Serum Concentrations Of Olanzapine Research Articles

Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia.

Olanzapine is an atypical antipsychotic drug which is effective in the treatment of schizophrenia. Cigarette smoking, age, and sex could be related to the pharmacokinetics and serum concentrations of olanzapine in patients with schizophrenia. The aim of the study was to examine whether there was a significant difference in the serum olanzapine concentrations with regard to the mentioned factors. A total of 58 outpatients with schizophrenia (37 smokers, 42 men, 35 older than 40 years) participated in the study. Blood was sampled in serum tubes just before taking the next dose of olanzapine. Olanzapine was extracted by liquid-liquid extraction and was measured by an in-house high-performance liquid chromatography method on Shimadzu Prominence HPLC System with diode array detector SPD-M20A (Shimadzu, Kyoto, Japan). The results were expressed as the ratio of concentration to the daily dose of olanzapine (C/D). Non-parametric statistical tests were used to analyse differences between variables. The median C/D of olanzapine (interquartile range) in smokers was 6.0 (3.4-10.2) nmol/L/mg and in non-smokers 10.1 (5.9-17.6) nmol/L/mg; P = 0.007. The median C/D of olanzapine in patients younger than 40 years was 5.6 (4.5-10.2) nmol/L/mg and in patients older than 40 years 8.4 (5.6-13.0) nmol/L/mg; P = 0.105. The median C/D of olanzapine in male patients was 6.6 (4.6-10.4) nmol/L/mg and in female patients 9.0 (5.9-15.3) nmol/L/mg; P = 0.064. The serum olanzapine concentration was significantly lower in smoking than in non-smoking patients with schizophrenia. No significant difference was demonstrated with regard to age and sex.

Does China's competitive generic substitution policy deliver equivalent clinical outcomes? A pilot study with two generic formulations of olanzepine.

With the National Centralized Drug Procurement policy gradually applied nationally in China, concerns about the effectiveness and safety of bid-winning generic drugs are growing again, but relevant studies are lacking. This real-world, before-and-after study was conducted to explore the clinical effects of switching between two versions of generic olanzapine (one of them was bid-winning product). Pre-and post-switching serum olanzapine concentrations were compared. A total of 30 patients were included and results showed the log-transformed, dose-adjusted concentration of bid-winning generic olanzapine was significantly lower than that of another generic olanzapine, while no significant differences were shown on Clinical Global Impressions Severity of Illness or Improvement ratings before and after switching. This study suggest that a generic version of a psychotropic medication may not be of therapeutic equivalence or bioequivalence with another generic one. Changes in efficacy or tolerability are possible in every switch. Therapeutic drug monitoring could be a valuable tool during switches between generic drugs. Larger prospective clinical studies for other generic psychotropic medications in target populations are warranted.

Olanzapine poisoning in patients treated at the National Poison Control Centre in Belgrade, Serbia in 2017 and 2018: a brief review of serum concentrations and clinical symptoms.

Olanzapine is a thienobenzodiazepine class antipsychotic that strongly antagonises the 5-HT2A serotonin receptor, but acute poisonings are reported rarely. Symptoms of an overdose include disorder of consciousness, hypersalivation, myosis, and coma. Serum concentration higher than 0.1 mg/L is toxic, while concentration above 1 mg/L can be fatal. Here we report key data about 61 patients admitted to the National Poison Control Centre in Belgrade, Serbia over olanzapine poisoning in 2017 and 2018. The ingested doses ranged from 35 to 1680 mg, and time from ingestion to determination from two to 24 hours. In 34 patients olanzapine serum concentrations were in the therapeutic range and in 27 in the toxic range. In five patients they were higher than fatal, but only one patient died. The most common symptoms of poisoning were depressed consciousness (fluctuating from somnolence to coma), tachycardia, hypersalivation, hypotension, myosis, and high creatine kinase. All patients but one recovered fully after nonspecific detoxification and symptomatic and supportive therapy.

A Retrospective Analysis of Steady-State Olanzapine Concentrations in Chinese Patients Using Therapeutic Drug Monitoring: Effects of Valproate and Other Factors.

The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine.

Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dose-dependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapine-induced acute hyperglycemia.

Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching.

Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response. Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. A total of 25 patients (13 women and 12 men, mean age 41.2 ± 12.8 years) concluded the study. Mean olanzapine dose was 12.2 ± 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 ± 14.4 ng/mL during treatment with the branded formulation to 22.6 ± 12.3 ng/mL after switching to the generic formulation (P < 0.01). The log-transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72-0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 ± 8.3 versus 48.6 ± 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry.

CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations.

Although several polymorphisms in olanzapine-metabolizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in the UGT1A4 gene (*3), and in the POR gene (rs2302429) on olanzapine serum concentrations and the clinical outcome. Ninety-eight white inpatients who received olanzapine as part of their treatment for at least 4 weeks were included in the retrospective investigation. Moreover, a sample of 209 inpatients receiving olanzapine or clozapine was built to investigate the influence of the relevant polymorphisms CYP1A2*1F, *1D, and CYP1A2 inducers on the clinical outcome. Carriers of the delT-allele (*1D) developed significantly higher dose-corrected olanzapine serum concentrations (analysis of covariance; P < 0.001, delT + delTdelT: 3.1, TT: 1.6 ng·mL·mg, adjusted model including the confounding factors age, sex, baseline weight, CYP1A2*1F genotype, and concomitant CYP1A2 inducers). Moreover, the CYP1A2*1F (AA) genotype also revealed a significant impact on olanzapine serum concentrations according to the analysis of covariance model (P = 0.028; CC + CA: 2.05, AA: 1.44 ng·mL·mg). The other polymorphisms studied revealed no significant influence. Regarding response and adverse effects, a higher increase of weight could be observed in schizophrenic Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005). We, for the first time, identified a significant influence of polymorphisms in CYP1A2 in combination with CYP1A2 inducer status on the clinical outcome. Therefore, genotyping for CYP1A2*1D and *1F may be a useful tool for dose optimization and identification of high-risk patients. Further and larger studies are needed before genotype-based dosage recommendations can help patients treated with CYP1A2 metabolized drugs.

No influence of CYP3A43 rs472660G&gt;A on steady-state serum olanzapine concentrations in White psychiatric patients

The potential involvement of CYP3A43 in systemic olanzapine (OLA) metabolism has been suggested by one reported association between the intronic polymorphism CYP3A43 rs472660G>A and OLA clearance in 235 White and African-American patients. Trough plasma OLA concentrations in AA carriers were predicted on average 48% lower than in GG carriers. In the current study, we evaluated this finding by genotyping 374 White psychiatric patients on long-term OLA treatment. No significant difference in dose-adjusted trough serum OLA concentrations was observed between the seven AA carriers identified and the other two genotypes, without (P=0.6) or with (P=0.23) adjustment for additional covariates previously known to influence systemic OLA exposure. Because of the low prevalence of the rs472660 AA genotype in White populations (2%), larger study cohorts are needed for future association confirmation. Overall, CYP3A43 rs472660 is not likely to be a major contributor towards variability in systemic OLA exposure among White patients.

Influence of polymorphism in the CYP1A2, the UGT1A4 and the POR gene on olanzapine serum concentrations and clinical outcome

Olanzapine is one of the most widely prescribed antipsychotic drugs. Large interindividual variations of serum concentration have been documented. Differences in activity of drug metabolizing enzymes may substantially contribute to these variations. Genotyping for mutations influencing enzyme activity may be useful for dose optimization and identification of high risk patients. Therefore, we investigated the influence of polymorphisms in the CYP1A2 gene (*1D,*1F), the UGT1A4 gene (*3) and in the POR gene (rs2302429) on olanzapine serum concentrations and clinical outcome in a naturalistic study with 98 Caucasian inpatients. Our results for the first time clearly indicate that carriers of the delT-allele develop significantly higher dose corrected olanzapine serum concentrations (heterozygous, n = 5, +65%, homozygous, n = 3, +115%), independent of the confounding factors age, sex, baseline weight and concomitant CYP1A2 inducers (ANCOVA, p = 0.004). The other genotypes studied revealed no significant influence on olanzapine serum concentrations. For clinical outcome only the CYP1A2*1D polymorphism indicated a significant correlation for adverse drug reactions (r2= 0.478, p = 0.020). This effect was found despite the majority (98%) of patients displayed concentrations in or below the therapeutic range (20 – 80 ng/mL) which was probably due to dose optimization following TDM. Further studies are needed before genotype-based dosage may be recommended for clinical use in olanzapine therapy.

