objective : In order to evaluate whether poor metabolizers ( PM ) of debrisoquine are overrepresented among patients with acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs  , the CYP2D6 genotype was determined in schizophrenic patients . Methods : Allele status for CYP2D6 * 3 , CYP2D6 * 4 , CYP2D6 * 5 , and CYP2D6 * 6 as well as gene duplication was determined by allele-specific PCR , long-PCR and restriction fragment length polymorphism analysis ( RFLP ) in 119 schizophrenic patients ( 99 males and 20 females ) . All subjects were treated with antipsychotics metabolized , at least partially , by this isozyme . Sixty-three of the patients ( 52.9 % ) had a history of extrapyramidal side effects ( EPS ) , while 56 ( 47.1 % ) had not experienced such problems ( controls ) . Results : Sixty-five patients ( 54.6 % ) were homozygous for a functional CYP2D6 * 1 allele , 44 ( 37.0 % ) were heterozygous for detrimental alleles , and 4 ( 3.4 % ) , who carried two detrimental alleles , were classified as PM . In six patients ( 5.0 % ) duplication of a functional CYP2D6 gene was found , and they were consequently classified as ultrarapid metabolizers ( UM ) . Homo- and heterozygous extensive metabolizers ( EM ) as well as UM were equally distributed between patients with and without EPS , whereas all the PM had a history of EPS . No significant differences in allele frequencies between the two groups were found . Conclusion : Although the results can not be considered conclusive due to the small number of PM patients in our study , the PM genotype may be a predisposing factor for antipsychotic-induced EPS . Knowledge of the CYP2D6 genotype , before starting antipsychotic therapy , might be useful in identifying subjects at risk of developing EPS Abstract Introduction Assessment of the relation between oral risperidone dose , serum drug levels and clinical response may provide important information for rational treatment decisions . Inter – individual differences in the liver cytochrome P450 system , especially in the CYP2D6 subsystem , which account for a significant portion of risperidone metabolism , may also influence plasma drug levels and alter clinical response parameters . We thus prospect ively investigated risperidone serum concentrations in relation to clinical efficacy and side – effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters . Methods Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6–week open dose clinical trial . Weekly assessment s including CGI and PANSS ratings to assess psychopathology ; SAS to assess medication side effects ; and blood draws to quantify steady state plasma levels of risperidone and 9–OH – risperidone were carried out . In addition , major CYP2D6 polymorphisms including alleles * 4 , * 6 and * 14 were genotyped . Results Eighty – two patients were recruited . Mean oral dose of risperidone was 4.3 ± 0.9 mg . Mean plasma level of both risperidone and 9–OH – risperidone together ( “ active moiety ” ) was 41.6 ± 26.6 ng/ml . Significant improvements in PANSS scales and the various subscales ensued . There was a positive linear correlation between active moiety plasma levels and dose ( r = 0.291 , p = 0.015 ) and between risperidone and 9–OH – risperidone levels ( r = 0.262 ; p = 0.016 ) . Nonresponders to pharmacotherapy ( PANSS – Improvement < 30 % ) showed significantly higher active moiety plasma levels ( 49.9 ± 30.7 ng/ml ) than responders ( 38.2 ± 17.0 ng/ml ; p = 0.045 ) without significantly higher oral doses ( p = 0.601 ) . Patients with longer illness duration ( ≥ 3 years ) had significantly higher plasma drug levels than those with a shorter course ( < 3 years ; p = 0.039 ) . Extrapyramidal side effects ( EPS ) and plasma levels were not correlated ( r = 0.028 ; p = 0.843 ) , but higher plasma levels at week 2 predicted an incidence for EPS ( p < 0.050 ) . Accordingly , patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course . Eight patients ( 9.8 % ) were heterozygous carriers of the CYP2D6 allele * 4 . CYP2D6 polymorphisms did not predict clinical response , but predicted a tendential increase in the plasma risperidone to 9–OH – risperidone ratio ( 0.5 ± 0.6 vs. 1.9 ± 1.8 ; p = 0.120 ) . Discussion The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9–OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses . The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy , but affected risperidone to 9–OH – risperidone ratios . Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects . Conversely , the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances . Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration . The high inter – individual variability in risperidone and 9–OH – risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinical ly relevant active moiety AIM Cytochrome P450 2C9 ( CYP2C9 ) is a polymorphic enzyme responsible for the metabolism of a large number of clinical ly important drugs . Individuals with mutant enzymes may risk serious side effects under routine therapy with certain drugs metabolized by CYP2C9 . In order to facilitate the detection of the known SNPs of CYP2C9 , an allele-specific oligonucleotide ( ASO ) based microarray was made . METHODS An oligonucleotide microarray was made to facilitate the SNP ( single nucleotide polymorphism ) screening and was applied for the detection of CYP2C9 polymorphism in 62 high blood pressure ( HBP ) patients who received Irbesartan for treatment . Part of the genotyping results was confirmed by direct sequencing . And the relation between CYP2C9 polymorphism and therapeutic outcome of Irbesartan was statistically analyzed . RESULTS Heterozygous alleles of CYP2C9 * 1/*3 were found in 7 out of 62 subjects . No mutant alleles of CYP2C9 * 2 , * 4 and * 5 and no homozygous mutant alleles were detected . The 7 heterozygous CYP2C9 * 1/*3 and 13 r and om wild type DNA sample s were subjected to direct sequencing with purified PCR products and same genotyping results were obtained with the 20 DNA sample s. There was no significant difference in the odds of effectiveness of Irbesartan between the wild type ( normal ) group and CYP2C9 * 1/*3 ( mutant ) group ( P>0.05 ) . CONCLUSION The oligonucleotide microarray made in this study is a reliable assay for detecting the CYP2C9 known alleles and the heterozygous CYP2C9 * 1/*3 has no significant effects on the therapeutic outcome of Irbesartan Tardive dyskinesia ( TD ) is a movement disorder characterized by involuntary oro‐facial , limb , and truncal movements . As a genetic basis for inter‐individual variation is assumed , there have been a sizeable number of c and i date gene studies . All subjects met diagnostic criteria for schizophrenia and were r and omized to receive antipsychotic medications as participants in the Clinical Antipsychotic Trials of Intervention Effectiveness project ( CATIE ) . TD was assessed via the Abnormal Involuntary Movement Scale at regular intervals . Probable TD was defined as meeting Schooler – Kane criteria at any scheduled CATIE visit ( 207/710 subjects , 29.2 % ) . A total of 128 c and i date genes were studied in 710 subjects—2,580 SNPs in 118 c and i date genes selected from the literature ( e.g. , dopamine , serotonin , glutamate , and GABA pathways ) and composite genotypes for 10 drug‐metabolizing enzymes . No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons . Thus , we found no support for either novel or prior associations from the literature . © 2009 Wiley‐Liss , BACKGROUND The relative effectiveness of second-generation ( atypical ) antipsychotic drugs as compared with that of older agents has been incompletely addressed , though newer agents are currently used far more commonly . We compared a first-generation antipsychotic , perphenazine , with several newer drugs in a double-blind study . METHODS A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and r and omly assigned to receive olanzapine ( 7.5 to 30 mg per day ) , perphenazine ( 8 to 32 mg per day ) , quetiapine ( 200 to 800 mg per day ) , or risperidone ( 1.5 to 6.0 mg per day ) for up to 18 months . Ziprasidone ( 40 to 160 mg per day ) was included after its approval by the Food and Drug Administration . The primary aim was to delineate differences in the overall effectiveness of these five treatments . RESULTS Overall , 74 percent of patients discontinued 
    Output:
    
However , there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy , although there was an association between CYP2D6 genotype and extrapyramidal adverse effects .