The association of weight gain and olanzapine plasma concentrations

Atypical antipsychotics, including olanzapine, have been associated with clinically significant weight gain in some patients. The purpose of this study was to determine if weight gain was associated with increasing plasma concentrations during olanzapine treatment in subjects with schizophrenia. This study included 39 acutely ill subjects with schizophrenia, schizoaffective disorder, or schizophreniform disorder (DSM-III-R or DSM-IV). Assessments included the Brief Psychiatric Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a dose of 5 to 20 mg/d for 2 to 6 weeks. A 24-hour plasma concentration was obtained after 6 weeks of treatment. Analysis using a receiver operator characteristic curve identified a threshold dose-weighted plasma concentration of 20.6 ng/mL being associated with an increased likelihood of clinically significant weight gain (> or =7% baseline weight) during olanzapine treatment. The associations remained significant after adjusting for age, gender, baseline body mass index, baseline symptom severity, and symptom improvement (OR = 10.1; 95% CI, 1.3-75.0; P = 0.024). Similar analysis determined that a threshold olanzapine dose of 13.3 mg/d was associated with > or =7% weight gain. However, after adjusting for potential confounders, the results did not remain significant. The association of weight gain with plasma concentrations during treatment with olanzapine may support the utilization of plasma drug concentration as a marker for antipsychotic-induced weight gain in the treatment of schizophrenia.     

奥氮平对器质性精神障碍的疗效分析

目的：了解奥氮平对器质性精神障碍的治疗作用及安全性.方法：对36例器质性精神障碍的患者用奥氮平1.7～10 mg•d 1治疗1周,按用药前后的兴奋因子(BPRS)、临床总体印象量表(CGI SI)、睡眠时间、心电图、肝肾功能进行自身t检验.结果：除1例脑炎患者无效外,兴奋因子(BPRS)、CGI SI测评的一同减分率＞75% 1例、50%～75% 16例、25%～ 18例,显效率47.2%,总有效率97.2%.CGI SI、睡眠时间、医疗保健评分前后比较差异有极显著性(P＜0.01)、BPRS(兴奋因子)减分率≥40%,而不良反应量表(TESS)、心电图、肝肾功能治疗前、后差异无显著性(P＞0.05).结论：奥氮平对器质性精神障碍的治疗有效,且安全性较高.     

Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder

The aim of this study was to estimate the long-term effectiveness of olanzapine as adjunctive therapy in patients with bipolar disorder who exhibited an inadequate response to mood stabilizers. Twenty-three Research Diagnostic Criteria (RDC) patients with bipolar I and II were assessed by means of the Schedule for Affective Disorders and Schizophrenia and entered if they gave their consent to participate. All of them had experienced frequent relapses, residual subsyndromal symptoms, and inadequate responses to other drugs, such as lithium, valproate, or carbamazepine. While maintaining other drugs, they all received open-label, increasing doses of olanzapine, until achieving clinical response. Other drugs were maintained. The patients were assessed several consecutive times from baseline to the endpoint with the Clinical Global Impressions (CGI) scale for use in bipolar illness. Records of recurrences, hospitalizations, and side effects were also collected. The last-observation-carried-forward analysis showed that there was a significant reduction of CGI scores after the introduction of olanzapine, either in manic symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p = 0.0003). The most frequent adverse events were somnolence (17%) and weight gain (13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1 mg/day. Olanzapine may be a useful medication for the long-term adjunctive treatment of patients with bipolar disorder who exhibit a poor response to mood stabilizers, such as lithium, valproate, or carbamazepine. These results suggest mood-stablizing properties of olanzapine.     

Olanzapine pharmacokinetics in pediatric and adolescent inpatients with childhood-onset schizophrenia

Well-designed studies investigating how pediatric or adolescent patients with mental disorders respond to and metabolize the newer antipsychotic drugs are practically nonexistent. Without such data, clinicians have difficulty designing appropriate dosage regimens for patients in these age groups. The results from a study of olanzapine pharmacokinetics in children and adolescents are described. Eight inpatients (ages 10-18 years) with treatment-resistant childhood-onset schizophrenia received olanzapine (2.5-20 mg/day) over 8 weeks. Blood samples, collected during dose titration and at a steady state provided pharmacokinetic data. The final evaluation (week 8) included extensive sampling for 36 hours after a 20-mg dose. Olanzapine concentrations in these eight pediatric patients were of the same magnitude as those for nonsmoking adult patients with schizophrenia but may be as much as twice the typical olanzapine concentrations in patients with schizophrenia who smoke. Olanzapine pharmacokinetic evaluation gave an apparent mean oral clearance of 9.6 +/- 2.4 L/hr and a mean elimination half-life of 37.2 +/- 5.1 hours in these young patients. The determination of the initial olanzapine dose for adolescent patients should take into consideration factors such as the patient's size. In general, however, the usual dose recommendation of 5 to 10 mg once daily with a target dose of 10 mg/day is likely a good clinical guideline for most adolescent patients on the basis of our pharmacokinetics results.     

Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.     

Treatment of severely psychotic inpatients with schizophrenia: olanzapine versus other antipsychotic drugs

Nine hundred and ten schizophrenic inpatients suffering from acute psychotic episodes were included in a naturalistic study. Patients were prescribed treatment with olanzapine (OLZ) or with typical antipsychotic (TYP) drugs. Patients receiving another atypical antipsychotic were excluded. Of the whole sample, 483 (53.4%) were treated with olanzapine and 421 (46.6%) with typical antipsychotics. Three specific subpopulations of greater severity were defined: patients with prominent psychotic symptoms, agitated patients, and patients initially treated with intramuscular (i.m.) medication because of their acute clinical condition. Severity of illness was assessed using the Clinical Global Impression (CGI) scale for severity, the Brief Psychiatric Rating Scale (BPRS) and the Nursing Observational Scale for Inpatient Evaluation. Baseline differences were adjusted per data analysis. The mean change from baseline to endpoint of overall symptomatology (total BPRS score) was significantly greater in the olanzapine group compared to the typical antipsychotic-treated group, both in the sample of patients with prominent positive symptoms (P < 0.001) and in the sample of agitated patients (P =0.015). Significant differences were also found in BPRS positive scores, BPRS negative scores and CGI scores in these two populations. Patients who had received previous i.m. drugs showed no statistically significant differences in symptomatic improvement between both treatments groups, except for a more favourable response of BPRS negative subscores in the olanzapine group (P =0.015). The results suggest that olanzapine may be considered as a first line treatment for severely psychotic inpatients with schizophrenia.     

Olanzapine. Pharmacokinetic and pharmacodynamic profile.

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.     

Olanzapine compared to lithium in mania: a double-blind randomized controlled trial

Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.     

Olanzapine treatment of eight adolescent patients with psychosis

Although olanzapine is known as a widely used atypical antipsychotic there have been very few studies about its use in children and adolescents. Eight adolescent patients who were diagnosed as having schizophrenia or schizoaffective disorder, and treated with olanzapine are reported in this case series. The patients were followed-up for 17.5 weeks in the range 4-26 weeks. According to the CGI improvement assessment at the end of the follow-up period, three of eight cases were rated as very much or much improved, three as minimally improved and two as not improved. Olanzapine was well tolerated by the adolescents in this case series except for weight gain. Our results suggest that olanzapine may be an effective antipsychotic for some psychotic adolescents and during olanzapine trials weight gain. Should be monitored.     

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Effects of age and sex on olanzapine plasma concentrations

Age and sex may influence both efficacy and side effects of second-generation antipsychotics. Women and elderly patients tend to have a higher prevalence for several side effects. Higher plasma levels in these groups of patients may be one reason. We studied the hypothesis that steady-state olanzapine plasma concentrations depend on age and sex. Sixty-seven inpatients on stable olanzapine dose were referred to routine therapeutic drug monitoring of olanzapine. Plasma levels were determined by high-performance liquid chromatography with electrochemical detection. Obtained data were then analyzed by analysis of covariance. Olanzapine plasma levels showed a marked sex difference with significantly higher mean concentrations in female patients (adjusted mean concentrations, 18.5 ng/mL for men and 31.7 ng/mL for women; P = 0.003). On average, the weight-corrected concentration/dose ratios shown by women were 33.5% higher than those shown by men, irrespective of age. Regarding the effect of age, weight-corrected concentration/dose ratios increased by an average of 9.4% per decade of life. All results were adjusted for smoking. Comedication did not significantly influence these results. In conclusion, age and sex are important variables to consider when prescribing olanzapine for women and in the elderly.     

Olanzapine therapy in elderly patients with schizophrenia.

