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PubMed2000

Olanzapine for schizophrenia.

BACKGROUND: Olanzapine is an atypical antipsychotic that is reported to be effective without producing the disabling extrapyramidal side effects associated with the older, typical antipsychotic drugs. OBJECTIVES: To determine the clinical effects and safety of olanzapine as compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and schizophreniform psychoses. SEARCH STRATEGY: The reviewers undertook electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 2, 1999), The Cochrane Schizophrenia Group's Register (September 1999), EMBASE (1980-1999), MEDLINE (1966-1999), and PsycLIT (1974-1999). References of all identified studies were searched for further trials, and the reviewers contacted relevant pharmaceutical companies and authors of trials. SELECTION CRITERIA: All randomised clinical trials comparing olanzapine to placebo or any antipsychotic treatment for those with schizophrenia or schizophreniform psychoses. DATA COLLECTION AND ANALYSIS: Data were independently extracted. For homogeneous dichotomous data the random effects relative risk (RR), the 95% confidence intervals (CI) and, where appropriate, the number needed to treat (NNT) were calculated on an intention-to-treat basis. For continuous data the reviewers calculated weighted mean differences. MAIN RESULTS: Twenty trials are included. Attrition from olanzapine versus placebo studies was so great (olanzapine - 61%, placebo - 73% by six weeks, RR 0.85 CI 0. 7-0.98, NNT 8 CI 5-40) that interpretation of results is problematic. Olanzapine appeared superior to placebo at six weeks for the outcome of 'no important clinical response' (RR 0.88 CI 0.8-0.98, NNT 8 CI 5-27), but trial data regarding negative symptoms are equivocal for this comparison. Dizziness and dry mouth were more common in the olanzapine-treated group, and, although not statistically significant, the olanzapine group gained more weight. Data from several small trials are incomplete; but, for the short term outcome of 'no important clinical response', olanzapine seem as effective as typical antipsychotics (n=2778, RR 0.9 CI 0.76-1.06). Brief Psychiatric Rating Scale (BPRS) data tended to be equivocal but Positive and Negative Syndrome Scale (PANSS) rating of total score and negative and positive symptom sub-scores favoured olanzapine. With high attrition in both groups (olanzapine - 36%, typical drug - 49% by 6 weeks, n=2738, RR 0.85 CI 0.66-1.1; olanzapine - 83%, typical drug - 90% by 1 year, n=2738, RR 0.9 CI 0. 86-1.02), the assumptions included in all continuous data are considerable. Participants allocated olanzapine experienced fewer extrapyramidal side effects than people given haloperidol. Weight change data for the short term are not conclusive (n=2455, WMD 0.8kg CI -0.6-2.2) but the three to 12 month results suggest an average gain of four kilograms (n=233, WMD 4 CI 0.3-7.8). It is difficult to distinguish between olanzapine and other atypical drugs, although it may cause fewer extrapyramidal side effects than risperidone (n=339, RR 0.6 CI 0.4-0.9, NNH 8 CI 4-29). Olanzapine did cause more weight gain than its comparators but current data are not statistically significant (3-12 months, n=535, WMD 2.2kg CI -0.6-5). One study (n=180) found no clear differences between olanzapine and clozapine for people with treatment-resistant illness. REVIEWER'S CONCLUSIONS: For people with schizophrenia olanzapine may offer antipsychotic efficacy with fewer extrapyramidal side effects than typical drugs but more weight gain. The large proportions of participants leaving the studies early, in the large multi-centre trials makes it difficult to draw firm conclusions on clinical effects. Large, long-term randomised trials with participants, interventions and primary outcomes that are familiar to those wishing to help those with schizophrenia are long overdue.

Antipsychotic Agents↗
PubMed2003

Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.

BACKGROUND: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. OBJECTIVE: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. DESIGN: Double-blind, 8-week, randomized controlled trial. SETTING: Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86). MAIN OUTCOME MEASURE: Changes in MADRS total scores using mixed-effects model repeated-measures analyses. RESULTS: During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and > or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea. CONCLUSIONS: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

Adult↗
PubMed2001

Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial.

Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations > or = 9.3 ng/mL (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours (11.7 +/- 1.7 hours) after the last dose was administered. Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study. Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a > or = 20% reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of < or = 3 or a final BPRS score of < or = 35. The final ROC analysis included data from 84 patients and suggested an olanzapine concentration > or = 23.2 ng/mL to be a predictor of therapeutic response. Fifty-two percent of patients with 12-hour olanzapine concentrations > or = 23.2 ng/mL responded, whereas only 25% of patients with concentrations < 23.2 ng/mL responded. Furthermore, an olanzapine concentration > or = 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (> or = 20% decrease and endpoint CGI < or = 3). Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of > 23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.

Acute-Phase Reaction↗
PubMed2006

A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression.

OBJECTIVE: Olanzapine-fluoxetine combination has shown efficacy in the acute treatment of depressive episodes in patients with bipolar I disorder. The present analyses examined the efficacy and safety of longer term treatment with olanzapine-fluoxetine combination or olanzapine monotherapy in a 6-month open-label extension study. METHOD: 376 patients with DSM-IV bipolar I disorder, depressed, who completed an acute trial entered the open-label study and received 1 week of olanzapine monotherapy (5-20 mg/day). At all subsequent visits, patients could choose between olanzapine monotherapy or olanzapine-fluoxetine combination (6/25, 6/50, or 12/50 mg/day). Three treatment groups were defined retrospectively according to the medication course taken from week 1: olanzapine, olanzapine-fluoxetine combination, or switched. The efficacy measures were the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Bipolar Version, and Young Mania Rating Scale. The study was conducted from July 2000 to May 2002. RESULTS: Among patients who started in remission, MADRS total scores did not change significantly from baseline to endpoint in the olanzapine-fluoxetine combination (0.8) or olanzapine (0.3) groups, but increased slightly in the switched (2.3, p = .02) group. For patients who started in nonremission, MADRS total scores decreased significantly in all groups (olanzapine-fluoxetine combination: -5.7, p = .001; olanzapine: -11.6, p = .004; switched: -6.4, p = .015). The majority of patients who entered the study in nonremission achieved remission (MADRS total score < or = 12) during the trial (olanzapine-fluoxetine combination: 66.7%, olanzapine: 64.7%, switched: 62.5%). The overall rate of depressive relapse was 27.4%, and the overall incidence of mania emergence was 5.9%. CONCLUSIONS: The present findings suggest that long-term treatment with olanzapine-fluoxetine combination may be a useful option for the management of depressive symptoms and carries a low risk of mania emergence.

Adult↗
PubMed2004

Effect of repeated treatment with olanzapine or olanzapine plus fluoxetine on tyrosine hydroxylase in the rat locus coeruleus.

Repeated treatment of rats with antidepressant drugs down-regulates tyrosine hydroxylase (TH) in the locus coeruleus (LC). Using this effect as a model system, this study evaluated the antidepressant potential of the atypical antipsychotic drug, olanzapine. In an initial study, rats were treated i.p. with saline, olanzapine (3 mg/kg), or imipramine (15 mg/kg) once daily for 18 d. Three additional groups of rats received the same treatments that were overlapped with reserpine administration (0.5 mg/kg.d for 21 d). In a second study, groups of rats were treated twice daily with saline, olanzapine (5 mg/kg.d), fluoxetine (15 mg/kg.d), or fluoxetine (15 mg/kg.d) plus olanzapine (5 mg/kg.d) for 1, 6, 12 and 18 d. In the initial study, imipramine produced a 45% reduction in LC TH levels, while olanzapine had no effect. In reserpinized rats, olanzapine exhibited an action that was opposite to that of imipramine, although this effect did not reach statistical significance. In the second study, olanzapine treatment alone or in combination with fluoxetine up-regulated TH in the LC, while fluoxetine alone had no effect. When fluoxetine was co-administered, olanzapine-induced increases in LC TH were more robust and occurred earlier in the time-course of treatment. Based on this preclinical model alone, olanzapine did not exhibit typical antidepressant properties. The unique effect of olanzapine to elevate LC TH may result from olanzapine-induced increases in LC activity. Such an action may contribute to novel behavioural effects of this atypical antipsychotic drug, including enhanced attention.

