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Variables Associated With High Olanzapine Dosing in a State Hospital
Abstract
Olanzapine has a U.S. Food and Drug Administration-approved dosing range of 10 to 20 mg/day but is often used at doses exceeding this range. Olanzapine is largely metabolized by cytochrome P450 (CYP) 1A2. Smoking, which induces CYP1A2, is expected to increase clearance of olanzapine by 40%; however, dosage adjustment in smokers is not currently recommended. Additionally, female gender is expected to reduce clearance by 30%. Many institutions target high-dose olanzapine prescribers in an effort to reduce unnecessary drug costs. However, factors such as smoking or gender may necessitate increased doses.
A retrospective review of all patients receiving olanzapine during an inpatient stay at a state psychiatric hospital in Kentucky during 2001 was conducted. Demographic information and smoking status were collected for all patients. Olanzapine doses of > 20 mg/day were considered high doses.
Nine percent (48/522) of olanzapine patients were prescribed high doses. The percentages were similar in women and men (10% vs. 9%, p =.69) and in smokers and nonsmokers (9% vs. 9%, p =.82). Moreover, the mean maximum olanzapine dose was also similar in men and women (15.4 +/- 7.2 vs. 14.9 +/- 7.3 mg/day, p =.51). The odds of receiving a high dose of olanzapine were increased 2.1 for patients with a schizophrenia spectrum diagnosis (DSM-IV schizophrenia or other psychotic disorder). The odds of receiving a high dose of olanzapine were increased with each incremental increase in length of stay (intermediate length of stay [8-60 days], OR = 5.6; long-term length of stay [> 60 days], OR = 12.0, relative to acute length of stay [< 8 days]).
Neither gender nor smoking status was associated with receiving a high dose of olanzapine. The association of increased length of stay with high dose suggests that treatment resistance may be an important factor in receiving high daily doses of olanzapine.
... However, the patients in this dataset included those with nonschizophrenic and nonaffective disorders (these so-called 'miscellaneous disorders' comprised 29.7% of all patients in 1999 and 31.5% in 2002). In 2001 in a 160-bed state-operated psychiatric hospital in Kentucky, USA, the mean daily dose of olanzapine was 15 mg, with only 9% receiving a dose greater than 20 mg/day [11]. The majority of the patients had a length of stay of less than 61 days (83%), as compared with a majority having a length of stay of at least 1 year in the New York State data [5], suggesting that length of stay (as a proxy for severity of illness) is correlated with dose. ...
... The majority of the patients had a length of stay of less than 61 days (83%), as compared with a majority having a length of stay of at least 1 year in the New York State data [5], suggesting that length of stay (as a proxy for severity of illness) is correlated with dose. Supporting this statement are the observations that in Kentucky the mean dose of olanzapine among patients whose length of stay exceeded 60 days was 19.0 mg/day, and that the odds of receiving a high dose of olanzapine were increased with each incremental increase in length of stay [11]. This relationship between length of stay and dose was also reported for patients with schizophrenia receiving quetiapine, another second-generation antipsychotic where doses above the product label maximum are commonly encountered [5,6]. ...
... In a NNT effectiveness outcome analysis for Phase I, olanzapine demonstrated advantages over perphenazine, quetiapine, risperidone and ziprasidone with regard to all-cause discontinuation (NNTs range: 6-11) [59]. The advantage of olanzapine over all the other tested antipsychotics was also found for discontinuation owing to lack of efficacy (NNTs range: [8][9][10][11]. Risperidone had an advantage over olanzapine with regard to discontinuation due to intolerability (NNH: 12). Patients treated with olanzapine gained more weight than patients in any other group (p < 0.001), with an average weight gain of 2 lb (0.9 kg) per month and 9.4 lbs (4.3 kg) over the length of the study. ...
