Drugs

, Volume 61, Issue 1, pp 111–161

Olanzapine

An Updated Review of its Use in the Management of Schizophrenia
  • Nila Bhana
  • Rachel H. Foster
  • Roger Olney
  • Greg L. Plosker
Adis Drug Evaluation

Summary

Abstract

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 ≥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.

Pharmacodynamic Properties

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has binding affinity for a broad range of neurotransmitter receptors. It has significant in vitro inhibitory activity at dopamine D2, D3, D4, serotonin 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, histamine H1, α1-adrenergic and muscarinic receptors. The mixed receptor activity of olanzapine is similar to that of clozapine as is its greater affinity for serotonin 5-HT2A than dopamine D2 receptors.

In electrophysiological studies, olanzapine inhibited neuronal firing in the mesolimbic but not the nigrostriatal systems within the CNS, which may be predictive of a low potential for the induction of extrapyramidal symptoms (EPS).

Olanzapine is active in many animal behavioural models of antipsychotic activity. Inhibition of a number of dopamine and serotonin agonist-induced behaviours was demonstrated in vivo, confirming in vitro evidence of the receptor affinity profile of olanzapine. In animal models considered predictive of the potential to induce EPS, most studies indicated that olanzapine has less propensity than classical antipsychotics to induce these effects.

Pharmacokinetic Properties

The absorption of olanzapine is extensive after oral administration in healthy volunteers and is unaffected by food. Plasma olanzapine concentrations increase proportionally with dosage, reaching a maximum at about 5 hours after administration.

The large volume of distribution (Vd), approximately 10 to 22 L/kg in healthy volunteers after a single oral dose, indicates the drug has broad tissue distribution. Olanzapine is highly (93%) protein bound in plasma, primarily to albumin and α1-acid glycoprotein. In vitro, about 5 to 14% of olanzapine (83% as unchanged drug) crosses the human placenta.

Olanzapine is extensively metabolised in the liver by uridine disphosphate glucuronyltransferase and the cytochrome P450-1A2 and -2D6 isoenzymes to the major metabolite 10-N-glucuronide and other inactive metabolites. Excretion of olanzapine and its metabolites is mainly in the urine (57%) and partly in the faeces (30%). The elimination half-life (t&#x00BD;β) of olanzapine is about 30 hours for young males and is prolonged in young female and elderly individuals. The total body clearance (CL) of olanzapine ranges from 12 to 47 L/h in healthy individuals, is decreased in the elderly and increased in smokers compared with nonsmokers.

Olanzapine pharmacokinetics were not significantly altered in different ethnic groups or in patients with renal or hepatic impairment although the combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in populations. Some cytochrome P450 isoenzyme inducers (e.g. carbamazapine) or inhibitors (e.g. fluvoxamine) also affect olanzapine pharmacokinetic parameters.

Therapeutic Use

Olanzapine is more effective than placebo and at least as effective as haloperidol in the treatment of overall psychopathology symptoms as shown in a number of randomised double-blind trials in patients with schizophrenia and related psychoses.

In the largest trial (n = 1996), olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day for overall improvements in psychopathology as assessed by reductions in the Brief Psychiatric Rating Scale total score (33 vs 23%, p < 0.05), in the treatment of depressive symptoms as assessed by improvements in Montgomery-Åsberg Depression Rating Scale scores (36 vs 18%, p = 0.001) and in the treatment of negative symptoms as assessed by improvements in the Positive and Negative Syndrome Scale (PANSS) negative symptom scores (19 vs 13%, p < 0.05). Olanzapine was similar to haloperidol in effects on positive psychotic symptoms.

Olanzapine 10 to 20 mg/day was superior to placebo and olanzapine 5 to 20 mg/day was superior to haloperidol 5 to 20 mg/day in the maintenance therapy of schizophrenia. In pooled analyses of 1-year double-blind extensions of three 6-week acute phase studies, the risk of relapse (defined as rehospitalisation for psychopathology) was significantly lower for olanzapine than haloperidol recipients (20 vs 28%, p < 0.05).

