Olanzapine

Abstract

Olanzapine is a thienobenzodiazepine derivative which displays efficacy in patients with schizophrenia and related psychoses. It has structural and pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the classical antipsychotic haloperidol. In several large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine generally 5 to 20 mg/day was at least as effective as haloperidol (5 to 20mg) and more so than placebo, as assessed by overall rating scales for psychoses. Olanzapine improved negative symptoms to a greater extent than haloperidol in 2 of 3 comparative trials, including the largest trial. Efficacy of olanzapine has a rapid onset (within 1 to 2 weeks). Its clinical benefits appear to be maintained for treatment periods of up to I year, as shown by analysis of the extension phase of several trials demonstrating decreased probability of hospitalisation over this period, compared with haloperidol. Preliminary data suggest the drug may also improve quality of life. Olanzapine was associated with significantly fewer adverse movement disorders (e.g. akathisia, dystonia, hypertonia, extrapyramidal symptoms) than haloperidol. There have been no reports of agranulocytosis (as occurs with clozapine) or any other haemotoxicity attributed to olanzapine, and the drug has shown minimal effect on prolactin levels. Transient increases in levels of hepatic transaminases seem to be clinically unimportant. The only events recorded more frequently during olanzapine than during haloperidol therapy were weight gain, dry mouth and increased appetite. Although the antipsychotic activity of olanzapine has been well demonstrated, its efficacy in refractory schizophrenia and its place relative to other atypical antipsychotic s remain to be determined. Nevertheless, if the long term tolerability profile of olanzapine is confirmed, the drug should provide a valuable therapeutic alternative in the management of schizophrenia and related psychoses. Olanzapine is a thienobenzodiazepine derivative with affinity for a number of neurotransmitter receptors. It has significant in vitro inhibitory activity at dopamine D₁, D₂, D₄, serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A, 5-HT2C, histamine H₁, α₁-adrenergic and muscarinic receptors. The mixed receptor activity of olanzapine is similar to that of clozapine. The in vitro binding affinity of olanzapine, like that of clozapine, is greater for 5-HT2 receptors than for dopamine D₂ receptors. In electrophysiological studies, olanzapine produced a differential effect on nigrostriatal and mesolimbic 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 predictive of antipsychotic activity. Olanzapine also inhibited a number of dopamine and serotonin agonist-induced behaviours in vivo, confirming in vitro evidence of its receptor affinity profile. In animal models considered predictive of the potential to induce EPS, most studies indicate that olanzapine has less propensity than classical anti-psychotics to induce these effects. In patients with schizophrenia, olanzapine produced minimal effects on prolactin levels. Increases seen in some patients appear to be transient and smaller than those produced by haloperidol. As shown in healthy volunteers, maximum plasma olanzapine concentrations (C_max) after single oral doses (2.5 to 12.2mg) are reached within about 5 hours. Values for C_max and area under the plasma concentration-time curve are proportional to the dose. The volume of distribution of olanzapine is large (reported to range from 10.3 to 18.4 L/kg). Olanzapine is extensively metabolised: at least 10 different metabolites, which appear to be inactive, have been identified. The elimination half-life (t1/2β) of olanzapine ranged from 27 to 38.6 hours in young healthy individuals. Elderly and female volunteers have shown a decreased total body clearance and a prolonged t1/2β. Although the metabolism of olanzapine is mediated, at least in part, by cytochrome P450 enzymes, there appears to be little potential for olanzapine to interact with other drugs metabolised by these enzymes. Olanzapine is more effective than placebo and at least as effective as haloperidol, as shown in a number of large, randomised, double-blind trials in patients with schizophrenia and related psychoses. Indeed, in 2 of 3 comparative trials, including the largest, some significant differences were evident between olanzapine and haloperidol. Reductions in BPRS total scores with olanzapine tended to be dose dependent. Mean reductions in BPRS total scores ranged from 16 to 39% for patients receiving olanzapine 2.5 to 17.5 mg/day, 0.5 to 8% for placebo groups and were about 30% in those given haloperidol 10 to 20 mg/day. Significant differences between olanzapine ≥7.5 mg/day and placebo were evident within 1 to 2 weeks, indicating a relatively rapid onset of effect. Olanzapine ameliorates both the positive and negative symptoms of schizophrenia and appears to produce greater improvements than haloperidol in the latter. In 2 comparisons, olanzapine was associated with significantly greater reductions than placebo in the BPRS-positive subscale (23 to 33% vs 0% and 12%) and the BPRS-negative subscale (20 to 41% vs 3% and 6%). In some, but not all, assessments of subscales for negative symptoms, olanzapine in dosages >7.5 mg/day was more effective than haloperidol 5 to 20 mg/day, as measured by the BPRS-negative subscale and the SANS scale. The largest trial demonstrated a significant difference between the 2 drugs as shown by the negative subscales of the PANSS and BPRS scales. According to a path analysis, olanzapine appears to exert a direct influence on primary as well as secondary negative symptoms. Pooled data from the extension phases of randomised, controlled trials revealed that olanzapine 2.5 to 20 mg/day for up to 1 year was associated with a higher probability of maintaining a response (defined as the absence of hospitalisation for psychosis) than either placebo or haloperidol (5 to 20mg). This suggests that the efficacy of olanzapine is maintained over this treatment period. Preliminary data indicate that olanzapine may improve quality of life to a greater extent than haloperidol. In placebo-controlled trials, the only adverse events occurring more often with olanzapine than with placebo were somnolence (12 to 39%), constipation (6 to 15%) and weight gain (0 to 12%). When compared with haloperidol, olanzapine was associated with significantly fewer adverse movement disorders, tremor, nervousness and salivation but a higher frequency of weight gain, dry mouth and increased appetite. Olanzapine demonstrated little potential for the induction of EPS, as measured by rating scales assessing parkinsonism, akathisia and dystonia. Olanzapine produced either no effect on or small improvements in rating scale scores and was associated with significantly lower scores than haloperidol. The incidence of treatment-emergent dyskinetic effects was significantly lower with olanzapine than with haloperidol, as shown by combined analysis of 3 long term trials in 1155 patients. Using the AMDP-5 scale, olanzapine was associated with a significantly higher incidence of 2 items (excessive appetite and dry mouth) compared with 25 for haloperidol. Treatment with olanzapine causes occasional elevations in levels of hepatic transaminases; however, the increases appear to be transient and no clinical evidence of hepatotoxicity has been documented. No significant effect on haematological parameters (e.g. agranulocytosis) has been reported in patients receiving olanzapine, including those who had previously experienced clozapine-induced dyscrasias. The recommended dosage of olanzapine is 5 to 1 Omg once daily initially, without regard for meals, aiming to reach a dosage of 10 mg/day within several days. Dosage may be adjusted using 5mg increments at intervals of at least 1 week. Dosages ≥15 mg/day should be implemented only after clinical assessment. The tolerability of dosages of 20 mg/day has not been assessed. A starting dosage of 5 mg/day is used in patients who are debilitated or predisposed to hypotension, or who may exhibit slower olanzapine metabolism (women aged ≥65 years who are nonsmokers). Responding patients should receive maintenance treatment using the lowest effective dose. Olanzapine should be used with caution in patients with, or at risk of, the following conditions: cardiovascular, cerebrovascular or other disease which may predispose to the development of hypotension; hepatic dysfunction; and seizures. Because somnolence may occur with olanzapine, patients should use caution if operating machinery or driving.