A substantial number of patients with schizophrenia or bipolar disorder receive olanzapine in amounts that are greater than what is recommended in the product labeling approved by drug regulatory agencies. The purpose of this review is to describe the evidence supporting the use of olanzapine in excess of 20 mg/day. PubMed was queried using the keywords 'olanzapine' and 'dose' or 'dosing' for all English-language articles published between 1990 and December 2008, inclusive of articles that describe utilization of olanzapine at doses in excess of 20 mg/day. Also queried was clinicaltrials.gov for studies involving 'olanzapine'. Efficacy and safety data were extracted from case reports, case series, observational studies and double-blind, randomized clinical trials. We found that the use of olanzapine at doses greater than 20 mg/day appears to be increasing. Among patients hospitalized for intermediate and long-term care in New York State psychiatric centers in the period from 1997 to 2003, the average dose of olanzapine increased from 17.4 to 22.5 mg/day. The percentage of patients receiving olanzapine at a dose exceeding 20 mg/day increased from 16.2 to over 50% from 1997 to 2006. Case reports of patients receiving doses up to 60 mg/day describe a favorable benefit-risk ratio. Double-blind clinical trials that have examined doses of olanzapine greater than 20 mg/day are limited in number, but suggest that these doses may be helpful in selected patients who are treatment resistant, have high levels of psychopathology or who are acutely agitated. This must be balanced by an increased risk of weight gain and elevated prolactin that was observed among those receiving 40 mg/day in a large randomized clinical trial comparing doses of 40 versus 20 versus 10 mg/day. In conclusion, dosing of olanzapine in clinical practice is higher than what has been established in the registration program for schizophrenia or bipolar disorder. This is somewhat supported by double-blind, controlled clinical trial evidence, but only for selected patients with severe and/or persistent symptoms.
... Our own previous high-dosing studies in a naturalistic setting suggested that high antipsychotic dosing appears to follow complex patterns. 42,43 Thus, in naturalistic studies, high dosing may be explained by some patient variables but, more importantly, by physician practices. A study on high dosing of typical antipsychotics suggested that some patient variables (e.g., age and schizophrenia diagnosis) were important, but physician variables (e.g., working in 1 of the 2 hospitals) were also found to be important. ...
... 42 We recently showed that smoking or gender did not predict high olanzapine doses (although they are reported to affect olanzapine's metabolism and disposition). 43 Instead, high olanzapine dosing was best predicted by a diagnosis of schizophrenia, physician response to the length of stay, and preferences by some individual physicians. 43 Risperidone appears to have a narrower therapeutic window for extrapyramidal ADRs than olanzapine. ...
... 43 Instead, high olanzapine dosing was best predicted by a diagnosis of schizophrenia, physician response to the length of stay, and preferences by some individual physicians. 43 Risperidone appears to have a narrower therapeutic window for extrapyramidal ADRs than olanzapine. This study does not suggest that risperidone dosing is irrelevant in this naturalistic setting, but that dosing effects may be-come more meaningful after knowing the patient's genetic CYP2D6 phenotype. ...
The cytochrome P450 2D6 (CYP2D6) enzyme metabolizes risperidone. CYP2D6 poor metabolizers have no CYP2D6 activity (7% of whites and 1%-2% of other races). This study tested whether the CYP2D6 poor metabolizer phenotype was associated with adverse drug reactions (ADRs) and discontinuation due to ADRs.
Adult inpatients and outpatients were recruited from July 2000 to March 2003 including (1) 325 who were stabilized on risperidone therapy and classified as either expressing moderate-to-marked ADRs (22%, 73/325) or not (78%, 252/325) and (2) 212 who discontinued risperidone and were classified as discontinued due to ADRs (38%, 81/212) or for other reasons (62%, 131/212). Genetic tests were performed by allele-specific polymerase chain reaction and/or by the AmpliChip CYP450 microarray system for up to 34 separate CYP2D6 alleles. Two logistic regression models with dependent variables (moderate-to-marked ADRs while taking risperidone and risperidone discontinuation due to ADRs) were evaluated with respect to the CYP2D6 phenotype.
The odds ratios (ORs) and 95% confidence intervals (CIs) for the CYP2D6 poor metabolizer phenotype in the univariate analyses and after correcting for clinical variables were (1) OR = 3.1 (CI = 1.4 to 7.0) and 3.4 (CI = 1.5 to 8.0) for moderate-to-marked ADRs on risperidone and (2) OR = 3.0 (CI = 0.85 to 10.6) and 6.0 (CI = 1.4 to 25.4) for discontinuation due to ADRs.
The CYP2D6 poor metabolizer phenotype appears to be associated with risperidone ADRs and discontinuation due to ADRs; however, this finding requires further study in larger patient populations. The CYP3A5 and p-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.
