Uses
Olanzapine is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia) in adults and adolescents 13-17 years of age. In addition, oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the management of acute manic or mixed episodes associated with bipolar I disorder; the drug also is used for longer-term maintenance monotherapy in patients with this disorder. Short-acting olanzapine injection is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia. Long-acting olanzapine pamoate injection is used IM for the management of schizophrenia in adults.
Olanzapine is used orally in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age. The drug also is used orally in combination with fluoxetine for the acute and maintenance therapy of treatment-resistant depression.
-
Psychotic Disorders
Olanzapine is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.
-
Schizophrenia
Olanzapine is used orally for the management of schizophrenia in adults and adolescents from 13 to 17 years of age. The long-acting pamoate ester of olanzapine is used parenterally for the management of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.
The American Psychiatric Association (APA) considers most atypical antipsychotic agents (e.g., olanzapine, aripiprazole, quetiapine, risperidone, ziprasidone) first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional (first-generation) and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents may be considered first-line in patients who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.
To compare the long-term effectiveness and tolerability of older, first-generation antipsychotic agents (i.e., perphenazine) with those of newer, atypical antipsychotic agents (i.e., olanzapine, quetiapine, risperidone, ziprasidone), a double-blind, multicenter study (the first phase of Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE]) was sponsored by the National Institute of Mental Health. More than 1400 patients with schizophrenia received one of these antipsychotics for up to 18 months or until therapy was discontinued for any reason. Patients with tardive dyskinesia could enroll in this trial; however, the randomization scheme prevented their assignment to the perphenazine group. The primary outcome measure in this study was the discontinuance of treatment for any cause; this measure was selected because discontinuing or switching an antipsychotic agent occurs frequently and is an important problem in the management of schizophrenia. In addition, this measure integrates the patient's and clinician's judgments concerning efficacy, safety, and tolerability into a more comprehensive measure of effectiveness reflecting therapeutic benefits in relation to adverse effects. Overall, 74% of patients in this study discontinued their medication before receiving the full 18 months of therapy because of inadequate efficacy, intolerable adverse effects, or for other reasons, suggesting substantial limitations in the long-term clinical effectiveness of currently available antipsychotic agents. Olanzapine appeared to be more effective than the other drugs evaluated in this study with a lower (64%) discontinuance rate and a lower rate of hospitalization for exacerbation of schizophrenia, while no significant differences between the effectiveness of the conventional agent, perphenazine, and the other second-generation agents studied were observed (discontinuance rates were 75, 82, 74, and 79% for perphenazine, quetiapine, risperidone, and ziprasidone, respectively). The time to discontinuance of therapy for any cause was found to be longer in the olanzapine group than in the quetiapine, risperidone, perphenazine, and ziprasidone groups in this study; however, the differences between the olanzapine and perphenazine groups and between the olanzapine and ziprasidone groups did not achieve statistical significance. Although there were no significant differences in the time until discontinuance of therapy because of drug intolerance among the drugs studied, the incidences of discontinuance for certain adverse effects differed among the drugs with olanzapine discontinued more frequently because of weight gain or metabolic effects (e.g., increases in glycosylated hemoglobin [hemoglobin A1c; HbA1c], cholesterol, and triglycerides) and perphenazine discontinued more frequently because of adverse extrapyramidal effects.
An open, multicenter, randomized, controlled trial comparing the relative long-term effectiveness (over a 1-year period) of a group of first-generation antipsychotic agents (e.g., chlorpromazine, flupentixol [not commercially available in the US], flupentixol decanoate [not commercially available in the US], fluphenazine decanoate, haloperidol, haloperidol decanoate, loxapine, methotrimeprazine [no longer commercially available in the US], pipothiazine palmitate [not commercially available in the US], sulpiride [not commercially available in the US], trifluoperazine, zuclopenthixol [not commercially available in the US], zuclopenthixol decanoate [not commercially available in the US]) with a group of second-generation antipsychotic agents other than clozapine (e.g., olanzapine, amisulpride [not commercially available in the US], quetiapine, risperidone, zotepine [not commercially available in the US]) in patients with schizophrenia was conducted throughout the United Kingdom by the National Health Service. In the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1), the primary outcome measure was the Quality of Life Scale score, and secondary outcome measures included symptom improvement, adverse effects, patient satisfaction, and costs of health care. Patients in the first-generation antipsychotic group demonstrated a trend toward greater improvements in the Quality of Life Scale and symptom improvements scores in this study. In addition, the patients studied did not report a clear preference for either group of drugs and costs of health care in the 2 groups were found to be similar.