Compared to young adults, elderly individuals with schizophrenia may have a six-fold increase in the prevalence of tardive dyskinesia. The atypical antipsychotic, olanzapine, may offer particular benefit for this population. This is a prospective, open-label trial of olanzapine therapy in elderly schizophrenic patients. Individuals aged 65 years or older with DSM-IV schizophrenia and a history of neuroleptic responsiveness were given olanzapine as an add-on therapy to their existing medication regimen. Other antipsychotic medication was gradually discontinued. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS). Abnormal movements were assessed with the Simpson-Angus Neurological Rating Scale (SA), the Barnes Akathisia Scale (BA), and the Abnormal Involuntary Movement Scale (AIMS). Cognitive status was assessed with the Mini-Mental State Evaluation (MMSE). Twenty-seven individuals received a mean dosage of 8.4 (+/- 4.2) mg/day. Mean age of the group was 70.6 (+/- 4.1) with a range of 65 to 80 years. Patients had a mean of 1.6 (+/- 1.4) significant comorbid medical illnesses. Change in BPRS scores were not significant for the group as a whole, whereas SA score change was substantial, with a pre-treatment mean of 13.7 (+/- 10.3), compared with a mean of 4.8 (+/- 4.1) for those treated with olanzapine (p < .0002). Changes in AIMS and BA score were also significant on olanzapine therapy. MMSE score change was not statistically significant. Comorbid medical illnesses were not adversely affected. Olanzapine is an effective antipsychotic medication in older adults with schizophrenia, and is associated with significant improvement in extrapyramidal side effects. Implications for effect on cognitive status should be explored in larger, long-term trials.     

Olanzapine treatment during breast feeding: a case report

Postpartum psychosis constitutes a severe complication that entails risk for both mother and child. Little is known about the use of olanzapine in the treatment of postpartum psychosis. In previous studies, it has been reported on mothers receiving relatively low doses of olanzapine. We report a 38-year-old patient who was admitted to the hospital for an acute psychotic exacerbation. She was breast feeding her 5-month-old child, and she wished to continue breast feeding. Olanzapine treatment was started with a daily dosage of 15 mg. The weight-corrected maternal dose was 270 mug/kg. The olanzapine concentration in the mother's plasma was 24 ng/mL. The analysis of olanzapine in breast milk applying two different high-performance liquid chromatography procedures revealed similar results: 12.2 ng/g without and 11.5 ng/g with additional hydrochloric acid extraction, respectively. In addition, breast milk of an unmedicated mother was used for establishing the analytical procedure so that the validity of the results was better confirmed. The milk-plasma ratio arising from our data was 0.5, and the relative infant dose was 0.3%. The olanzapine concentration was below the limit of detection (<5 ng/mL) in the infant's plasma sample. No adverse effects were noticed, and the mother experienced a rapid improvement in her psychopathology during her hospital stay. In future studies, long-term follow-up of both mother and child would be useful.     

奥氮平的国内临床应用概况

目的：总结奥氮平在国内的临床应用情况。方法：汇总国内公开发表的9种杂志中刊登的临床应用文献27篇，综合其治疗方法、疗效和不良反应等情况。结果：经PANSS，BPRS，SANS，SAPS，和TESS等量表测试和临床观察，认为奥氮平对治疗精神分裂症有相当的疗效；临床疗效等同或优于氯氮平、利培酮和舒必利；对精神分裂症的思维障碍和敌对猜疑疗效显著；对精神分裂症的阳性症状、阴性症状有效。不良反应小，安全性高，患者依从性好。结论：奥氮平可选用于精神分裂症等精神病的治疗，是目前比较满意的抗精神病药物。     

Olanzapine pamoate for the treatment of schizophrenia

Introduction: Nonadherence is still a major problem in the long-term treatment of schizophrenia. Long-acting injectable or depot atypical antipsychotics are associated with better maintenance. Olanzapine pamoate, available since 2010, is the second depot atypical antipsychotic. Areas covered: This review covers data on the efficacy and tolerability/safety of olanzapine pamoate, the long-acting formulation of the atypical antipsychotic olanzapine. Administered as a pamoate salt, it has an elimination half-life of 30 days, allowing a 2- or 4-week injection interval. Antipsychotic efficacy was documented in an 8-week trial in 404 acutely ill schizophrenia patients with maintenance therapy in a 24-week trial in 1065 chronic patients. The side-effect profile is comparable to that of oral olanzapine. The most relevant adverse event is the post-injection delirium/sedation syndrome, occurring at a rate of 0.07% of injections or 1.4% of patients. It requires administration by qualified personnel in settings where a post-injection observation period for 3 h by medical personnel is available. Expert opinion: Olanzapine pamoate is an efficacious formulation, particularly for patients with a history of good response to oral olanzapine and doubtful adherence. Psychiatrists should reconsider their negative attitudes toward long-acting or depot antipsychotics and should offer this administration to the majority of patients, not only to a negatively selected population.     

Amantadine for weight gain associated with olanzapine treatment.

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.     