Actins↗
PubMed1997

Standard olanzapine versus placebo and ineffective-dose olanzapine in the maintenance treatment of schizophrenia.

OBJECTIVE: Two studies compared the efficacy of standard-dose oral olanzapine (5 to 15 mg a day) with placebo and with ineffective-dose olanzapine (1 mg a day) in maintenance therapy of schizophrenia. METHODS: The studies were 46-week double-blind extensions of multicenter studies that assessed the efficacy of olanzapine in the acute treatment of schizophrenia. Subjects were 120 adults who met DSM-III-R criteria for schizophrenia with an acute exacerbation and who had a minimum score of 24 on the Brief Psychiatric Rating Scale, who had responded to acute therapy (defined as at least a 40 percent reduction in the BPRS score from baseline or a score of 18 or less during up to six weeks of treatment), and who were outpatients at their last acute-phase visit. Relapse was defined as hospitalization for psychopathology. Relapse risk was analyzed using Kaplan-Meier survival analysis and life table analysis. Patients who relapsed were discontinued from the studies. RESULTS: In the first study (N = 58), patients in the standard-dose olanzapine group experienced a significantly lower relapse risk (p = .002) over one year than patients treated with placebo. The estimated one-year risk of relapse with olanzapine was 28.6 percent, compared with 69.9 percent with placebo. Results were similar in the second study (N = 62); patients treated with standard-dose olanzapine had a significantly reduced risk of relapse (p = .018) over one year compared with patients treated with ineffective-dose olanzapine. The estimated one-year risks of relapse were 19.6 percent for standard-dose olanzapine and 45.5 percent for ineffective-dose olanzapine. CONCLUSIONS: Olanzapine is superior to placebo and ineffective-dose olanzapine in the maintenance therapy of schizophrenia.

Acute Disease↗
PubMed1997

Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial.

A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.

Adult↗
PubMed2006

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.

Adipocytes↗
PubMed1999

Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group.

OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group. CONCLUSIONS: The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.

Acute Disease↗
PubMed2006

Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine.

OBJECTIVE: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. METHOD: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization). RESULTS: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). CONCLUSIONS: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.

Acute Disease↗
PubMed2006

A double-blind, randomized trial to evaluate the pharmacokinetics and tolerability of 30 or 40 mg/d oral olanzapine relative to 20 mg/d oral olanzapine in stable psychiatric subjects.

BACKGROUND: Prescription monitoring in the United States suggests that oral olanzapine is prescribed in doses that exceed the approved range of 5 to 20 mg/d. OBJECTIVE: In this double-blind, randomized study, the pharmacokinetics and tolerability of higher-dose (30 or 40 mg/d) olanzapine were examined relative to the highest approved dose (20 mg/d) among non-treatment-resistant patients with psychiatric illnesses. METHODS: After a 10-day period in which all patients were stabilized on 20 mg/d olanzapine, 37 patients with schizophrenia, schizoaffective disorder, or bipolar I disorder were randomized to receive treatment with olanzapine 20 mg/d for 20 days (group A, n=12), 30 mg/d for 10 days followed by 40 mg/d for 10 days (group B, n=11), or 40 mg/d for 20 days (group C, n=14). On days 10, 20, and 30, blood samples were collected before dosing and at 1, 2, 5, 6, 10, 14, 18, and 24 hours after dosing. Plasma olanzapine concentrations were assayed using high-performance liquid chromatography with electrochemical detection. Tolerability was assessed by spontaneously reported treatment-emergent adverse events; changes from baseline in vital signs, electrocardiograms, and standard laboratory test values; incidences of categorically defined treatment-emergent akathisia and parkinsonism; and 2-hour standard oral glucose tolerance tests. RESULTS: Of the 53 subjects who entered the study, 16 were excluded (7 because entry criteria were not met, 6 because of subject's decision, and 3 for other reasons). Subjects were primarily men (group A, 75%; group B, 55%; group C, 79%), approximately 40 years old (mean [SD] age: group A, 40.6 [8.6]; group B, 37.9 [8.6]; group C, 39.4 [9.2] years), and black (group A, 83%; group B, 55%; group C, 64% [the remainder were white]). Mean (SD) baseline weight was 84.0 (17.5) kg for group A, 82.1 (12.0) kg for group B, and 100.9 (23.3) kg for group C. By day 20, dose-proportional increases were observed in plasma olanzapine Cmax,ss and AUC. Geometric mean (percent coefficient of variation) values for groups A, B, and C at day 20 were as follows: Cmax,ss 57.8 (40.2), 75.6 (86.7), and 94.1 (50.2) ng/mL, respectively; and AUC: 997 (38.5), 1220 (88.0), and 1630 (53.9) ng . h/mL, respectively. The most frequently reported adverse events were weight gain (group A, 2/12 [17%]; group B, 3/11 [27%]; group C, 2/14 [14%]) and sedation (group A, 3/12 [25%]; group B, 2/11 [18%]; group C, 2/14 [14%]). Mean (SD) weight gain from baseline to end point was 3.5 (2.81) kg for group A, 3.0 (3.15) kg for group B, and 3.1 (2.22) kg for group C. Changes in glucose tolerance, vital signs, or laboratory parameters did not appear to be dose dependent. During double-blind therapy, 7 subjects experienced akathisia (spontaneously reported, n=3 [group C]; categorically defined, n=3 [group B]; both, n=1 [group C]). Of the subjects with categorically defined akathisia, 2 had a history of akathisia and the other had a score of 1 (questionable) on the Barnes Akathisia Scale at baseline. No cases of parkinsonism were observed at any time. CONCLUSIONS: Among these subjects with psychiatric illnesses, olanzapine at doses of 30 and 40 mg/d displayed a pharmacokinetic profile consistent with that of 20 mg/d. Higher-dose olanzapine exhibited a tolerance profile similar to that of 20 mg/d; however, akathisia may be more likely to occur at higher doses, particularly in subjects with a history of akathisia.

Adult↗
PubMed2004

A study of matrix effects on an LC/MS/MS assay for olanzapine and desmethyl olanzapine.

The purpose of this research project was to investigate potential matrix effects of anticoagulant and lipemia on the response of olanzapine, desmethyl olanzapine, olanzapine-D(3) and desmethyl olanzapine-D(8) in an LC/MS/MS assay. Blank human serum and sodium heparin, sodium citrate, and K(3)EDTA plasma with various degrees of lipemia were fortified with olanzapine, desmethyl olanzapine, olanzapine-D(3) and desmethyl olanzapine-D(8). Six replicates of each sample were extracted using Waters Oasis MCX cartridges and analyzed using electrospray LC/MS/MS. The analytes were separated on a Phenomenex LUNA phenyl hexyl, 2 mm x 50 mm, 5 microm, analytical column and a gradient rising from 2 to 85% mobile phase B. Mobile phase A consisted of acetonitrile-ammonium acetate (20 mM) (52:48 v/v) and mobile phase B was formic acid-acetonitrile (0.1:100 v/v). Ion suppression was investigated through post column infusion experiments. The degree of lipemia of each sample, indicated by turbidity, was ranked into categories from least to greatest and used for statistical analyses. The results from analysis of variance testing indicated that lipemia, anticoagulant and their interaction significantly influenced mass spectral matrix effects and extraction matrix effects. Differential behavior between the analytes and labeled internal standards contributed to variability. The most significant source of variability however, was ion suppression due to co-eluting matrix components.

Anticoagulants↗
PubMed2000

The safety of olanzapine compared with other antipsychotic drugs: results of an observational prospective study in patients with schizophrenia (EFESO Study). Pharmacoepidemiologic Study of Olanzapine in Schizophrenia.

INTRODUCTION: Results of controlled clinical trials should be confirmed through safety and effectiveness studies in nonselected patient cohorts treated according to routine clinical practice. METHOD: Outpatients with schizophrenia (ICD-10 criteria) entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Safety was evaluated through the collection of spontaneous adverse events and a specific questionnaire for extrapyramidal symptoms. Global clinical status was measured through the Clinical Global Impressions-Severity (CGI-S) and the Global Assessment of Functioning (GAF) scales. RESULTS: From the 2967 patients included, 2128 patients were treated with olanzapine as monotherapy or combined with other drugs (olanzapine group), and 821 were treated with other antipsychotic drugs as monotherapy or combined with other drugs (control group). There were no statistical differences between treatment groups at baseline regarding age, gender, disease duration, or severity of symptoms. Olanzapine was well tolerated and effective in this study. Overall incidence of adverse events was significantly lower in the olanzapine group compared with the control group (p < .001). Somnolence and weight gain were significantly more frequent in the olanzapine group, and akathisia, dystonia, extrapyramidal syndrome, hypertonia, hypokinesia, and tremor were significantly higher in the control group. Clinical improvement at endpoint, measured through the mean change in the CGI-S and the GAF, was significantly higher in the olanzapine group compared with the control group (p = .004). CONCLUSION: These results show that olanzapine is safe and effective in nonselected schizophrenic outpatients and are consistent with the efficacy and safety profile that olanzapine has shown in previous controlled clinical trials.

Adolescent↗
PubMed2005

Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats.

RATIONALE: Atypical antipsychotic drug (APD)-induced weight gain causes non-compliance, increasing the risk of relapse and medical complications. OBJECTIVES: In an animal model, we assessed body weights, food intake, body fat/lean body mass contents and blood serum levels of glucose and lipids in female rats treated with olanzapine (Experiment 1). Also, we investigated the effect of aripiprazole vs olanzapine treatment on weight gain (WG) and plasma prolactin secretion in two strains (Wistar and Sprague-Dawley) and in two housing conditions (singly and group housed; Experiment 2). METHODS: In Experiment 1, Wistar females received either vehicle or olanzapine (5.0 mg kg(-1), p.o.) twice daily for 14 days. In Experiment 2, female rats (Wistar or Sprague-Dawley), housed singly or in groups, received either vehicle, aripiprazole (2.0-8.0 mg kg(-1), p.o.), or olanzapine (1.0-10 mg kg(-1), p.o.) twice daily for 7 days. Body weights and food intake were assessed daily. Body composition and blood assays were analyzed at the end of the treatment. RESULTS: WG induced by chronic olanzapine treatment was characterised by hyperphagia, increased body fat, and serum free fatty acid content and reduced lean tissue and serum glucose content. Subchronic aripiprazole treatment resulted in rapid and robust WG similar to those observed with olanzapine. In spite of similar effects on body weight, aripiprazole and olanzapine stimulated markedly different patterns of prolactin secretion. Body weight changes and prolactin secretion induced by these APDs were significantly modulated by housing and by strain. CONCLUSION: Assessment of body weight in the present model may not have predictive validity, and other measures may be needed to differentiate between WG-inducing and weight-neutral drugs.

Animals↗
PubMed2001

Olanzapine versus haloperidol in the treatment of patients with chronic schizophrenia: results of the Japan multicenter, double-blind olanzapine trial.