Emerging data from the first phase of the pivotal CATIE trial and the CUtLASS 1 trial suggest that newer, atypical antipsychotics may not provide clinically important advantages over older, first-generation antipsychotics in patients with chronic schizophrenia and that several factors, including adequacy of symptom relief, tolerability of adverse effects, and cost of therapy, may influence a patient's ability and willingness to remain on long-term antipsychotic medication. In addition, these results suggest that it may often be necessary to try 2 or more different antipsychotic agents in an individual patient in order to provide optimal therapeutic benefit with an acceptable adverse effect profile.
In a randomized, double-blind, second phase trial, patients with schizophrenia who had discontinued an atypical antipsychotic agent during the first phase of the CATIE trial were reassigned to treatment with a different atypical antipsychotic agent (olanzapine, quetiapine, risperidone, or ziprasidone). Similarly to the first phase of the CATIE trial, efficacy and tolerability in this second phase study were principally measured by time until drug discontinuance for any reason. The time until antipsychotic treatment was discontinued was longer for patients receiving risperidone and olanzapine than for those receiving quetiapine and ziprasidone (median: 7, 6.3, 4, and 2.8 months, respectively). Among patients who discontinued their prior antipsychotic agent because of lack of efficacy, olanzapine was found to be more effective than quetiapine and ziprasidone, while risperidone was more effective than quetiapine.
In another study that was part of the second phase of the CATIE investigation, schizophrenic patients who had discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone during the first phase of the CATIE investigation, principally because of inadequate efficacy, were randomized to receive open-label clozapine therapy or blinded treatment with another atypical antipsychotic agent not previously received in the trial. Clozapine was found to be more effective in this study than switching to another atypical antipsychotic agent. Patients receiving clozapine also were found to be less likely to discontinue treatment for any reason than patients receiving quetiapine or risperidone. In addition, the clozapine-treated patients were less likely to discontinue therapy because of an inadequate clinical response than were patients receiving the other atypical antipsychotic agents.
Pending further data clarifying the relative effectiveness and tolerability of first- and second-generation antipsychotics in the treatment of schizophrenia, many clinicians recommend that the choice of an antipsychotic agent be carefully individualized taking into consideration the clinical efficacy and adverse effect profile (including the risk for extrapyramidal effects, weight gain, and adverse metabolic effects) of the antipsychotic agent as well as the individual patient's risk factors; the patient's previous experience of subjective effects such as dysphoria; the patient's preference for and willingness to take (i.e., compliance) a specific drug, including route of administration; and the relative cost of therapy. Olanzapine and clozapine may be reasonable alternatives in any patient with schizophrenia who has not achieved a full clinical remission with other antipsychotic agents; however, the risk of adverse metabolic effects with both drugs necessitates dietary and exercise counseling before therapy is initiated, monitoring during drug therapy, and possible discontinuance of therapy if these effects become troublesome during therapy. Additional analyses from data generated by the CATIE trial addressing other schizophrenia treatment-related issues such as quality of life and predictors of response are ongoing.
Atypical antipsychotic agents, including olanzapine, generally appear less likely to induce adverse extrapyramidal effects and tardive dyskinesia than conventional, first-generation antipsychotic agents. In addition, stabilization of or improvement in tardive dyskinesia associated with conventional antipsychotic agents has been reported in some patients when they have been switched to second-generation antipsychotic therapy, including olanzapine. Therefore, the APA and some clinicians recommend that atypical antipsychotic agents be considered in patients with schizophrenia who have experienced tardive dyskinesia associated with conventional antipsychotic agents.
For additional information on the symptomatic management of schizophrenia, .
The efficacy of oral olanzapine for the management of psychotic disorders in adults has been established in hospital settings by 2 placebo-controlled studies of 6 weeks' duration in patients who met the DSM-III-R criteria for schizophrenia. In these and several other studies, improvement in manifestations of schizophrenia was based principally on the results of various psychiatric rating scales, including the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbances, activation, hostility/suspiciousness, and anxiety/depression; the Scale for the Assessment of Negative Symptoms (SANS); the Positive and Negative Symptoms Scale (PANSS); and the Clinical Global Impression (CGI).
In the first 6-week, placebo-controlled study, olanzapine was given in a fixed dosage of 1 or 10 mg once daily. Results indicated that the 10-mg, but not the 1-mg, once-daily dosage was more effective than placebo in improving the scores on the PANSS total (also on the extracted BPRS total), the BPRS psychosis cluster, the PANSS Negative subscale, and the CGI Severity assessments. Results of the second 6-week, placebo-controlled study, which evaluated 3 fixed dosage ranges (5 +/- 2.5 mg once daily, 10 +/- 2.5 mg once daily, and 15 +/- 2.5 mg once daily), found that the 2 highest dosages (actual mean dosages were 12 and 16 mg once daily, respectively) were more effective than placebo in reducing the BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest dosage also was superior to placebo on the SANS. There appeared to be no therapeutic advantage for the higher dosage of olanzapine compared with the medium dosage in this study. No race- or gender-related differences in outcome were noted in either of these studies.
The efficacy of oral olanzapine for long-term use (i.e., longer than 6 weeks) in schizophrenia has been established in one controlled study in adults, and the drug has been used in some other patients for prolonged periods (e.g., reportedly up to 1 year) without apparent loss of clinical effect. In the long-term clinical trial, adult outpatients who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine therapy during an open-label treatment phase lasting at least 8 weeks were randomized to continue receiving their current olanzapine dosage (ranging from 10-20 mg daily) or to receive placebo. Although the follow-up period to observe patients for relapse, which was defined in terms of increases in BPRS positive symptoms or hospitalization, initially was planned for 12 months, criteria were met for stopping the trial early because of an excess of placebo relapses compared with olanzapine relapses. In addition, olanzapine was found to be superior to placebo on prolonging time to relapse, which was the primary outcome measure in this study. Therefore, olanzapine was more effective than placebo at maintaining efficacy in schizophrenic patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months. If oral olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically.
The short-term efficacy of long-acting IM olanzapine pamoate in schizophrenia has been established in a randomized, double-blind, placebo-controlled, multicenter study of 8 weeks' duration in 404 adults who were experiencing acute psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia. Patients were randomized to receive IM injections of olanzapine pamoate (Zyprexa Relprevv) in dosages of 210 mg (of olanzapine) every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks or placebo every 2 weeks. Patients were discontinued from their previous antipsychotic regimen and underwent a washout period lasting 2-7 days. Supplementation with oral antipsychotics was not allowed throughout the study. The primary efficacy measure in this study was the change from baseline to end point in the total PANSS score (the mean baseline total PANSS score was 101). Total PANSS scores showed improvement from baseline to end point with each dosage of olanzapine pamoate compared with placebo. At week 8, PANSS total scores decreased by a mean of 22.5, 22.6, or 26.3 points in patients receiving IM olanzapine pamoate 210 mg every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks, respectively, compared with a mean decrease of 8.5 points in patients receiving placebo. There were no substantial differences in efficacy among the 3 olanzapine pamoate dosage groups at the study end point. The onset of antipsychotic efficacy for the long-acting olanzapine pamoate injection was evident within the first week of treatment. The manufacturer states that the effectiveness of olanzapine pamoate injection in the treatment of schizophrenia also is supported by the established effectiveness of orally administered olanzapine.
