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.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Olanzapine: new indication. New indication in acute mania: just another neuroleptic

(1) Lithium is the first-line treatment for patients with acute mania. For patients with psychosis or intense agitation, an oral neuroleptic can be added (haloperidol or chlorpromazine, the best-assessed drugs of this class). (2) The licensed indications for oral olanzapine, a neuroleptic, explicitly mention the treatment of acute mania. (3) The clinical evaluation dossier on olanzapine in this setting (10 mg to 15 mg/day) is not particularly impressive. In particular, clinical trials included patients with a variety of associated psychotic symptoms. (4) The only comparative trial against another neuroleptic, haloperidol at a high starting dose (10 mg), showed that olanzapine was no more effective. The same applies to a trial comparing olanzapine with disodium valproate. (5) One placebo-controlled trial tested olanzapine as an additional treatment in patients who did not respond adequately to lithium or valproate disodium. Olanzapine potentiated the antimanic effects of the original treatment but also increased the incidence of adverse effects. (6) In patients with acute mania, the main adverse effects of olanzapine are drowsiness, weight gain, dizziness, and dry mouth. In the trial comparing olanzapine with haloperidol, olanzapine caused fewer extrapyramidal side effects but more weight gain than haloperidol. (7) Olanzapine costs 20 times more than haloperidol in France. (8) In practice, olanzapine is just another neuroleptic approved for the treatment of acute mania in patients with psychotic symptoms and agitation. There is no evidence that olanzapine has the best risk-benefit ratio in this category.     

Olanzapine for injection: new formulation. No advantage in agitated patients

(1) The intramuscular neuroleptic of choice for the treatment of agitated schizophrenic patients and patients with acute mania is haloperidol, at a dose of 5 mg. Olanzapine is now marketed in France for hospital use in both these indications. (2) In two comparative trials in patients with schizophrenia, olanzapine 10 mg was shown to be no better than haloperidol 7.5 mg (a high dose). Control of agitation was satisfactory in three-quarters of patients after a single injection of either neuroleptic. (3) Olanzapine has not been compared with other neuroleptics in the treatment of acute mania. In one trial, olanzapine acted faster than lorazepam for injection (used at a rather low dose). (4) In one trial, patients given olanzapine had a lower incidence of acute dystonia and extrapyramidal symptoms (about 1%) than patients given haloperidol (about 6-7%), but the haloperidol dose (7.5 mg) was higher than recommended in the SPC (5 mg). The incidence of postural hypotension was significantly higher among patients given olanzapine (about 12%) compared with haloperidol (about 3%). (5) In practice, haloperidol remains the intramuscular neuroleptic of choice for the treatment of agitated patients with schizophrenia or acute mania.     

Olanzapine. A pharmacoeconomic review of its use in schizophrenia.

Olanzapine is an atypical antipsychotic agent which is at least as effective as the conventional agent haloperidol and the atypical agent risperidone. Olanzapine may be superior to haloperidol in some respects, including treatment of negative symptoms. A major advantage of olanzapine over haloperidol is its lower risk of extrapyramidal symptoms. Olanzapine improves quality of life and other aspects of functioning to a greater extent than haloperidol, and improves quality of life to at least the same extent as risperidone. However, olanzapine has a high acquisition cost compared with conventional antipsychotics. Despite this, most pharmacoeconomic analyses indicate that treatment with olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Total direct medical costs calculated from prospective resource utilisation data were lower with olanzapine than with haloperidol by $US388 (1995 values) per patient over 6 weeks and by $US55 per patient per month during 46 weeks extended treatment. In a mixed effects linear model of the same data, total costs over 1 year were $US10,301 (1996 values) per patient lower with olanzapine than haloperidol, and olanzapine was associated with 18.3 more symptom-free days per patient. Compared with risperidone, mean total direct medical costs over 28 weeks were $US493 (1995 values) per patient lower with olanzapine. In a Markov model of 5 years' treatment, olanzapine was associated with more time in a disability-free state than haloperidol at a total cost per patient that was lower by $US1539 (1995 values), 816 Pounds (1995/1996 values), 977 Dutch guilders (NLG; 1995 values) and 2296 Deutschmarks in US, UK, Dutch and German analyses, respectively. In a similar Spanish analysis, the overall total cost was higher with olanzapine, giving an incremental cost effectiveness for olanzapine of 32,516 pesetas (1995 values) per month of disability-free time gained. When risperidone was a comparator, the total cost per patient was $US1875 and NLG202 lower with olanzapine in US and Dutch analyses, respectively. CONCLUSIONS: The high acquisition cost of olanzapine is offset by reductions in other treatment costs in patients with schizophrenia. Compared with haloperidol, the drug improved patient outcome and quality of life, while overall direct treatment costs were generally not increased, or even decreased. Olanzapine has also been reported to decrease overall treatment costs compared with risperidone, but confirmation is required. Olanzapine is a cost-effective alternative to conventional agents for the treatment of moderately to severely ill patients with longstanding schizophrenia.     