... When doctors use newer drugs with wide therapeutic windows, they are freer to use wide dose ranges since they see little or no toxicity. In these situations doctor preferences or biases may be much more important than pharmacology in determining dose or drug selection [63]. When drug dosing is heavily influenced by physician choice it is much harder to predict the effects; thus the system has a lot of noise and the pharmacological signals may be lost in the noise [63]. ...
... In these situations doctor preferences or biases may be much more important than pharmacology in determining dose or drug selection [63]. When drug dosing is heavily influenced by physician choice it is much harder to predict the effects; thus the system has a lot of noise and the pharmacological signals may be lost in the noise [63]. Therefore, personalized dosing of A c c e p t e d M a n u s c r i p t 12 wide therapeutic window drugs may be quite difficult to develop or be completely irrelevant, since dosing in the real world of clinical practice may have little relevance in predicting drug response. ...
Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber’s role, and (4) idiosyncratic and dose-related adverse drug reactions. Personalized prescription in the clinical environment can be expressed in two main ways: as personalized selection of the drug and as personalized dosing.The future, or lack of future, of personalized drug selection and of personalized dosing in psychiatry is reviewed. Currently, the author thinks that, in psychiatry, pharmacogenetic tests have some potential in two areas: (1) excluding some drugs for some unusual patients (HLA-B*1502 genotyping in Asians for carbamazepine), and (2) using pharmacokinetic genes for personalizing dosing in narrow therapeutic window drugs. In the short term, there is dubious potential for other pharmacogenetic tests and no potential for pharmacogenetic testing to ascertain the best drug for each patient. Personalized dosing has immediate application if one understands it as the use of our current scientific knowledge of genetic, environmental and personal variables to determine dosing; its sole requirement is well-trained psychiatrists.
... In a large naturalistic OLZ study, neither gender nor smoking predicted OLZ mean or high doses. 37 The reason for this is that OLZ may be less dependent than CLZ on CYP1A2 metabolism, and UGT1A4 may have a major role. 35,37 Naturalistic studies of CLZ (or caffeine, another typical CYP1A2 substrate) easily demonstrate gender and smoking effects. ...
... 37 The reason for this is that OLZ may be less dependent than CLZ on CYP1A2 metabolism, and UGT1A4 may have a major role. 35,37 Naturalistic studies of CLZ (or caffeine, another typical CYP1A2 substrate) easily demonstrate gender and smoking effects. ...
Drug-drug interactions or genetic variability may require using doses different from those recommended for atypical antipsychotics. Dosage alterations of olanzapine and clozapine, dependent on cytochrome P450 1A2 (CYP1A2) for clearance, and quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Smoking cessation can significantly increase clozapine, and perhaps olanzapine, levels. Ziprasidone pharmacokinetic drug-drug interactions are not likely to be important. Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.
... [5][6][7][8][9][10][11] For some individuals, alternative treatments are required due to clinical contraindications precluding clozapine use, including clozapine discontinuation due to Over the past 20 years, a handful of double-blind trials and open-label studies have indicated that high-dose olanzapine (>20 mg daily) may be an effective therapy in TRS. 19,20 However, the use of high-dose olanzapine for this purpose is not well recognised in the wider clinical community. A metaanalysis of randomised controlled trials (RCTs; n = 7) of olanzapine (both standard and high dose) compared with clozapine in TRS identified greater reductions in PANSS positive and negative symptom scores for clozapine compared with olanzapine but with no significant differences in PANSS total symptom scale scores and time to discontinuation between those treated with olanzapine and those treated with clozapine. ...
Background
Treatment-resistant schizophrenia (TRS) affects approximately 30% of people with schizophrenia. Clozapine is the gold standard treatment for TRS but is not always suitable, with a proportion of individuals intolerant of side effects or unable to engage in necessary blood monitoring. Given the profound impact TRS can have on those affected, alternative pharmacological approaches to care are needed.
Objectives
To review the literature on the efficacy and tolerability of high-dose olanzapine (>20 mg daily) in adults with TRS.
Design
This is a systematic review.
Data Sources and Methods
We searched for eligible trials published prior to April 2022 in PubMed/MEDLINE, Scopus and Google Scholar. Ten studies met the inclusion criteria [five randomised controlled trials (RCTs), one randomised crossover trial and four open label studies]. Data were extracted for predefined primary outcomes (efficacy, tolerability).