Efficacy of long-acting IM olanzapine pamoate for long-term use (i.e., longer than 8 weeks) in the maintenance treatment of schizophrenia has been established in a randomized, double-blind, multicenter study in 1065 adults. Adult outpatients with schizophrenia who had remained stable on oral olanzapine therapy during an open-label treatment phase lasting 4-8 weeks were randomized to continue receiving their current olanzapine dosage orally (10, 15, or 20 mg daily) or to receive long-acting IM olanzapine pamoate (Zyprexa Relprevv) in a low-dosage regimen (150 mg [of olanzapine] every 2 weeks), a medium-dosage regimen (405 mg every 4 weeks), or a high-dosage regimen (300 mg every 2 weeks), or a very low reference dosage regimen (45 mg every 4 weeks) for 24 weeks in the double-blind maintenance phase. No supplementation with oral antipsychotics was allowed throughout the study. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia, which was defined as either increases in BPRS positive symptoms or hospitalization. IM olanzapine pamoate was found to be effective in the maintenance treatment of schizophrenia for up to 24 weeks and IM olanzapine pamoate dosage regimens of 150 mg every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks were found to be superior to 45 mg every 4 weeks. Olanzapine pamoate generally demonstrated a similar safety profile to oral olanzapine with the exception of injection-related adverse effects. If IM olanzapine pamoate injection is used for extended periods, the need for continued therapy should be reassessed periodically.
Parenteral antipsychotic therapy with a long-acting IM preparation may be particularly useful in patients with schizophrenia and a history of poor compliance. In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug. The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur. The manufacturer of Zyprexa Relprevv recommends that patients first receive oral olanzapine therapy to establish tolerability of the drug before long-acting IM olanzapine pamoate is used. Long-acting IM olanzapine pamoate may be most useful in schizophrenic patients who respond well to oral olanzapine therapy and for whom a depot antipsychotic can improve compliance.
Olanzapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both controlled and uncontrolled studies of patients with schizophrenia. Like other second-generation antipsychotic agents, olanzapine appears to improve both positive (florid symptomatology such as hallucinations, conceptual disorganization, and suspiciousness) and negative (''deficit'' symptomatology such as emotional withdrawal, motor retardation, blunted affect, and disorientation) manifestations of schizophrenia; conventional antipsychotic agents may have lesser effects on negative manifestations of the disorder. Some evidence also suggests that atypical antipsychotic agents may be more effective in treating cognitive and mood symptoms as well as global psychopathology than conventional antipsychotic agents, but this is controversial and remains to be fully established. In addition, some patients with schizophrenia who have been stabilized on long-term conventional antipsychotic therapy have demonstrated further improvement following a switch to an atypical antipsychotic agent.
Results from one comparative study in adults suggest that oral olanzapine dosages of 7.5-17.5 mg daily may be as effective as oral haloperidol dosages of 10-20 mg daily in reducing positive symptoms of schizophrenia, while oral olanzapine dosages of 12.5-17.5 mg daily may be more effective than oral haloperidol dosages of 10-20 mg daily in reducing negative symptoms of schizophrenia. A randomized, controlled trial comparing the long-term (i.e., 1 year) effectiveness and cost of olanzapine and haloperidol therapy in patients with schizophrenia or schizoaffective disorder did not reveal any important advantage of olanzapine compared with haloperidol on measures of compliance, symptom improvement, adverse extrapyramidal effects, overall quality of life, and cost; olanzapine also was more frequently associated with weight gain. However, olanzapine therapy was associated with reduced akathisia, less tardive dyskinesia in a secondary analysis, and small but significant improvements in measures of memory and motor function compared with haloperidol. In other comparative studies, olanzapine usually was found to be at least as effective as or more effective than haloperidol and several other atypical antipsychotic agents, including quetiapine, risperidone, and ziprasidone. In a comparative, double-blind trial conducted in patients with schizophrenia or schizoaffective disorder, both olanzapine and risperidone were found to be effective and well tolerated, although greater reductions in the severity of positive and affective symptoms were noted in the risperidone-treated patients compared with those receiving olanzapine.