The possibility that requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia

We examined clinical characteristics including serum olanzapine concentrations for acute schizophrenia patients who required above conventional doses. We performed a rater-blinded, randomized clinical trial in 12 psychiatric emergency sites. Eligible patients were 18–64 years old and met diagnostic criteria for schizophrenia, acute schizophrenia-like psychotic disorder, or schizoaffective disorder. A total of 42 patients were randomly assigned by means of sealed envelopes to receive risperidone (3–12mg/day; n=20) and olanzapine (10–40mg/day; n=22), with follow-up at 8 weeks. The Negative score of the Positive and Negative Syndrome Scale was significantly higher in patients who required high doses than in patients who responded to conventional doses. Serum olanzapine concentrations at the time of oral 20mg/day could be obtained from 5 out of 7 patients who subsequently required high-dose olanzapine. All values were more than 30ng/mL after 11–16h from dosing to sample collection, and the mean value was 47.876 (S.D. 21.546) ng/mL. Such concentrations are appropriate with respect to a therapeutic range of 20–50ng/mL. The present study has shown evidence that the reason for requiring high-dose olanzapine cannot be explained by pharmacokinetics in the treatment of acute-phase schizophrenia.

Pharmacogenetics of Olanzapine Metabolism

The pharmacokinetics of the atypical antipsychotic, olanzapine, display large interindividual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need for individualized dosing in order to avoid concentration-dependent adverse effects or therapeutic failure. Genetically determined differences in olanzapine metabolism represent a less studied source of variability in comparison to environmental and physiological factors. In this review, we summarize available in vitro and in vivo data addressing the influence of polymorphisms in drug-metabolizing enzymes on olanzapine serum exposure. The polymorphic CYP2D6 enzyme appears to have no significant influence on olanzapine steady-state serum concentrations. The formation of the various olanzapine metabolites is influenced by polymorphisms in the genes coding for CYP1A2, CYP1A expression regulator AHR, UGT1A4 and UGT2B10, as well as FMO3. An impact on steady-state olanzapine serum concentrations has been suggested for variants of CYP1A2 and UGT1A4, with somewhat conflicting findings. The potential involvement of FMO1 and CYP3A43 in olanzapine disposition has also been suggested but needs future validation.

Valproic Acid Significantly Lowers Serum Concentrations of Olanzapine—An Interaction Effect Comparable With Smoking

Preliminary reports have indicated that valproic acid (VPA) reduces serum concentrations of olanzapine (OLZ). The aim of this study was to investigate the impact of VPA and other antiepileptic drugs (AEDs) on serum concentrations of OLZ and 3 of its major metabolites in a large-scale material of therapeutic drug monitoring samples. OLZ-treated patients were stratified into subgroups according to coadministration of various AEDs, that is, lamotrigine (LTG; 110 patients/153 samples), VPA (92/166), LTG + VPA (7/12), carbamazepine (CBZ) (8/8), oxcarbazepine (2/3), gabapentin (3/4), levetiracetam (2/3), and topiramate (2/2). A control group treated with OLZ without AEDs was also included (205/247). Dose-adjusted serum concentrations (C:D ratios) of OLZ and its major metabolites (N-desmethyl, N-oxide, and 10-N-glucuronide) were compared between AED subgroups and controls, using linear mixed model analyses with age, gender, and cigarette smoking as covariates. Significantly lower OLZ C:D ratios were found in patients comedicated with VPA (-32%, P < 0.001), VPA + LTG (-31%, P < 0.01), and CBZ (-50%, P < 0.001), compared with controls. The 10-N-glucuronide concentration was significantly lower in patients comedicated with VPA (-26%, P < 0.001), whereas CBZ significantly lowered N-desmethyl (-42%, P = 0.001) and N-oxide (-52%, P < 0.001) metabolite concentrations. C:D ratios of OLZ and metabolites were not significantly affected by comedication with LTG or any of the other AEDs. All covariates were significant determinants of OLZ C:D ratio, that is, age 60 years or above +35% (P < 0.001), female gender +11% (P < 0.01) and smoking -32% (P < 0.001). Concurrent use of VPA significantly decreases serum concentrations of OLZ to an extent comparable with smoking. The mechanism behind the interaction could not be derived from the results of this study.