This randomized double-blind trial was conducted to test the efficacy and safety of olanzapine in Japanese patients with schizophrenia. Importantly, this study also represents the first large clinical trial of olanzapine conducted in an Asian population. Patients (n = 182) were randomly assigned to treatment with olanzapine or haloperidol over a period of 8 weeks. The primary analyses included: (i) a test of non-inferiority of olanzapine compared with haloperidol in efficacy using the Final Global Improvement Rating (FGIR); and (ii) comparison between the treatment groups in extrapyramidal symptom severity using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). Olanzapine was comparable to haloperidol in efficacy in treating positive symptoms and significantly superior in treating negative symptoms. Extrapyramidal symptom severity was significantly improved for olanzapine-treated patients versus haloperidol-treated patients. Olanzapine was shown to be more effective and better tolerated than haloperidol in the treatment of Japanese patients suffering from chronic schizophrenia.

Adult↗
PubMed2004

Olanzapine plus fluvoxamine and olanzapine alone for the treatment of an acute exacerbation of schizophrenia.

The objective of the present study was to compare the efficacy and adverse effects of olanzapine plus fluvoxamine and those of olanzapine alone, in schizophrenic patients with acute exacerbation. A randomized, placebo-controlled, 6-week trial was carried out at a University Hospital in Bangkok, Thailand. The efficacy and adverse effects were assessed biweekly by using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Undersogelser side-effect scale, respectively. Twenty schizophrenic patients with acute exacerbation were randomly assigned to receive olanzapine plus fluvoxamine or olanzapine alone. The study found that the means of BPRS total and BPRS general psychopathology score changes were significantly larger in olanzapine plus fluvoxamine group (P = 0.037 and P = 0.045, respectively). The incidence of treatment adverse effects is comparable. In conclusion, the study findings suggest that fluvoxamine augmentation to olanzapine is well tolerated and more effective than olanzapine alone for short-term (6-week) treatment of an acute exacerbation of schizophrenia. Due to a number of limitations, further studies are warranted to confirm.

Acute Disease↗
PubMed2006

[Reversed phase high-performance liquid chromatography for determination of plasma olanzapine and pharmacokinetics of olanzapine in healthy Chinese volunteers].

OBJECTIVE: To establish a reversed phase high-performance liquid chromatography (HPLC) system for determining plasma concentration of olanzapine and analyze the pharmacokinetics of olanzapine in healthy Chinese volunteers. METHODS: Ten healthy male subjects received a single oral dose of 20 mg olanzapine tablets. The plasma concentrations of olanzapine were determined by HPLC, and the data were analyzed using 3P97 program. RESULTS: The plasma concentration curve of olanzapine following a single oral dose conformed to the two compartment open model. The main pharmacokinetics parameters of olanzapine were as follow: C(max) was 113.7-/+33.1 microg/L, T(max) 5.07-/+0.65 h, t(1/2) 35.44-/+4.21 h, AUC(0-144) 2,235-/+257 microg.h.L(-1), and AUC(0-inf) 2,516-/+301 microg.h.L(-1). CONCLUSION: The system established in this study allows for highly sensitive, selective and accurate determination of plasma concentration of olanzapine, and provides valuable information for clinical trials.

Adult↗
PubMed2006

Severe liver enzyme elevations after three years of olanzapine treatment: a case report and review of olanzapine associated hepatotoxicity.

Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Among these atypical antipsychotics, mostly transient, asymptomatic increase in hepatic enzymes has been reported with olanzapine, however olanzapine rarely may induce a clinical and/or biological hepatic toxicity. The pathogenesis of olanzapine-associated hepatotoxicity is not well known and is mostly a transient phenomenon. However, substantial and lasting changes may occur and result in symptomatic hepatitis. In the following case report, we report on a 44-year-old female patient diagnosed as Bipolar Disorder Type I, whose liver enzyme levels increased ten fold of normal ranges during the third year of the olanzapine treatment and returned to the normal levels within three weeks after olanzapine discontinuation. Although significant liver enzyme elevations are uncommon during olanzapine treatment, based on reports of serious hepatotoxicity, controlled and longitudinal research are needed to learn side effects of this drug on liver. Clinicians should be aware of possible hepatotoxic effects of atypical antipsychotics and should monitor the liver enzyme levels whenever they feel necessary.

Adult↗