Olanzapine also has been studied in patients with treatment-refractory schizophrenia (i.e., patients who have demonstrated an inadequate response to prior antipsychotic therapy) in both open and comparative clinical trials. In an open trial of 6 weeks' duration, olanzapine (15-25 mg daily) was found to be effective and well tolerated in adult patients with treatment-refractory schizophrenia with 36% responding to the drug. In a double-blind trial of 8 weeks' duration, although olanzapine (25 mg daily) was found to be as effective as chlorpromazine (1.2 g daily with benztropine), the total amount of improvement with either drug was modest; olanzapine was better tolerated than chlorpromazine. In a double-blind trial of 14 weeks' duration comparing efficacy and safety of several atypical antipsychotics (olanzapine, clozapine, and risperidone) with each other and with haloperidol, olanzapine (mean dosage of approximately 30 mg daily) and clozapine produced greater clinical improvement in global psychopathology and negative symptoms than haloperidol (mean dosage of approximately 26 mg daily) in patients with chronic schizophrenia or schizoaffective disorder, but the effects of atypical antipsychotic agents were considered small and of limited clinical importance. In another study using the manufacturer's clinical trial database to retrospectively identify treatment-resistant schizophrenic patients, olanzapine (mean dosage of approximately 11 mg daily) was found to be more effective than haloperidol therapy (mean dosage of approximately 10 mg daily) in improving positive, negative, and mood symptoms and produced fewer extrapyramidal effects. The results of clinical trials to date suggest that olanzapine may be somewhat less effective than or similarly effective to clozapine in the management of resistant schizophrenia patients. Clozapine generally appears to be more effective in the management of treatment-refractory schizophrenia than most first-generation and other second-generation antipsychotic agents and may produce greater improvement in negative symptoms of schizophrenia than other antipsychotic agents; however, tolerability concerns (e.g., hematologic toxicity, hypotension, dizziness, sedation) limit its use in many patients. Although higher olanzapine dosages (i.e., up to 60 mg daily) have been used in some patients with treatment-resistant schizophrenia, it remains to be established whether higher dosages of the drug result in improved efficacy in such patients, and higher dosages may increase the risk of extrapyramidal and other adverse effects.
Like some other atypical antipsychotic agents (e.g., clozapine, risperidone), olanzapine therapy appears to reduce the risk of violent behavior in patients with schizophrenia. Although the precise mechanism(s) for the antiaggressive effects are not known, improved compliance with atypical antipsychotic agents may play a role.
Olanzapine also has been used with a variety of adjunctive agents, including other antipsychotic agents, antidepressants (including selective serotonin-reuptake inhibitors such as fluoxetine and fluvoxamine), valproate (e.g., divalproex sodium, valproic acid, valproate sodium), and topiramate, in some patients with treatment-refractory schizophrenia, inadequate response to antipsychotic therapy, or acute exacerbations of schizophrenia in both controlled and uncontrolled trials. Further controlled trials of olanzapine combined with these agents are necessary to more clearly determine the potential risks and benefits of such combined therapy.
-
Pediatric Considerations
Olanzapine is used orally for the management of schizophrenia in adolescents 13 to 17 years of age. Clinicians treating pediatric patients with schizophrenia should be aware that pediatric schizophrenia is a serious mental disorder; however, its diagnosis can be challenging. Symptom profiles in such patients can be variable. Therefore, it is recommended that drug therapy for pediatric schizophrenia be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment should only be part of a total treatment program that often includes psychological, educational, and social interventions.
When deciding among the alternative treatments available for adolescents with schizophrenia, clinicians should consider the increased potential for weight gain and dyslipidemia in adolescents treated with olanzapine (as compared with adults). Clinicians also should consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in adolescent patients.
(See Cautions: Endocrine and Metabolic Effects, Cautions: Precautions and Contraindications, and see also Cautions: Pediatric Precautions.) The short-term efficacy and tolerability of oral olanzapine in 107 adolescent inpatients and outpatients 13-17 years of age with schizophrenia were established in a randomized, double-blind, placebo-controlled, multicenter trial of 6 weeks' duration in which olanzapine was given in a flexible dosage range of 2.5-20 mg once daily. The principal rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the BPRS for Children (BPRS-C) total score. Olanzapine (mean modal dosage: 12.5 mg daily; mean dosage: 11.1 mg daily) was found to be more effective than placebo in treating adolescents with schizophrenia, since the olanzapine-treated adolescents had a substantially greater mean reduction in the BPRS-C total score compared with those receiving placebo. However, weight gain and hyperprolactinemia occurred more often in patients receiving olanzapine compared with those receiving placebo.
Olanzapine has been successfully used orally for the management of childhood-onset schizophrenia in a limited number of children and other adolescents. However, the manufacturers state that the safety and effectiveness of the drug in children younger than 13 years of age have not been established.
Although there is no body of evidence available to determine how long adolescent patients treated with oral olanzapine should be maintained on the drug, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. If olanzapine is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.
Based on the observed efficacy and tolerability of atypical antipsychotics in adults and the available clinical experience in pediatric patients, the American Academy of Child and Adolescent Psychiatry (AACAP) currently states that the use of atypical antipsychotic agents in children and adolescents with schizophrenia is justified, and many clinicians consider atypical antipsychotic agents, with the exception of clozapine, among the drugs of first choice in the management of childhood-onset schizophrenia. However, well-controlled studies are necessary to more clearly establish the efficacy and safety of atypical antipsychotics in pediatric patients, particularly during long-term therapy. For additional information on the symptomatic management of childhood-onset schizophrenia,
-
Acute Agitation
Short-acting olanzapine injection (e.g., Zyprexa IntraMuscular) is used IM for the management of acute agitation in adult patients with schizophrenia for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). According to DSM-IV, psychomotor agitation is excessive motor activity associated with a feeling of inner tension. The efficacy of IM olanzapine for the management of acute agitation in patients with schizophrenia was established in 2 short-term (single-day), placebo-controlled trials in hospital settings; an active comparator treatment arm using haloperidol injection was included in both studies. The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (''moderate'') or greater using a 1-7 scoring system, where scores of 1 or 7 indicate absent or extreme agitation, respectively. The primary measure used for assessing efficacy in managing agitation in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections of IM olanzapine; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed.
In the first placebo-controlled trial, short-acting IM olanzapine was given in fixed single doses of 2.5, 5, 7.5, or 10 mg in agitated hospitalized patients with schizophrenia. All 4 IM olanzapine doses were found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours following injection; however, the effect was larger and more consistent for the 3 highest doses studied. There were no significant differences in efficacy noted for the 7.5- and 10-mg doses compared with the 5-mg dose in this study. In the second placebo-controlled trial in agitated patients with schizophrenia, a fixed, 10-mg dose of short-acting IM olanzapine was evaluated and found to be superior to placebo on the PANSS Excited Component at 2 hours following injection. An analysis of these 2 controlled studies as well as an additional controlled study conducted in agitated patients with bipolar mania for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.
-
-
-
Bipolar Disorder
Oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the acute management of manic or mixed episodes associated with bipolar I disorder; the drug also is used orally for longer-term maintenance monotherapy in adults and adolescents 13-17 years of age with this disorder. In addition, oral olanzapine is used in combination with fluoxetine hydrochloride for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age. According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).
For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy. For further information on the management of bipolar disorder,
-
Acute Treatment of Manic or Mixed Episodes
Efficacy of oral olanzapine monotherapy in the acute treatment of manic or mixed episodes in adults has been demonstrated in 2 short-term (i.e., 3 or 4 weeks' duration), randomized, double-blind, placebo-controlled, parallel-group trials in patients who met DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). Olanzapine was given in an initial dosage of 10 mg once daily in the 3-week trial and 15 mg once daily in the 4-week trial; the dosage was subsequently adjusted within the range of 5-20 mg once daily in both of these trials. The principal rating instrument used for assessing manic symptoms in these trials was the Y-MRS score, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (e.g., irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, insight) in a range from 0 (no manic features) to 60 (maximum score). All patients were hospitalized at the onset of these trials, but some patients were allowed to continue the studies on an outpatient basis after 1 week of hospitalization if their Clinical Global Impressions-Bipolar Version of severity of illness (CGI-BP) mania score was no greater than 3 (mild) and they had at least a 50% reduction in their Young Mania Rating Scale (Y-MRS) scores. In the 3- and 4-week placebo-controlled trials, approximately 49-65% of patients receiving 5-20 mg of olanzapine once daily achieved a 50% or greater improvement in Y-MRS total score from baseline compared with approximately 24-43% of those who received placebo. In addition, unlike therapy with typical antipsychotic agents, patients receiving olanzapine in these clinical studies did not experience a worsening in depressive symptoms (defined as an increase in the Hamilton Psychiatric Rating Scale for Depression-21 item [HAMD-21] score of at least 3 points) compared with those receiving placebo. In another 3-week, placebo-controlled trial that was designed identically to the first 3-week trial and was conducted simultaneously, olanzapine demonstrated a similar treatment difference in reduction of the Y-MRS total score but was not found to be superior to placebo on this outcome measure, possibly due to sample size and site variability.
