Published in:
01-12-2004 | Adis Drug Evaluation
Olanzapine
A Review of its Use in the Management of Bipolar I Disorder
Authors:
Paul L. McCormack, Lynda R. Wiseman
Published in:
Drugs
|
Issue 23/2004
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Summary
Abstract
Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder, and for maintenance therapy to prevent recurrence in responders.
Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics, such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders, and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated, and although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms (EPS). Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.
Pharmacological Properties
Olanzapine is believed to exert its antimanic and antipsychotic effects predominantly by binding to and blocking dopamine D2 and serotonin (5-hydroxy-tryptamine) 5-HT2A receptors. Long-term administration of olanzapine selectively blocks dopaminergic neurons in the mesolimbic (A 10) pathway, but not in the nigrostriatal (A9) pathway, which may account for the lower incidence of EPS than is seen with conventional antipsychotic agents. Olanzapine binds with high or moderate affinity to 5-HT2A-C,3,6,7, D1–5, muscarinic M1–5, histamine H1, and α1- and α2-adrenergic receptors, giving rise to many of the recognised clinical and adverse effects of the drug.
Olanzapine displays linear pharmacokinetics across the dose range 0.5–30mg, with steady-state peak plasma levels of 20 μg/L attained after orally administering 10mg once daily for 8 days. The drug is widely distributed in the body. Olanzapine is rapidly and extensively metabolised by cytochrome P450 (CYP) 1A2, CYP2D6 and the flavin mono-oxygenase-3 system, and is excreted mainly in the urine, with an elimination half-life of approximately 33 hours. The clearance of olanzapine is moderately reduced by inhibitors of CYP1A2 (fluvoxamine) and CYP2D6 (fluoxetine), and increased by potent inducers of CYP1A2 (carbamazepine, smoking).
Therapeutic Efficacy
In randomised, double-blind trials, olanzapine was superior to placebo and was at least as effective as lithium, valproate semisodium, haloperidol or risperidone in the treatment of acute mania associated with bipolar I disorder. Olanzapine was also superior to placebo in treating acute bipolar mania when added to existing therapy with lithium or valproate semisodium.
During maintenance therapy over 12 months in responders, olanzapine was superior to placebo in delaying relapse and reducing the rate of relapse into an affective episode. Olanzapine was also superior to lithium in preventing relapse into mania, but not in preventing relapse into a depressive episode or for relapse overall. Olanzapine was not different from valproate semisodium with respect to time to relapse or rate of relapse.
Health-Related Quality of Life and Pharmacoeconomic Considerations
Olanzapine improved the health-related quality of life (HR-QOL) of patients with bipolar disorder relative to either baseline or placebo during both acute andmaintenance therapy. Improvements in patients’ HR-QOL produced by olanzapine were significantly greater than those with haloperidol and equal to or greater than those with valproate semisodium.
Limited pharmacoeconomic data suggest that the cost effectiveness of olanzapine is largely similar to that of risperidone, lithium or valproate semisodium.
Tolerability
Olanzapine was generally well tolerated during both acute and long-term maintenance therapy. The adverse events with a significantly higher incidence with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain during acute therapy, and bodyweight gain, fatigue and akathisia during maintenance therapy. The incidence of EPS with olanzapine was low and similar to that with placebo, lithium or valproate semisodium, but was significantly less than that with haloperidol. The overall incidence of adverse events, and bodyweight gain in particular, was higher with olanzapine than all comparators in clinical trials.