Results
Compared with standard treatment, high-dose olanzapine was non-inferior in four RCTs, three of which used clozapine as the comparator. Clozapine was superior to high-dose olanzapine in a double-blind crossover trial. Open-label studies demonstrated tentative evidence in support of high-dose olanzapine use. It was better tolerated than clozapine and chlorpromazine in two respective RCTs, and was generally well tolerated in open-label studies.
Conclusion
This evidence suggests high-dose olanzapine is superior for TRS when compared with other commonly used first- and second-generation antipsychotics, including haloperidol and risperidone. In comparison with clozapine, the data are encouraging for the use of high-dose olanzapine where clozapine use is problematic, but larger, better designed trials are needed to assess the comparative efficacy of both treatments. There is insufficient evidence to consider high-dose olanzapine equivalent to clozapine when clozapine is not contraindicated. Overall, high-dose olanzapine was well tolerated, with no serious side effects.
Registration
This systematic review was preregistered with PROSPERO [CRD42022312817].
... Correlates of smoking in schizophrenia include male gender, early onset of the illness, severity of psychiatric symptoms, more frequent hospitalizations, cognitive deficits, high doses of antipsychotic medications, frequent substance use, and poor treatment adherence and response (Botts et al., 2004;Culhane et al., 2008;de Leon et al., 1995). Smoking patterns can be best understood in the given sociocultural context (Chen et al., 2009;Hou et al., 2011;Kelly et al., 2008;Tang et al., 2007a). ...
... In the context of dose optimization, it is not uncommon for clinicians to employ doses exceeding recommended therapeutic guidelines (Barbui et al., 2007;Botts et al., 2004;Hanssens et al., 2006;Sernyak and Rosenheck, 2007), although the value of high doses has been challenged (Kinon et al., 1993(Kinon et al., , 2008Leucht et al., 2011;McEvoy et al., 1991). Similarly, antipsychotic switching is commonly undertaken as the illness unfolds (Buckley and Correll, 2008) despite recent evidence calling into question the benefit of switching between two non-clozapine antipsychotics (Essock et al., 2006;McEvoy et al., 2006;Rosenheck et al., 2008Rosenheck et al., , 2009. ...
Clinicians treating schizophrenia routinely employ high doses and/or antipsychotic switching to achieve response. However, little is actually known regarding the value of these interventions in early schizophrenia. Data were gathered from a treatment algorithm implemented in patients with first-episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine. Patients were initially treated with either olanzapine or risperidone across three dose ranges, (low, full, high), and in the case of suboptimal response were switched to the alternate antipsychotic. We were interested in the value of (a) high dose treatment and (b) antipsychotic switching. A total of 244 patients were evaluated, with 74.5% (184/244) responsive to Trial 1, and only 16.7% (10/60) responsive to Trial 2. Percentage of response for subjects switched from olanzapine to risperidone was 4.0% (1/25) vs. 25.7% (9/35) for those switched from risperidone to olanzapine. High doses yielded a 15.5% response (14.6% for risperidone vs. 16.7% for olanzapine).The present findings concur with other research indicating that response rate to the initial antipsychotic trial in first-episode schizophrenia is robust; thereafter it declines notably. In general, the proportion of responders to antipsychotic switching and high dose interventions was low. For both strategies olanzapine proved superior to risperidone, particularly in the case of antipsychotic switching (i.e. risperidone to olanzapine vs. vice versa). It remains to be established whether further antipsychotic trials are associated with even greater decrements in rate of response. Findings underscore the importance of moving to clozapine when treatment resistance has been established.
... A number of studies on smoking in schizophrenia patients have been carried out in Westerns settings. Risk factors of smoking included male sex, early onset of the illness, more hospital admissions, severity of psychopathology, cognitive deficits, high doses of antipsychotic drugs, extrapyramidal side effects, more frequent substance use and poor response to treatment (Botts et al., 2004;Culhane et al., 2008;de Leon et al., 1995;Goff et al., 1992;Hughes et al., 1986;McEvoy et al., 1999;Ziedonis et al., 1994). ...
This study examined the prevalence of cigarette smoking and its socio-demographic and clinical characteristics in Chinese schizophrenia patients. A sample of 540 community-dwelling patients (female/male: 50.4% vs. 49.6%) with schizophrenia was interviewed using standardized assessment instruments. The patients' basic socio-demographic and clinical data including smoking were collected. The prevalence of cigarette smoking was 28.5% in the whole sample, and 53.6% and 4.0% for men and women, respectively. In univariate analyses, male sex, use of first generation antipsychotics (FGAs) and alcohol consumption were significantly associated with smoking. In multiple logistic regression analysis, male sex, alcohol consumption, older age and lower level of education were independently associated with smoking. The prevalence of smoking in Chinese schizophrenia patients is considerably lower than most figures reported from Western settings. The dramatic differences between males and females underscore the influence of cultural norms on smoking.
... Higher antipsychotic doses may be needed in more severe illness and in manifestations of hostility [26], such as the association with physical aggression as found in this study. Botts et al. [30] also pro-posed pharmacokinetic reasons for the possible use of high antipsychotic doses such as in those with genetic polymorphism variations associated with unusually high metabolic rates and the presence of inducers such as co-prescriptions of other medications and smoking. The association of high antipsychotic doses with younger age in this study is consistent with the findings of other studies [8,9]. ...
We aimed to examine the frequency of high-dose (defined as mean chlorpromazine mg equivalent doses above 1000) antipsychotic prescriptions in schizophrenia and their clinical correlates in the context of a comparison between studies in 2001 and 2004 within six East Asian countries and territories.
Prescriptions of high-dose antipsychotic for a sample of 2136 patients with schizophrenia from six countries and territories (mainland China, Hong Kong, Korea, Japan, Taiwan and Singapore) were evaluated in 2004 and compared with data obtained for 2399 patients in 2001.
Overall, the comparison between 2001 and 2004 showed a significant decrease in high-dose antipsychotic use from 17.9 to 6.5% [odds ratio (OR) 0.32, 95% confidence interval (CI) 0.26, 0.39, P < 0.001]. Patients who received high-dose antipsychotics were significantly more likely to have multiple admissions (OR 1.96, 95% CI 1.16, 3.33, P = 0.009), more positive psychotic symptoms such as delusions (OR 2.05, 95% CI 1.38, 3.05, P < 0.001) and hallucinations (OR 1.85, 95% CI 1.30, 2.64, P = 0.001), but less likely to have negative symptoms (OR 0.58, 95% CI 0.40, 0.82, P = 0.002). Multivariate regression analyses revealed that prescription of high-dose antipsychotics was also predicted by younger age (P < 0.001), time period of study (2001; P < 0.001), use of first-generation antipsychotic (P < 0.001) and depot antipsychotics (P < 0.001) as well as antipsychotic polytherapy (P < 0.001).
We identified the clinical profile and treatment characteristics of patients who are at risk of receiving high antipsychotic doses. These findings should provide impetus for clinicians to constantly monitor the drug regimes and to foster rational, evidence-based prescribing practices.
... difficulty in being implemented and published. The smoking was associated with requirement for high olanzapine basic scientist approach is characterized by smaller, well-condose in a large naturalistic study, but individual physician practice trolled experiments with only one dependent variable, use of the and hospital unit type had some influence. [89] These two pharmadesign to control for confounding variables, and the belief that cological examples of real world prescription of high atypical lack of statistical significance represents failure. The applied sciantipsychotic doses point out extrapolation difficulties from conentist approach is characterized by larger studies of many un ...
The US FDA has granted market approval for the first pharmacogenetic test using a DNA microarray, the AmpliChip CYP450, which genotypes cytochrome P450 (CYP)2D6 and CYP2C19. The test uses software to predict phenotypes and tests for 27 CYP2D6 alleles, including the deletions and duplications, and three CYP2C19 alleles. Other DNA microarray platforms are being developed for CYP testing, but none have been completely developed or approved by the FDA to date. The differences between an implementation of pharmacogenetic tests centered on the individual and implementation using a public health approach are discussed. In this review, the major obstacles to the wide implementation of pharmacogenetic testing in the clinical environment are summarized.
... Neither gender nor dose predict high olanzapine dose in a large naturalistic study, but individual physician practice and hospital unit type had some influence. [89] These two pharmacological examples of real world prescription of high atypical antipsychotic doses point out extrapolation difficulties from controlled clinical trials to the clinical arena. ...