Data from one limited comparative study suggest that oral olanzapine dosages of 10 mg daily may be as effective as lithium carbonate dosages of 400 mg twice daily in the treatment of manic episodes in adults with bipolar disorder. In a randomized, double-blind trial of 3 weeks' duration comparing olanzapine (5-20 mg daily) and divalproex sodium therapy in hospitalized adults with bipolar disorder experiencing acute manic or mixed episodes, olanzapine therapy was found to produce greater improvement in Y-MRS total scores, which was the primary efficacy measure in this trial. In addition, a substantially greater proportion of patients in the olanzapine group achieved remission compared with the divalproex group. In a randomized, double-blind study of 12 weeks' duration comparing olanzapine and divalproex sodium in patients with bipolar I disorder hospitalized for acute mania, the drugs were found to be equally effective although divalproex sodium was somewhat better tolerated than olanzapine.
-
Combined Therapy
Efficacy of oral olanzapine when used in combination with lithium or valproate in the short-term treatment of acute manic or mixed episodes has been demonstrated in 2 randomized, double-blind, placebo-controlled studies of 6 weeks' duration in adult patients who met the DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). In these studies, patients with bipolar disorder experiencing manic or mixed episodes (Y-MRS scores of 16 or greater) who had not responded to at least 2 weeks of lithium or divalproex sodium monotherapy despite adequate plasma drug concentrations (in a therapeutic range of 0.6-1.2 mEq/L for lithium or 50-125 mcg/mL of valproate for divalproex sodium) were randomized to receive either olanzapine (initial dosage of 10 mg once daily; range: 5-20 mg once daily) or placebo, in combination with their original therapy. Addition of olanzapine to lithium or divalproex sodium was shown to be superior to continued monotherapy with lithium or divalproex sodium in the reduction of Y-MRS total score in both of these studies.
The manufacturer states that efficacy of adjunctive therapy with olanzapine for longer-term use (i.e., longer than 6 weeks) in patients with bipolar I disorder has not been systematically evaluated in controlled trials.
-
Maintenance Monotherapy of Bipolar Disorder
Oral olanzapine is used for maintenance monotherapy in adults and adolescent patients 13-17 years of age with bipolar I disorder. The long-term efficacy of oral olanzapine as maintenance monotherapy in adults with bipolar disorder has been demonstrated in a double-blind, placebo-controlled trial and in double-blind comparative trials. In the placebo-controlled study, adult patients who met DSM-IV criteria for bipolar I disorder and experienced manic or mixed episodes and who had responded during an initial open-label treatment phase to oral olanzapine therapy (5-20 mg daily) for an average of about 2 weeks were randomized either to continue olanzapine at the same dosage or to receive placebo for up to 48 weeks and were observed for relapse. Response during the open-label phase was defined as a reduction in the Y-MRS total score of 12 or more and in the 21-item Hamilton Depression Rating Scale (HAM-D 21) of 8 or more; relapse during the double-blind phase of the study was defined as an increase in the Y-MRS or HAM-D 21 total score to 15 or more or being hospitalized for either mania or depression. Approximately 50% of the patients in the olanzapine group had discontinued therapy by day 59, and approximately 50% of the patients in the placebo group had discontinued placebo by day 23 of the double-blind phase. A longer time until relapse was observed in the patients receiving olanzapine compared with those receiving placebo (median of 174 and 22 days, respectively, for relapse into any mood episode) during the randomized phase of this study. The relapse rate also was significantly lower in the olanzapine group (approximately 47%) than in the placebo group (approximately 80%). If olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically.
In a double-blind, 52-week trial comparing olanzapine and lithium maintenance therapy in adults with bipolar disorder, olanzapine was found to be significantly more effective than lithium in preventing relapses and recurrences of manic and mixed episodes following initial stabilization with combined olanzapine and lithium therapy. Olanzapine and lithium demonstrated comparable efficacy in preventing relapses and recurrences of depression in this study. In a retrospective analysis from this trial, patients were subcategorized into illness stage (early, intermediate, or later) based on the number of prior manic or mixed episodes they had experienced. The rates of relapse or recurrence of manic or mixed episodes were approximately 2 and 26%, 13 and 24%, and 24 and 33% for olanzapine and lithium in the early, intermediate, and later stage groups of bipolar patients, respectively; no substantial treatment effect for treatment or illness stage for depressive relapse or recurrence was observed. Because olanzapine was associated with a lower rate of relapse or recurrence of manic and mixed episodes in early-stage patients, it was suggested that the drug may be particularly effective early in the course of bipolar disorder.