P-1109 - Synergistic effect of some psychopharmacs may lead to an side effect

To show that a combination of psychopharmacotherapy can result in unwanted side effect. We are presenting a 31-year-old patient addmitted to the hospital with diagnosis of a Acute stress reaction due to divorce. Before hospitalization, the patient was in occesional psychiatric treatment because of Anorexia Nervosa on Axis I, and with Borderline personality disorder on Axis II. The pre-hospital pharmacological treatment were consisted of olanzapine, diazepam and fluvoxamine.Upon addmitence the patient was restless and in persistent moving and diagnosis of akathisia was established. In the mental status dominated depressive ideas, listless. After addmission to the hospital, to the pharmacotherapy mentioned earlier were added lamotrigine as a mood stabilizer,and propranolol for akathisia, and the dose of fluvoxamine was reduced. After four days of hospitalization (the patient insists on a discharge from the hospital) was succeeded partially to regulate sleep, but there were still present early-morning awakening, appetite was slightly better, there was no loss of weight. Patient was less intrapsychic tense. Depressive ideas were paler but present. Symptoms of akathisia were reduced. Considering that the patient was treated with fluvoxamine and olanzapine, we believe that their synergistic effect was responsible for the occurrence of akathisia. Although the antipsychotic alone can have this side effect,in combination with fluvoxamine these side effect may intensify. Specifically fluvoxamine is an inhibitor CY P1A2. This cytochrome is responsible for the metabolic pathway of olanzapine,so when using fluvoxamine may increase serum concentrations of olanzapine, which may result in the appearance of akathisia.

The effect of ethinylestradiol‐containing contraceptives on the serum concentration of olanzapine and N‐desmethyl olanzapine

To investigate the potential interaction between olanzapine, a CYP1A2 substrate, and ethinylestradiol-containing contraceptives (ECC). The study was carried out at a routine therapeutic drug monitoring service. To identify patients who were co-administered ECC or other contraceptives, a questionnaire was sent to the physician who ordered serum monitoring of olanzapine for women aged 18-40 years during an 18 month period. The physicians were asked to provide information about contraceptive use and smoking habits. When questionnaires were returned by the physicians, the respective serum concentration data were included in the analysis. Patients were stratified into users of ECC, progestogen-based contraceptives (PBC) or no contraceptives. Dose-adjusted serum concentrations of olanzapine and the metabolite N-desmethyl olanzapine were compared between the subgroups. A total of 149 patients were included in the study (10 ECC users and 10 PBC users). In users of ECC, we found no differences in serum concentrations of olanzapine, but significantly lower concentrations of the CYP1A2-mediated metabolite N-desmethyl olanzapine compared with users of PBC (P = 0.019) and non-contraceptive users (P = 0.012). The present study confirms that ECC exhibit CYP1A2-inhibitory properties in terms of significantly lower exposure of N-desmethyl olanzapine. However, the inhibition does not provide clinically relevant changes in serum concentrations of olanzapine.

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms.

Are Weight Gain and Metabolic Side Effects of Atypical Antipsychotics Dose Dependent?

Numerous publications have provided evidence for clinically important metabolic adverse effects of antipsychotics, but there is no systematic evaluation as to whether weight gain and other metabolic changes are dose dependent. This review of the available literature aimed to explore a possible relationship between dosage of second-generation antipsychotics (SGAs) and the degree of metabolic side effects. A literature review was conducted in 3 steps: (1) Articles published between 1975 and 2004 were identified on the basis of the bibliography of an extensive review of the metabolic effects of SGAs. (2) Articles published between 2004 and 2008 were identified by a PubMed search with the keywords weight gain, metabolic, glucose, insulin, and lipid AND dose combined with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, and ziprasidone. (3) A hand search was conducted based on the bibliography of the identified articles. All studies that provided information on metabolic side-effects in different dose ranges were selected. Data extraction was carried out independently by 2 observers. Preliminary evidence suggests a dose-response relationship between clozapine and olanzapine serum concentrations and metabolic outcomes, although the association between administered daily dose and metabolic outcomes is not clear. Data are controversial with regard to risperidone, and no study has as yet assessed risperidone serum concentrations in association with metabolic outcomes. For the other SGAs, there was little evidence to suggest a dose-response relationship, although, in these agents also, no assessment of serum concentrations was conducted. The finding that metabolic complications may be associated with clozapine and olanzapine plasma concentrations provides further evidence for a causal contribution to the metabolic disturbances observed with these agents. Further well-designed, prospective studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.