The AmpliChip™ CYP450 Test, which analyzes patient genotypes for cytochrome P450 (CYP) genes CYP2D6 and CYP2C19, is a major step toward introducing personalized prescribing into the clinical environment. Interest in adverse drug reactions (ADRs), the genetic revolution, and pharmacogenetics have converged with the introduction of this tool, which is anticipated to be the first of a new wave of such tools to follow over the next 5–10 years. The AmpliChip™ CYP450 Test is based on microarray technology, which combines hybridization in precise locations on a glass microarray and a fluorescent labeling system. It classifies individuals into two CYP2C19 phenotypes (extensive metabolizers [EMs] and poor metabolizers [PMs]) by testing three alleles, and into four CYP2D6 phenotypes (ultrarapid metabolizers [UMs], EMs, intermediate metabolizers [IMs], and PMs) by testing 27 alleles, including seven duplications.
CYP2D6 is a metabolic enzyme with four activity levels (or phenotypes): UMs with unusually high activity; normal subjects, known as EMs; IMs with low activity; and PMs with no CYP2D6 activity (7% of Caucasians and 1–3% in other ethnic groups). Levels of evidence for the association between CYP2D6 PMs and ADRs are relatively reasonable and include systematic reviews of case-control studies of some typical antipsychotics and tricyclic antidepressants (TCAs). Evidence for other phenotypes is considerably more limited. The CYP2D6 PM phenotype may be associated with risperidone ADRs and discontinuation due to ADRs. Venlafaxine, aripiprazole, duloxetine, and atomoxetine are newer drugs metabolized by CYP2D6 but studies of the clinical relevance of CYP2D6 genotypes are needed. Non-psychiatric drugs metabolized by CYP2D6 include metoprolol, tamoxifen, and codeine-like drugs.
CYP2C19 PMs (3–4% of Caucasians and African Americans, and 14–21% of Asians) may require dose adjustment for some TCAs, moclobemide, and citalopram. Other drugs metabolized by CYP2C19 are diazepam and omeprazole.
The future of pharmacogenetics depends on the ability to overcome serious obstacles, including the difficulties of conducting and publishing studies in light of resistance from grant agencies, pharmaceutical companies, and some scientific reviewers. Assuming more studies are published, pharmacogenetic clinical applications may be compromised by economic factors and the lack of physician education. The combination of a US FDA-approved test, such as the AmpliChip™ CYP450 Test, and an FDA definition of CYP2D6 as a ‘valid biomarker’ makes CYP2D6 genotyping a prime candidate to be the first successful pharmacogenetic test in the clinical environment. One can use microarray technology to test for hundreds of single nucleotide polymorphisms (SNPs) but, taking into account the difficulties for single gene approaches such as CYP2D6, it is unlikely that very complex pharmacogenetic approaches will reach the clinical market in the next 5–10 years.
Background and Objective
Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting.MethodsA total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate.ResultsTypical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h−1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model’s performance was good, stable, and precise.Conclusion
This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.
The article deals with definition, measurement and treatment possibilities of pharmacoresistant schizophrenia. Recently, when evaluating pharmacoresistance, we have concentrated especially on persistent symptoms because there are treatment options preferentially influencing some symptoms (positive, negative, affective symptoms and cognitive dysfunction). As for treatment possibilities, attention is first paid to the use of high doses of antipsychotic, i.e. higher doses than officially recommended. Further possibilities include switch to clozapine and polypharmacotherapy. Clozapine is still considered to be a gold standard in this indication. Polypharmacotherapy, especially a combination of antipsychotics and augmentation by drugs primary not intended for treatment of psychosis are very frequent. Based on available data in stabilised schizophrenic patients, it seems that polypharmacotherapy is abundant in many cases. For this reason the individual medication should be considered carefully and individually taking into consideration the most troublesome persistent symptoms.
There is increasing awareness that ethnic and cultural influences can alter individual responses to medications (Lambert & Minas, 1998). Ethno-psychopharmacology investigates cultural variations and differences that influence the effectiveness of prescription medicines used in the treatment of mental illnesses. Differences in response can be explained by both genetic and psychosocial variations. They range from genetic variants in drug metabolism to cultural practices, which may affect diet, adherence to prescribed patterns of medication use, placebo response, and the simultaneous use of traditional and alternative healing methods (Lin et al., 1991). However, predictions regarding genetic expression based on ethnicity alone need to be exercised with caution. Although connections between ethnicity and drug metabolism were recognized early, for example primaquine induced hemolysis based on G6PD deficiency in some Afro-Americans (Alving et al., 1956), such differences are based more on genetic endowment per se rather than racial or ethnic divisions. The validity of therapy based solely on racial differences has been questioned, for example, in relation to differential drug responses in cardiology for Black and White patients (Schwartz, 2001). All populations irrespective of racial group exhibit substantial intra-population variability (Jorde & Wooding, 2004). Within a single racial population between 93 and 95% of all human genetic variability is captured (Jones & Perlis, 2006). A small amount of genetic variation (~0.02% of all nucleotides) distinguishes populations from each other and no single marker can identify race or ancestry. © C. H. Ng, K.-M. Lin, B. S. Singh and E. Y. K. Chiu 2008 and Cambridge University Press, 2009.
SOUHRN Sdělení se zabývá definicí a stanovením farmakorezistentní schizofrenie a možnostmi její léčby. V poslední době se při hodnocení farmakorezistence soustřeďujeme hlavně na přetrvávající příznaky, protože máme k dispozici léčebné přístupy, které preferenčně ovlivňují některé příznaky (pozitivní, negativní, kognitivní deficit, afektiv-ní). Z léčebných postupů je nejprve věnována pozornost užití vysoký dávek, tj. dávek vyšších než maximálních oficiálně uvedených. Další možností je změna stávající léčby na klozapin a polyfarmakoterapie. Klozapin je v této indikaci stále považován za zlatý standard. Polyfarmakoterapie, hlavně kombinace antipsychotik i augmentace antipsychotik látkami, které nejsou primárně určeny k léčbě psychóz, je velmi častá. Z dostupných dat vyplývá, že u stabilizovaných nemocných se schizofrenní poruchou je často polyfarmakoterapie nadbytečná. Měla by být proto zvažována velmi pečlivě a individuálně s ohledem na přetrvávající symptomatologii. Klíčová slova: farmakorezistentní schizofrenie, antipsychotika, vysoké dávky, klozapin, polyfarmacie, kombi-nace antipsychotik, augmentace antipsychotik.
There have been few investigations into the relationship of smoking to the presentation of anxiety and depression in clients with a primary diagnosis of schizophrenia. Using a survey design, the current study sought to determine if there was a significant difference between smoking and non-smoking clients in this clinical group on self-report measures of anxiety and depression. The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression. One hundred clients (male = 74) with a primary diagnosis of schizophrenia completed the HADS. No significant difference was observed in anxiety and depression scores as a function of smoking status. A logistic regression analysis revealed that gender was a significant predictor of smoking status. The notion that smoking behaviour and mood state are associated with schizophrenia was not supported. However, a high proportion of the cohort were smokers (69%), and male gender was a significant predictive factor in smoking status. Further research in this area is recommended in order to develop strategies which reduce this current level of smoking in clients with a primary diagnosis of schizophrenia.
The aim of the present study was to explore the rate of cigarette smoking and its sociodemographic and clinical characteristics in Chinese schizophrenia patients.
In a multicentre, randomized, controlled, longitudinal study, 374 clinically stable patients with schizophrenia were interviewed at entry using standardized assessment instruments, and followed up for 1-2 years.
The rate of cigarette smoking was 13.9% in the whole sample, and 26.2% in men and 3.5% in women. On univariate analysis, male sex, unemployment, alcohol consumption, older age, older age at onset, longer duration of illness, more frequent admissions, more severe hostility-excitement at entry and less deterioration in hostility-excitement over the study period were significantly associated with cigarette smoking. On multivariate analysis, male sex, unemployment, alcohol consumption, more frequent admissions, less severe positive and negative symptoms at entry, smaller decline in negative symptoms and more deterioration in disorganized thoughts over the study period were independently associated with cigarette smoking.
The rate of cigarette smoking in Chinese schizophrenia patients is considerably lower than most figures reported in the Western literature.
The limited available information on plasma risperidone levels shows a stable relationship between daily doses of risperidone and total plasma concentration (risperidone plus its active metabolite 9-hydroxyrisperidone). The ratio between risperidone and 9-hydroxyrisperidone characterizes cytochrome P450 2D6 (CYP2D6) status. According to the manufacturer, the CYP2D6 genotype or drugs that influence CYP2D6 or other cytochrome P450 isoenzyme activity are not expected to be clinically significant. One case report suggests that CYP3A participates in the metabolism of risperidone.
A case series of 13 risperidone patients (the initial case and 12 new cases) who were genotyped for CYP2D6 were followed, and another 20 risperidone patients from a case-control study for the CYP2D6 genotype were reviewed.
The CYP2D6 poor metabolizers, who are enzyme deficient (2/13 in the case series and 3/20 in the case-control study), did not appear to tolerate risperidone well. Drugs affecting CYP3A, in particular powerful inducers and inhibitors, resulted in at least a 2-fold decrease or increase in plasma risperidone levels.
The anecdotal nature of this study is clearly a limitation. Drugs influencing CYP3A and CYP2D6 metabolic activity may significantly affect risperidone levels. Thus, plasma level monitoring of risperidone in a clinical setting may be useful, especially if patients are taking multiple medications or a CYP2D6 deficiency is suspected. New prospective studies under more controlled conditions are needed to verify these hypotheses.
The purpose of this review is to critically review the current literature on olanzapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of mood disorders and schizophrenia. New information continues to emerge on the impact of olanzapine on schizophrenia and on aspects of the course of mood disorders. There are also continued efforts to understand, predict and manage the side-effect risk with olanzapine.
The aim of this article is to critically review the current literature on treatment-refractory schizophrenia with an emphasis on emergent themes and key findings.
New information continues to emerge on the impact of each second-generation antipsychotic on the treatment-refractory patient population and on the traditionally more difficult-to-treat components (e.g. cognition, suicidality, violence) of the illness. There are continued efforts with pharmacogenetics to predict response and side-effect risk with antipsychotic medications. Polypharmacy continues to be a major and poorly understood treatment practice.
Our field is advancing the therapeutic nuances of therapy with second-generation antipsychotics in treatment-refractory schizophrenia. Additionally, there is a growing appreciation of the emergent adverse-effect profile of antipsychotic medications and these risk-benefit considerations are more pronounced in severely ill patients.
The self-medication hypothesis proposes that schizophrenia patients smoke to decrease their schizophrenia symptoms or antipsychotic side effects, but they usually start smoking before their illness and heavy smoking is not consistently associated with fewer symptoms or side effects. A narrow version of the self-medication hypothesis, heavy smoking reduces akathisia, is explored.
The sample included 250 outpatients with DSM-IV schizophrenia assessed with the Positive and Negative Syndrome Scale (PANSS) and the Barnes Akathisia Scale. Prevalences were 69% (173/250) for smoking, 39% (98/250) for heavy smoking (> or =30 cigarettes/day), 7% (17/250) for akathisia (Barnes Global score>1), 14% (35/250) for a broader akathisia definition (Barnes Global score>0) and 20% for excited symptoms (>1 on the PANSS factor score).
Heavy smoking was not associated with akathisia (41% of patients with akathisia were heavy smokers versus 39% of patients without akathisia; chi2=0.3, df=1, p=0.86), even after correcting for confounding factors and/or using a broader akathisia definition. Heavy smoking was associated with excited schizophrenia symptoms (possibly reflecting agitation). Particularly in patients taking lower doses of typical antipsychotics, excited symptoms, with or without akathisia, were strongly associated with heavy smoking and appear to interact with patients' reports of smoking's calming effect as the main reason for smoking.
The self-medication hypothesis does not explain increased smoking and heavy smoking in schizophrenia. Moreover, heavy smoking may be associated with more disturbed brain homeostatic mechanisms. Prospective studies need to explore whether temporary increases in cigarette smoking may be associated with periods of higher agitation, with or without akathisia.
The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age ≥ 18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient).
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This chapter describes one blood and one urine test that have served as indexes of CYP1A2 activity in clinical and epidemiological studies. Caffeine (1,3,7-trimethylxanthine, 137X) undergoes N-demethylation, ring hydroxylation, and acetylation to give di- and monomethylxanthines, urates, and an acetylated uracil in humans. The major enzyme involved in the biotransformation of caffeine and its metabolites is CYP1A2, a cytochrome P450. Other enzymes with contributions to caffeine metabolism are CYP2E1 (the ethanol-inducible cytochrome P450), the polymorphic N-acetyltransferase (NAT2), xanthine oxidase (XO), CYP3A4 and CYP2A6. A caffeine test for CYP2E1 is still being evaluated based on the shifting of the metabolite profile of caffeine 3-demethylation to the 1- and 7-demethylation pathways by CYP2E1. Thus, the caffeine test promises to become a single test for monitoring multiple liver enzymes identified in carcinogen activation, that is, CYP1A2, CYP2E1, NAT2, and XO.