In the first double-blind, multicentre, randomised trial in which 2 atypical antipsychotic agents have been compared in the treatment of schizophrenia, olanzapine 10 to 20 mg/day demonstrated superior efficacy compared with risperidone 4 to 12 mg/day against negative and depressive symptoms. No differential between-treatment effects were seen in the 28-week study (n = 339) on measures of overall psychotic symptoms, although treatment response (≥40% reduction from baseline PANSS total score) at end-point was seen in significantly more olanzapine-than risperidone-treated patients (37 vs 27%, p < 0.05). In contrast, preliminary results (reported as an abstract plus poster) from an 8-week double-blind, multicentre, randomised trial (n = 377) 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). Consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology.

Preliminary data from studies suggest that olanzapine improves cognitive deficits, as significant effects on some measures of executive function and verbal learning and memory were shown. Furthermore, 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 a comparative 8-week trial showed no significant between-treatment differences on any measures of cognitive performance with olanzapine or risperidone 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. Post hoc analyses of comparator trials with haloperidol or risperidone demonstrated that the effect of olanzapine on depressive symptoms was significantly greater than that seen with either comparator drug.

Olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall efficacy in a post hoc analysis of a cohort with first-episode psychosis from a large double-blind trial, but was of similar efficacy to haloperidol 2 to 20 mg/day in preliminary results of a prospective double-blind evaluation in a larger population. Results from double-blind trials comparing olanzapine 5 to 25 mg/day and clozapine 25 to 600 mg/day or haloperidol 5 to 20 mg/day, suggested olanzapine is beneficial in some treatment-resistant patients. In these trials, olanzapine was similar in efficacy to clozapine and superior to haloperidol treatment. However, in one study of severely treatment-refractory patients, neither olanzapine 25 mg/day nor chlorpromazine 1200 mg/day was effective. Olanzapine has shown some efficacy in the treatment of children and adolescents as well as elderly patients with schizophrenia, although further studies are required to support these findings.

Tolerability

In placebo-controlled 6-week trials the most common adverse events (reported by at least 10% of olanzapine-treated patients) were somnolence, asthenia, agitation, headache, nervousness, insomnia, hostility, paranoid reaction, rhinitis, constipation, dizziness, anxiety and bodyweight gain. However, only somnolence, constipation and bodyweight gain occurred in a significantly higher incidence with olanzapine treatment than with placebo. In comparison with haloperidol, the incidence of dry mouth, bodyweight gain and increased appetite was significantly higher with olanzapine and compared with risperidone, the incidence of bodyweight gain was higher. In clinical trials, adverse event-related study withdrawal rates were similar between olanzapine, placebo and risperidone but were significantly lower with olanzapine than with haloperidol (5.5 vs 8.1%; pooled data from three 6-week trials).

There were no reports of clinically relevant abnormalities in haematological parameters (e.g. agranulocytosis), laboratory tests, vital signs or electrocardiogram results (including QT interval prolongation), in clinical studies of olanzapine. Orthostatic blood pressure changes were not clinically significant despite the number of reports of dizziness. Hepatic transaminase levels were clinically elevated in 2% of olanzapine recipients; however, the increases were transient and clinical signs of hepatotoxicity were not apparent. Olanzapine treatment was associated with dose-dependent rises in serum prolactin levels which were mild and transient and of lesser magnitude than those seen with haloperidol or risperidone.

Bodyweight gain in the range of approximately 2 to 3.5kg was associated with olanzapine treatment in 6-week clinical trials and was significantly higher than that seen with haloperidol or risperidone. In extension phases (for up to 3 years) of the acute phase trials, bodyweight gain appeared to plateau at around 40 weeks.