Hormonal Markers of Metabolic Dysregulation in Patients With Severe Mental Disorders After Olanzapine Treatment Under Real-Life Conditions

Dyslipidemia independent of body mass has previously been reported in humans after antipsychotic treatment. The present study investigated the levels of several metabolic regulatory hormones in psychiatric outpatients treated with different antipsychotics under real-life conditions. The study included cross-sectional data from 234 subjects on stable monotherapy with any of the following: olanzapine (n = 72), any other antipsychotic (n = 80), or no medications (n = 82). Groups were well matched for sex, body mass index (BMI), ethnicity, and smoking. After adjustment for differences in age and illness duration, groups were compared for the insulin resistance index (homeostatic model assessment of insulin resistance) and fasting concentrations of glucose, lipids, insulin, sex hormone-binding globulin (SHBG), adiponectin, leptin, and cortisol. Correlations were examined between serum olanzapine and hormonal levels, and between leptin concentrations and BMI in both sexes. Significant intergroup differences in concentrations of insulin (P = 0.025), SHBG (P = 0.001), adiponectin (P = 0.017), and cortisol (P = 0.003) but no significant difference for homeostatic model assessment of insulin resistance (P = 0.051) were found, independent of body mass. Olanzapine-treated subjects had the highest insulin concentrations and the lowest SHBG, adiponectin, and cortisol concentrations. Olanzapine-treated female subjects had significantly higher leptin (P = 0.005) and lower SHBG (P = 0.023) concentrations than other subjects. In female subjects, serum olanzapine concentrations were correlated with hormonal levels, and a significant proportion of olanzapine-treated female subjects had abnormal correlations between serum leptin levels and BMI. Alterations in several interrelated metabolic hormonal markers were associated with olanzapine treatment, independent of body mass, particularly in female subjects.

Large Intraindividual Variability of Olanzapine Serum Concentrations in Adolescent Patients

Olanzapine (OLZ) is a widely used antipsychotic substance. Therapeutic drug monitoring (TDM) of OLZ is recommended but is based on known reference ranges derived from intraindividual and interindividual variability measurements. There have been few studies on the interindividual variability of OLZ serum concentrations in adolescents, and no data on intraindividual variability are available. This study explored the intraindividual variability of OLZ serum concentrations in 85 patients attending a child and adolescent psychiatric hospital (age at first assessment: mean +/- SD, 16.7 +/- 2.0; range, 10.3-20.6 years; 54 male, 31 female). A total of 577 steady-state OLZ serum concentrations (2 to 24 measurements per patient; mean, 6.8, and SD, +/-5.4) were measured, using high-performance liquid chromatography (HPLC). Intraindividual variability of dose-corrected OLZ serum concentrations was 1.04- to 10.7-fold. The intraindividual variabilities of the metabolites OLZ N-desmethyl (DMO) and OLZ 2-hydroxymethyl (2OH) were 1.08- to 83.2-fold and 1.0- to 47-fold, respectively. Intraindividual variability of OLZ (DMO; 2OH) serum concentration accounted for 47% (89.8%, 74.9%) of total variance. OLZ daily dose, number of co-medications, body mass index (BMI), age, and post-dose interval had a significant influence on the intraindividual variability of dose-corrected OLZ serum concentrations (all P < 0.001). The serum concentrations of OLZ and OLZ metabolites in adolescents show high intraindividual variability, potentially limiting the value of TDM. It is recommended that repeated serum concentration measurements are made in individuals treated with OLZ, in order to obtain a more precise estimate of the intraindividual variability of serum concentrations.

Prolonged toxicity after massive olanzapine overdose: two cases with confirmatory laboratory data

Olanzapine is a second-generation atypical antipsychotic that is increasingly used in preference to older antipsychotic agents. Limited data is available concerning the toxic effects of olanzapine after deliberate overdose. Two patients presented to our institution after massive olanzapine ingestion, and required prolonged ventilatory support due to the development of coma and respiratory depression. Serum olanzapine concentrations were orders of magnitude higher than those associated with therapeutic doses, and remained elevated for several days after ingestion. Both patients made a full recovery with only supportive care, despite having initial serum drug concentrations > 2500 microg/l. These reports indicate the potential for olanzapine ingestion to cause coma that may persist for several days after overdose.

Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30–35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2–1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans.