***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: Objective Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 ( CYP1A2 ) substrates clozapine and olanzapine . The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting . Methods In 73 schizophrenic patients recruited from psychiatric nursing homes , patient characteristics , smoking habits , drug dosing and serum concentrations of  clozapine ( n=33 ) and olanzapine  ( n=40 ) were registered . Concentration to dose ( C/D ) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared . Results Fifty-nine patients ( 80 % ) were smokers and these were stratified into the following groups according to smoking habits : 1–6 ( n=0 ) , 7–12 ( n=13 ) , 13–19 ( n=18 ) and ≥20 ( n=28 ) cigarettes daily . While the mean ratio was twice as high in non-smokers compared to smokers for both drugs ( p<0.01 ) , the C/D ratios of clozapine and  olanzapine were not significantly different between the subgroups of smokers ( p > 0.15 ) . Absolute serum concentrations were also higher in non-smokers compared to smokers : 50 % for clozapine ( p=0.058 ) and 67 % for olanzapine ( p<0.01 ) . Conclusion A daily consumption of 7–12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism . A 50 % lower starting dose of both drugs in non-smokers seems rational to avoid side effects Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenic patients . After a 2- to 9-day placebo lead-in , 79 in patients with schizophrenia according to DSM-III-R criteria were placed on an olanzapine dosage of 10 mg/day or 1 mg/day for up to 6 weeks .  Blood sample s were obtained weekly during this period . Receiver operating characteristic curve analyses of Brief Psychiatric Rating Scale ( BPRS ) and Positive and Negative Syndrome Scale rating scale data suggested a minimum effective therapeutic concentration of 9 ng/mL. Using an intent-to treat analysis , 45 % of the patients with olanzapine  plasma concentrations > or = 9.3 ng/mL responded ( > or = 20 % decrease in BPRS ) , whereas only 13 % of the patients with concentrations < 9.3 ng/mL responded . Use of olanzapine  plasma concentrations of > 9 ng/mL as a predictor for treatment response in acutely ill schizophrenic patients is practicable because this therapeutic marker significantly increases the likelihood of a patient responding to olanzapine A long-acting depot formulation of olanzapine that sustains plasma olanzapine concentrations for over a month after a single injection is currently under development . This multicenter , open-label study explored D2 receptor occupancy of a fixed dose of olanzapine pamoate ( OP ) depot given every 4 weeks . Patients ( nine male , five female ) with schizophrenia or schizoaffective disorder previously stabilized on oral olanzapine  were switched to OP depot 300 mg by intramuscular injection every 4 weeks for 6 months . No visitwise within-group significant changes were found in Brief Psychiatric Rating Scale Total or Clinical Global Impressions-Severity of Illness scores , although seven patients received oral olanzapine supplementation during the first four injection cycles . To minimize impact on D2 occupancy , positron emission tomography ( PET ) scans were not completed during injection cycles that required supplemental oral olanzapine . Two patients reported transient injection site adverse events , which did not result in discontinuation . The most frequently reported treatment-emergent adverse events were insomnia , aggravated psychosis , and anxiety . Mean striatal D2 receptor occupancy , as measured by [11C]-raclopride PET , was 69 % on oral olanzapine ( 5–20 mg/day ) and 50 % ( trough ) on OP depot at steady state . Following an initial decline , occupancy returned to 84 % of baseline oral olanzapine occupancy after six injections . Over the study period , D2 receptor occupancy and plasma olanzapine concentrations were significantly correlated ( r=0.76 , P⩽0.001 ) . OP depot result ed in mean D2 receptor occupancy of approximately 60 % or higher at the end of the 6-month study period , a level consistent with antipsychotic efficacy and found during treatment with oral olanzapine . However , supplemental oral olanzapine or another dosing strategy may be necessary to maintain adequate therapeutic response during the first few injection cycles Abstract The objective of this study was to assess the dose-response relationship of st and ard and higher doses of olanzapine in a r and omized , double-blind , 8-week , fixed-dose study comparing olanzapine 10 ( n = 199 ) , 20 ( n = 200 ) , and 40 mg/d ( n = 200 ) for patients with schizophrenia or schizoaffective disorder and suboptimal response to current treatment . Patients meeting criteria for antipsychotic treatment resistance were excluded . Dose-response relationship was assessed by linear regression analysis with log-transformed dose ( independent variable ) and Positive and Negative Syndrome Scale ( PANSS ) total score ( dependent variable ) . There were no significant dose group differences in patients completing the study ( overall , 67.8 % ) . All dose groups showed statistically significant improvement in PANSS total scores from baseline to end point without significant dose-response relationship ( P = 0.295 ) . Post hoc analysis of response showed significant interaction between baseline PANSS and dose ( P = 0.023 ) , indicating better response at higher doses for patients with higher baseline PANSS . There was a significant dose response for mean change in weight ( P = 0.003 ) with significant difference between the 10- and 40-mg-dose groups ( P = 0.002 ; 1.9 [ 10 mg/d ] , 2.3 [ 20 mg/d ] , and 3.0 kg [ 40 mg/d ] ) . There was a significant dose response for change in prolactin ( P < 0.001 ) with a significant difference between each group ( −10.5 [ 10 mg/d ] , −1.7 [ 20 mg/d ] , and 4.9 ng/mL [ 40 mg/d ] ; P ≤ 0.018 ) . Over 8 weeks , non-treatment-resistant patients with schizophrenia or schizoaffective disorder responded to all 3 doses of olanzapine , without a statistically significant dose-response relationship , suggesting that for many patients with schizophrenia or schizoaffective disorder , particularly those who are mildly or moderately ill , 10 mg/d should be the initial dose of choice Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia .  Olanzapine plasma concentrations ≥ 9.3 ng/mL ( 24 hours postdose ) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia . The authors report a receiver operating characteristic ( ROC ) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial . After a 4- to 7-day placebo lead-in , patients meeting DSM-III-R criteria for schizophrenia were r and omly assigned to receive olanzapine , haloperidol , or placebo . Patients who were r and omly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks . Blood sample s for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours ( 11.7 ± 1.7 hours ) after the last dose was administered . Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study . Plasma concentrations from previous visits were used if endpoint concentrations were invalid . Response was defined as a ≥ 20 % reduction in Brief Psychiatric Rating Scale ( BPRS ) scores and a Clinical Global Impression ( CGI ) Severity scale score of ≤ 3 or a final BPRS score of ≤ 35 . The final ROC analysis included data from 84 patients and suggested an olanzapine concentration ≥ 2 3.2 ng/mL to be a predictor of therapeutic response . Fifty-two percent of patients with 12-hour olanzapine concentrations ≥ 23.2 ng/mL responded , whereas only 25 % of patients with concentrations < 23.2 ng/mL responded . Furthermore , an olanzapine concentration ≥ 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms ( ≥ 20 % decrease and endpoint CGI ≤ 3 ) . Olanzapine concentrations were found to be a function of olanzapine dose ( in milligrams per day ) and gender such that prospect i ve olanzapine dosing is feasible . A 12-hour olanzapine plasma concentration of > 23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia . Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia ; however , their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated . We aim ed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol , in first-episode schizophrenia . METHODS We did an open r and omised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites , in 14 countries . Eligible patients were aged 18 - 40 years , and met diagnostic criteria for schizophrenia , schizophreniform disorder , or schizoaffective disorder . 498 patients were r and omly assigned by a web-based online system to haloperidol ( 1 - 4 mg per day ; n=103 ) , amisulpride ( 200 - 800 mg per day ; n=104 ) , olanzapine ( 5 - 20 mg per day ; n=105 ) , quetiapine ( 200 - 750 mg per day ; n=104 ) , or ziprasidone ( 40 - 160 mg per day ; n=82 ) ; follow-up was at 1 year . The primary outcome measure was all-cause treatment discontinuation . Patients and their treating physicians were not blinded to the assigned treatment . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N68736636 . FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 ( Kaplan-Meier estimate 72 % ) for haloperidol , 32 ( 40 % ) for amisulpride , 30 ( 33 % ) for olanzapine , 51 ( 53 % ) for quetiapine , and 31 ( 45 % ) for ziprasidone . Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride ( hazard ratio [ HR ] 0.37 , [ 95 % CI 0.24 - 0.57 ] ) , olanzapine ( HR 0.28 [ 0.18 - 0.43 ] ) , quetiapine ( HR 0.52 [ 0.35 - 0.76 ] ) , and ziprasidone ( HR 0.51 [ 0.32 - 0.81 ] ) . However , symptom reductions were virtually the same in all the groups , at around 60 % . INTERPRETATION This pragmatic trial suggests that clinical ly meaningful antipsychotic treatment of first-episode of schizophrenia is achievable , for at least 1 year . However , we can not conclude that second-generation drugs are more efficacious than is haloperidol , since discontinuation rates are not necessarily consistent with symptomatic improvement We explored the relationship between striatal dopamine-2 ( D(2 ) ) receptor occupancy and extra-pyramidal symptoms ( EPS ) in bipolar patients receiving olanzapine . Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5 - 45 mg/day olanzapine for at least 14 days . After that period , D(2 ) receptor occupancy was determined using Iodobenzamide ( IBZM ) and SPECT .  EPS were assessed by the Simpson-Angus Scale ( SAS ) and Barnes-Akathisia Scale ( BAS ) . We found a dose-dependent increase in occupancy : 5 mg led to 28 - 50 % , 10 mg to 40 - 
    Output:
    
The effect size-dose relationship showed a typical dose-response curve with minimal rise in slope for doses higher than 10 mg/d .
Our review suggests that the likelihood of a favorable response with olanzapine is maximized at doses of 10 to 15 mg/d ( perhaps lower in nonsmoking females ) .
Higher doses may be considered if 15 mg is ineffective and if plasma level is less than 20 ng/mL on that dose .
There is a direct linear relationship between  olanzapine dose and plasma concentration .