奥氮平与齐拉西酮治疗青少年精神分裂症疗效的对比研究

目的比较奥氮平与齐拉西酮治疗青少年精神分裂症的疗效及其不良反应。方法将60例青少年精神分裂症患者随机平分为两组。以奥氮平和齐拉西酮治疗,疗程8周。采用阳性与阴性症状量表(PANSS)及治疗中出现的不良反应例数评定疗效以及不良反应。结果奥氮平和齐拉西酮治疗青少年精神分裂症患者总体疗效相当,两药不良反应均较小,但奥氮平在语言表达流畅性方面明显优于齐拉西酮;齐拉西酮的体重增加方面则低于奥氮平。结论奥氮平与齐拉西酮治疗青少年精神分裂症均有效,奥氮平在治疗精神分裂症患者的阴性症状效果更好。     

Efficacy of olanzapine and ziprasidone for the treatment of schizophrenia: a systematic review

It is difficult to determine the relative efficacy of atypical antipsychotics for the treatment of schizophrenia, based on the available literature. The purpose of this article is to review and compare the efficacy of two atypical antipsychotics: olanzapine and ziprasidone.This review focused on randomised trials in which these two antipsychotics were compared with placebo, conventional antipsychotics and each other. Common efficacy measures were the Brief Psychiatric Rating Scale, Positive and Negative Syndrome Scale and Schedule for Assessment of Negative Symptoms. When sufficient data were available, the mean treatment effect (with 95% confidence intervals) was computed and presented.Olanzapine was consistently found to be significantly superior to placebo and comparable with, or superior to, haloperidol for the treatment of overall, positive and negative schizophrenic symptoms. Ziprasidone appears to have significantly greater efficacy than placebo for overall and negative symptoms, but it remains uncertain whether ziprasidone is comparable in efficacy with conventional antipsychotics such as haloperidol. Two unpublished clinical trials have directly compared olanzapine and ziprasidone. One of these trials found no significant efficacy differences between the two drugs, whereas the results of the other study favoured olanzapine.Compared with ziprasidone, olanzapine has a larger body of evidence supporting its efficacy, and a greater proportion of findings for olanzapine have been published, allowing for greater scrutiny of results. Both drugs appear to be superior to placebo for the treatment of overall and negative symptoms of schizophrenia, but olanzapine generally compares more favourably with conventional antipsychotics. Firm conclusions regarding the comparison between olanzapine and ziprasidone require additional published trials on ziprasidone, particularly in direct comparison with olanzapine.     

Olanzapine in bipolar disorder

Olanzapine is currently marketed not only for the treatment of schizophrenia, but also for the treatment of acute mania and the prevention of relapse in patients successfully treated with this drug for a manic episode. A large body of good clinical trials supports these indications. In the mania trials, olanzapine was more efficacious than placebo, equal or more efficacious than valproate and more efficacious than lithium or valproate monotherapy when used in combination with either drug. A trial that compared olanzapine with haloperidol failed to show superiority of the atypical versus the conventional. Olanzapine showed a modest but statistically significant effect in the treatment of bipolar depression; this modest effect was substantially enhanced in combination with fluoxetine. The long-term trials showed that olanzapine was better than placebo in the prevention of manic and depressive relapse and not inferior to lithium or valproate. The combination of olanzapine with lithium or valproate was also more efficacious than lithium or valproate alone in the prevention of manic relapse in patients partially non-responding to monotherapy with lithium or valproate. All these trials suggest that olanzapine may be a valuable drug in the short- and long-term treatment of bipolar I disorder. However, there are some concerns about the safety and tolerability of olanzapine in this population, as far as weight gain and metabolic syndrome are concerned, which may be addressed in future pharmacovigilance studies.     

Olanzapine in bipolar disorder

Olanzapine is currently marketed not only for the treatment of schizophrenia, but also for the treatment of acute mania and the prevention of relapse in patients successfully treated with this drug for a manic episode. A large body of good clinical trials supports these indications. In the mania trials, olanzapine was more efficacious than placebo, equal or more efficacious than valproate and more efficacious than lithium or valproate monotherapy when used in combination with either drug. A trial that compared olanzapine with haloperidol failed to show superiority of the atypical versus the conventional. Olanzapine showed a modest but statistically significant effect in the treatment of bipolar depression; this modest effect was substantially enhanced in combination with fluoxetine. The long-term trials showed that olanzapine was better than placebo in the prevention of manic and depressive relapse and not inferior to lithium or valproate. The combination of olanzapine with lithium or valproate was also more efficacious than lithium or valproate alone in the prevention of manic relapse in patients partially non-responding to monotherapy with lithium or valproate. All these trials suggest that olanzapine may be a valuable drug in the short- and long-term treatment of bipolar I disorder. However, there are some concerns about the safety and tolerability of olanzapine in this population, as far as weight gain and metabolic syndrome are concerned, which may be addressed in future pharmacovigilance studies.     

Sertindole: new drug. Another "atypical" neuroleptic; QT prolongation

(1) The first-line drug for the treatment of schizophrenic disorders is a neuroleptic such as haloperidol. Amisulpride may be preferable when haloperidol causes unacceptable neurological reactions. Overall, the risk-benefit balance of more recent, so-called atypical neuroleptics is no better. (2) Sertindole, a neuroleptic, was first marketed in 1996 in several European countries before being withdrawn two years later because of numerous cardiac adverse effects. It has once again been approved and should soon be available on the French market. (3) Two comparative double-blind trials suggest that a daily sertindole dose of 24 mg is about as effective as 10 mg of haloperidol. Sertindole was no more effective than risperidone in a trial comparing these two drugs. (4) Like other 'atypical' neuroleptics, sertindole has few short-term neurological adverse effects (extrapyramidal syndrome) at the doses used in clinical trials. However, it causes weight gain. Sertindole also has alpha blocking properties, which can cause postural hypotension and reduce ejaculate volume; it also has atropinic effects (constipation, dry mouth, etc.). (5) Sertindole provokes a dose-dependent increase in the QT interval more frequently than haloperidol in comparative trials, and apparently more frequently than other 'atypical' neuroleptics such as risperidone and olanzapine. Sertindole has been suspected of increasing cardiovascular mortality but this has not been established. (6) Sertindole is metabolised by cytochrome P450 isoenzymes CYP 2D6 and CYP 3A4, hence a high risk of pharmacokinetic interactions. (7) In practice, when haloperidol has to be withdrawn because of adverse effects, especially neurological reactions, it is better to continue to resort to amisulpride, for example, with close monitoring of adverse effects, rather than expose patients to the potential dangers of sertindole.     

Clinical efficacy of olanzapine]

The treatment of schizophrenic patients who fail adequate trials of typical neuroleptics is a major challenge. For these patients, the availability of atypical antipsychotics is a useful therapeutic advance. Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenia, particularly its negative symptoms, with a substantially more favorable safety profile than conventional antipsychotic agents (e.g., haloperidol). However, little information on the clinical effects of olanzapine is available in Japan. This article provides information on the efficacy of olanzapine for various symptoms of schizophrenic patients and drug safety. Olanzapine is significantly superior to haloperidol in positive, negative, and depressive symptoms of patients, and for tardive dyskinesia and extrapyramidal symptoms. Significantly greater improvement in avolition-apathy is achieved with olanzapine as compared to risperidone. These advantages are related to high affinity at the 5-HT2 binding site, no association with an alteration in dopamine A9 firing rates, and lower D2 striatal receptor blockade of olanzapine. Treatment with 10 mg/day olanzapine is more appropriate for positive symptoms, and 12.5-17.5 mg/day olanzapine is more effective for negative symptoms. Patients will need help adapting to a new level of functioning after a successful switch to olanzapine, and overcoming the disappointment that eventually occurs when the limitations of olanzapine become apparent.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

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.     

Does olanzapine warrant clinical pharmacokinetic monitoring in schizophrenia?

Olanzapine, a second-generation antipsychotic, is a first-line agent in the treatment of schizophrenia. The objective of this review was to determine whether olanzapine warrants clinical pharmacokinetic monitoring in patients with schizophrenia, using a previously published decision-making algorithm. Although olanzapine is an appropriate therapy for patients with schizophrenia and is readily measurable in biological fluids, significant interindividual variation exists in its pharmacokinetics. While the duration of therapy is expected to be long term, the correlation of olanzapine concentrations with efficacy and toxicity has not been well defined in the literature. There are multiple tools readily available for the assessment of efficacy in schizophrenia, and clinical signs and symptoms can be used to monitor both for efficacy and for adverse effects. Therefore, routine monitoring of olanzapine concentrations does not appear warranted in the general schizophrenic population. However, patients in whom a change in olanzapine pharmacokinetics is expected--such as during addition or removal of an enzyme-inducing or -inhibiting drug, or during initiation or cessation of smoking--may benefit from clinical pharmacokinetic monitoring, as would patients in whom non-compliance is suspected. Patients who fail to respond to maximum recommended doses and those who experience adverse effects from therapeutic doses may also benefit from therapeutic drug monitoring, as they may have inherent variations in hepatic enzyme activity. However, in the population at large who suffer from schizophrenia, monitoring of olanzapine concentrations is not expected to offer additional benefit beyond appropriate clinical monitoring alone.     

Comparing tolerability of olanzapine in schizophrenia and affective disorders: a meta-analysis

Background: Olanzapine is prescribed for a number of psychiatric disorders, including schizophrenia, bipolar mania, and unipolar and bipolar depression. Olanzapine treatment is associated with tolerability issues such as metabolic adverse effects (e.g. weight gain, increase in blood glucose, triglycerides and total cholesterol levels), extrapyramidal symptoms [EPS] (e.g. parkinsonism, akathisia, tardive dyskinesia) and sedative adverse effects. Metabolic issues lead to some long-term consequences, which include cardiovascular diseases (CVD) and type 2 diabetes mellitus, and these complications cause high rates of mortality and morbidity among patients with severe mental illnesses. The expanded indications of olanzapine in psychiatry suggest a need to investigate whether there is a difference in the incidence and severity of adverse effects related to category diagnosis. Are the adverse effects expressed differently according to phenotype? Unfortunately, there are no reported studies that investigated these differences in adverse effects associated with olanzapine treatment in psychiatric patients with different phenotypes. Objective: The aim of the present meta-analysis is to separately examine olanzapine-induced cardiometabolic adverse effects and EPS in patients with schizophrenia and affective disorders. Data Sources: A search of computerized literature databases PsycINFO (1967-2010), PubMed (MEDLINE), EMBASE (1980-2010) and the clinicaltrials.gov website for randomized clinical trials was conducted. A manual search of reference lists of published review articles was carried out to gather further data. Study Selection: Randomized controlled trials were included in our study if (i) they assessed olanzapine adverse effects (metabolic or extrapyramidal) in adult patients with schizophrenia or affective disorders; and (ii) they administered oral olanzapine as monotherapy during study. Data Extraction: Two reviewers independently screened abstracts for choosing articles and one reviewer extracted relevant data on the basis of predetermined exclusion and inclusion criteria. It should be mentioned that for the affective disorders group we could only find articles related to bipolar disorder. Data Synthesis: Thirty-three studies (4831 patients) that address olanzapine monotherapy treatment of adults with schizophrenia or bipolar disorder were included in the analysis. The primary outcomes were metabolic adverse effects (changes in weight, blood glucose, low-density lipoprotein, total cholesterol and triglyceride levels). The secondary outcomes of our study were assessing the incidence of some EPS (parkinsonism, akathisia and use of antiparkinson medication). The tolerability outcomes were calculated separately for the schizophrenia and bipolar disorder groups and were combined in a meta-analysis. Tolerability outcomes show that olanzapine contributes to weight gain and elevates blood triglycerides, glucose and total cholesterol levels in both schizophrenia and bipolar disorder patients. However, olanzapine treatment produced significantly more weight gain in schizophrenia patients than in bipolar disorder patients. In addition, increases in blood glucose, total cholesterol and triglyceride levels were higher in the schizophrenia group compared with the bipolar disorder group, even though these differences were not statistically significant. Based on our results, the incidence of parkinsonism was significantly higher in the schizophrenia group than in the bipolar disorder group. Subgroup analysis and logistic regression were used to assess the influence of treatment duration, dose, industry sponsorship, age and sex ratio on tolerability outcome. Conclusions: Our results suggest that schizophrenia patients may be more vulnerable to olanzapine-induced weight gain. The findings may be explained by considering the fact that in addition to genetic disposition for metabolic syndrome in schizophrenia patients, they have an especially high incidence of lifestyle risk factors for CVD, such as poor diet, lack of exercise, stress and smoking. It might be that an antipsychotic induces severity of adverse effect according to the phenotype.     

Reducing olanzapine-induced weight gain side effect by using betahistine: a study in the rat model

Olanzapine is effective at treating multiple domains of schizophrenia symptoms. However, it induces serious metabolic side effects. Antipsychotic drug's antagonistic affinity to histamine H(1) receptors has been identified as a main contributor for weight gain/obesity side effects. This study therefore investigated whether a combined treatment of betahistine (a H(1) receptor agonist and H(3) receptor antagonist) could reduce the body weight/obesity induced by olanzapine. Female Sprague Dawley rats were treated orally with olanzapine (1 mg/kg, t.i.d.) and/or betahistine (2.67 mg/kg, t.i.d.), or vehicle for two weeks. Rats treated with olanzapine exhibited significant body weight gain and increased food intake. Co-treatment of olanzapine with betahistine significantly prevented (-45%) weight gain and reduced feeding efficiency compared to sole olanzapine treatment. Betahistine treatment alone had no effect on weight gain and food intake. Olanzapine reduced locomotor activity, but not betahistine. These findings demonstrate that olanzapine-induced body weight gain can partially be reduced by co-treatment with betahistine. Betahistine has H(3) receptor antagonistic effects to increase histamine release, which may augment its direct agonistic effects on H(1) receptors. These findings have important implications for clinical trials using betahistine to control antipsychotic-induced obesity side effects.     

Olanzapine long-acting injection: a review of its use in the treatment of schizophrenia

Olanzapine pamoate (olanzapine long-acting injection [OLAI]; Zypadhera?; Zyprexa? Relprevv?) is the intramuscular depot formulation of the atypical antipsychotic olanzapine. In two pivotal, double-blind clinical trials of 8 or 24 weeks' duration, the efficacy of recommended dosages of OLAI injected every 2 or 4 weeks (without oral supplementation) was greater than that of placebo in improving symptoms in acutely ill patients with schizophrenia, and generally similar to that of continuing oral olanzapine in preventing psychotic exacerbations in patients with schizophrenia whose symptoms had previously been stabilized on oral olanzapine. The effectiveness of OLAI in the maintenance treatment of schizophrenia was also demonstrated in an (ongoing) open-label extension study in which the all-cause discontinuation rate was 34.3% after 18 months. OLAI is generally well tolerated. It has an adverse event profile similar to that of oral olanzapine, with the exception of adverse events related to the intramuscular route of administration; these include a manageable post-injection syndrome, which occurred in <0.1% of injections in clinical trials. The possibility of a post-injection syndrome event requires a risk management plan (RMP) to be adopted that includes observation by appropriately qualified personnel in a healthcare facility for at least 3 hours post-injection. With its potential to improve adherence to medication, and thereby treatment outcomes, OLAI is a useful addition to the pharmacological options available for the maintenance therapy of schizophrenia. Given its benefit/risk profile, OLAI appears most suited for patients who, despite responding well to oral olanzapine, have difficulties remaining adherent to this form of medication, provided they can comply with the conditions of the RMP.     

Time to study discontinuation, relapse, and compliance with atypical or conventional antipsychotics in schizophrenia and related disorders

To more clearly clarify the efficacy of the atypical antipsychotics compared to conventional antipsychotics, we add data on the outcome of patients diagnosed with schizophrenia from two large, international clinical trials comparing olanzapine with haloperidol (n = 1996) and olanzapine with risperidone (n = 339). Both studies comprised double-blinded, placebo controlled, random assignment trials. Health outcomes reported include: (i) time to discontinuation in the trial; (ii) clinical relapse; and (iii) time to drug non-compliance. When outcome was measured as time to discontinuation due to adverse events or lack of efficacy, olanzapine showed superiority over haloperidol and no difference compared to risperidone. Of those patients who had an initial response, there was no significant difference between olanzapine and haloperidol when outcome was measured using either: (i) 52-week relapse rates or (ii) time to first non-compliance. Using the measures of study discontinuation, relapse and non-compliance, in one trial the atypical antipsychotic olanzapine was superior to haloperidol, while in a second trial there were no differences between olanzapine and risperidone.     

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.