In clinical trials, the incidence of treatment-associated EPS, assessed by rating scales for parkinsonism, akathisia and dystonia, was comparable to that seen with placebo and significantly lower than that seen with haloperidol or risperidone, although the dosage of risperidone was higher than recommended in 1 trial. Indeed, improvements in existing symptoms were often noted with olanzapine. However, in 1 placebo-controlled trial, significant dose-related increases in spontaneously reported treatment-emergent EPS, particularly akathisia, were seen with olanzapine 2.5 to 17.5 mg/day. Treatment-emergent dyskinetic events were significantly lower with olanzapine than haloperidol or, in 1 trial, risperidone.

Pharmacoeconomic and Quality-of-Life Profile

Pharmacoeconomic comparisons of olanzapine and haloperidol generally suggest that olanzapine does not add to the overall treatment cost, and may even furnish small cost savings, in patients with schizophrenia and related disorders. The higher acquisition cost of olanzapine is counterbalanced by a reduction in inpatient and/or outpatient costs. Among 803 US patients participating in an international collaborative trial, mean total medical costs were $US388 (1995 values) per patient lower with olanzapine 5 to 20 mg/day than haloperidol 5 to 20 mg/day during the first 6 weeks of treatment. During the 46-week maintenance phase in 342 responding patients, total medical costs were $US636 per patient lower in the olanzapine group. Efficacy data from French patients in the same trial and a cost-effectiveness analysis of the data also favoured olanzapine. In a 5-year Markov model applied in various countries, olanzapine was more effective at a lower cost than haloperidol in 5 of 6 analyses; annual savings of approximately $US300 per patient were seen with olanzapine in most analyses. Olanzapine is more cost effective than haloperidol in modelled studies.

The daily acquisition cost for olanzapine at therapeutic dosages is 1.5- to 3.5-fold greater than that of risperidone, but most analyses of total medical costs and cost effectiveness have tended to favour olanzapine, although results were sensitive to changes in dosage levels. However, given that the differences have not been large, the reduction in medical resource costs (which offsets the higher drug acquisition cost of olanzapine) is clinically meaningful. In a prospective analysis, mean total per-patient costs were $US2843 (1997 values) lower with olanzapine 10 to 20 mg/day than with risperidone 4 to 12 mg/day in 150 evaluable US patients who completed a 28-week international study. In the 5-year Markov model, olanzapine was associated with slightly lower total costs ($US300 to $US500 per patient per year in most analyses) and similar effectiveness to risperidone. In a 1-year semi-Markov Belgian model, olanzapine produced slightly higher total costs than risperidone (1151 900 vs 1137 700 Belgian francs; 1998 values).

Treatment with olanzapine improves quality of life in patients with schizophrenia and related disorders. The extent of improvement tends to be greater than that with haloperidol treatment, and broadly similar to that with risperidone treatment.

Dosage and Administration

The recommended starting dosage of olanzapine is 5 to 10mg(1 to 5mg in elderly patients) once daily, regardless of meals. If clinically indicated, 5mg increments or decrements at intervals of at least 1 week may be implemented, up to a maximum recommended dosage of 15 mg/day. The effective dosage of olanzapine in clinical trials is in the range of 10 to 20 mg/day for most patients. Patients who respond to olanzapine should receive the lowest effective dosage for maintenance therapy, and treatment requirements should be reassessed periodically.

The risk of orthostatic hypotension can be minimised by dosage initiation at 5 mg/day followed by careful titration. Dosage modication should also be considered for patients who are debilitated or who may exhibit slower olanzapine metabolism (e.g. female patients who are nonsmokers and are aged ≥65 years). Olanzapine should be used with caution in patients with cardiovascular or cerebrovascular disease or any conditions which may predispose to the development of hypotension and in those with hepatic dysfunction or at risk of seizures. Somnolence is common with olanzapine and caution is advised if driving or operating machinery.

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Copyright information

© Adis International Limited 2001

Authors and Affiliations

  • Nila Bhana
    • 1
  • Rachel H. Foster
    • 1
  • Roger Olney
    • 1
  • Greg L. Plosker
    • 1
  1. 1.Adis International limitedMairangi Bay, Auckland 10New Zealand

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