Plasma olanzapine in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1999-2009

Olanzapine therapeutic drug monitoring (TDM) is the measurement of plasma olanzapine to assess adherence and guide dosage. We have audited data from an olanzapine TDM service, 1999-2009. Multiple linear regression analysis was conducted to investigate the contribution of dose, age, sex, body weight, and smoking status to the plasma olanzapine concentration. There were 5856 samples from 3207 patients. The prescribed olanzapine dosage was 2.5 to 95 mg/d. No olanzapine was detected in 6% of samples. For olanzapine dosages of 2.5 to 20 mg/d, only 35% of results were within a suggested target range of 20 to 39 ng/mL. At doses above 20 mg/d, 30% to 59% of results were 60 ng/mL or greater depending on dose band. In patients aged 17 years or younger (92 samples), median plasma olanzapine was higher than that in adult patients at almost all olanzapine doses. Multiple linear regression analysis of results from 627 adults from whom complete data were available showed that dose, smoking status, sex, age, and body weight together explained 24% the variance in plasma olanzapine. Degree of adherence, timing of sample postdose, drug-drug interactions, and pharmacogenetic factors also may have contributed to the observed variance. However, it is clear that female nonsmokers had higher plasma olanzapine concentrations for a given dose than male smokers. Olanzapine TDM is useful in assessing adherence and may have a role in limiting olanzapine dosage to minimize the risk of long-term toxicity.     

Maintenance treatment for schizophrenia with quetiapine

With the majority of current information being derived from short-term clinical trials, the impact of atypical antipsychotics during maintenance treatment of schizophrenia is of considerable interest, although only limited data are available at present. The present report is an analysis of data that are available up to 156 weeks after the start of an open-label extension (OLE) phase of three, double-blind randomized trials in quetiapine-treated patients who responded to an initial 6-week treatment period. The mean daily quetiapine dose (range 150-750 mg) was 439.5 mg for patients included in the brief psychiatric rating scale (BPRS) and 438.5 mg for patients included in the clinical global impression (CGI) analyses. The initial mean acute phase BPRS total score (40.67; n=258) and CGI severity of illness score (4.81; n=259) were reduced at the start of the OLE to 13.94 and 3.00, respectively. After 156 weeks, endpoint scores were 9.04 for BPRS and 2.43 for CGI severity of illness. Although limited by patient attrition, these OLE data suggest that an initial beneficial response with quetiapine treatment can be maintained over a long-term period.     

Olanzapine treatment is associated with reduced high molecular weight adiponectin in serum: a potential mechanism for olanzapine-induced insulin resistance in patients with schizophrenia

Treatment of schizophrenia with olanzapine and other atypical antipsychotic agents is associated with insulin resistance and diabetes mellitus. The mechanism for this is not understood. Adiponectin is an insulin-sensitizing cytokine secreted by adipocytes. It is present in serum in multimers of varying size. Trimers and hexamers are referred to as low molecular weight (LMW) adiponectin. Larger multimers (12-, 18-, and 24-mers) have been designated high molecular weight (HMW) adiponectin and seem responsible for the insulin-sensitizing action of this adipokine. The aim of this study was to examine total adiponectin and LMW and HMW multimers in serum from patients with schizophrenia treated with either olanzapine (n = 9) or other typical antipsychotics (n = 9) and compare results with 16 healthy sex-, body mass index-, and age-matched controls. The effects of olanzapine on adiponectin protein expression and secretion in in vitro-differentiated primary human adipocytes were also examined. Patients receiving olanzapine had significantly lower total serum adiponectin as compared with those on conventional treatment and controls (5.23 +/- 1.53 ng/mL vs. 8.20 +/- 3.77 ng/mL and 8.78 +/- 3.8 ng/mL; P < 0.05 and P < 0.01, respectively). The HMW adiponectin was also reduced in patients on olanzapine as compared with the disease and healthy control groups (1.67 +/- 0.96 ng/mL vs. 3.87 +/- 2.69 ng/mL and 4.07 +/- 3.2 ng/mL; P < 0.05 for both). The LMW adiponectin was not different between patient groups (P = 0.15) but lower in patients on olanzapine as compared with controls (3.56 +/- 0.85 ng/mL vs. 4.70 +/- 1.4 ng/mL; P < 0.05). In vitro, short duration (up to 7 days) olanzapine exposure had no effect on total adiponectin expression or multimer composition of secreted protein. In summary, this study demonstrates a correlation between olanzapine treatment and reduced serum adiponectin, particularly HMW multimers. This may not be a direct effect of olanzapine on adipocyte expression or secretion of adiponectin. These observations provide insights into possible mechanisms for the association between olanzapine treatment and insulin resistance.     

Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia. Results from a randomised clinical trial.

OBJECTIVE: The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia. DESIGN AND SETTING: Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data. PATIENTS AND PARTICIPANTS: 817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS) > or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy. INTERVENTIONS: Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase. MAIN OUTCOME MEASURES AND RESULTS: After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p < 0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p < 0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs. CONCLUSIONS: In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.