In a double-blind, 47-week trial comparing monotherapy with olanzapine or divalproex sodium in adults with bipolar disorder experiencing manic or mixed episodes, mean improvement in Y-MRS scores was greater for olanzapine-treated patients. In addition, the median time to symptomatic mania remission was shorter for patients receiving olanzapine compared with those receiving divalproex sodium (14 days vs. 62 days, respectively). However, no significant differences in the rates of symptomatic mania remission and symptomatic relapse into mania or depression between the olanzapine- and divalproex-treated patients were observed in this study. In a double-blind, 18-month, relapse prevention trial comparing the efficacy of combined olanzapine plus lithium or valproate therapy with lithium or valproate therapy alone in patients with bipolar disorder, more sustained symptomatic remission (163 days vs 42 days, respectively) occurred in the group receiving combined olanzapine plus lithium or valproate therapy than in the group receiving lithium or valproate therapy alone.
-
Rapid-Cycling Bipolar Disorder
In an analysis of pooled data from several trials comparing the clinical response to olanzapine therapy in rapid-cycling and non-rapid-cycling adult patients with bipolar disorder, relative clinical response to olanzapine was found to be similar in the 2 groups, although earlier responses were observed in the rapid-cycling group of patients, and long-term outcomes were more favorable in the non-rapid-cycling group. Rapid-cycling patients were found to be less likely to achieve an initial symptomatic remission, more likely to experience recurrences, especially of depression, and had more hospitalizations and suicide attempts than non-rapid-cycling patients in this study.
-
Depressive Episodes Associated with Bipolar Disorder
Oral olanzapine is used in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age. In 2 randomized, double-blind studies of 8 weeks' duration comparing a fixed combination of olanzapine and fluoxetine hydrochloride (Symbyax) with olanzapine monotherapy and placebo in adults, the fixed combination (given in flexible daily dosages of 6 mg olanzapine with 25 or 50 mg of fluoxetine or 12 mg of olanzapine with 50 mg of fluoxetine) was more effective than olanzapine monotherapy (5-20 mg daily) or placebo in improvement in depressive symptoms as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). Although the manufacturer states that efficacy beyond 8 weeks' duration remains to be established, patients have received the fixed combination for up to 24 weeks in clinical trials. Clinicians who elect to extend therapy beyond 8 weeks should reevaluate the risks and benefits of continued therapy periodically.
The manufacturers state that olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
-
Pediatric Considerations
Oral olanzapine is used as monotherapy in adolescents 13-17 years of age for the acute management of manic or mixed episodes associated with bipolar I disorder; the drug also is used orally for longer-term maintenance monotherapy in patients with this disorder. Oral olanzapine in combination with fluoxetine is used for the treatment of acute depressive episodes associated with bipolar I disorder in pediatric patients 10-17 years of age. When treating pediatric patients with bipolar I disorder, clinicians should be aware that pediatric bipolar I disorder is a serious mental disorder; however, its diagnosis can be challenging. Pediatric patients with bipolar disorder may have variable patterns of periodicity of manic or mixed symptoms. Therefore, it is recommended that drug therapy for pediatric bipolar disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment. Medication treatment should only be part of a total treatment program that often includes psychological, educational, and social interventions.
When deciding among the alternative treatments available for adolescents with bipolar disorder, clinicians should consider the increased potential for weight gain and dyslipidemia in adolescents receiving olanzapine (as compared with adults). Clinicians also should consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in adolescent patients.
(See Cautions: Endocrine and Metabolic Effects, Cautions: Precautions and Contraindications, and see also Cautions: Pediatric Precautions.) The short-term efficacy of oral olanzapine monotherapy in the acute treatment of bipolar I disorder in adolescents 13-17 years of age was established in a randomized, multicenter, double-blind, placebo-controlled trial of 3 weeks' duration in 161 patients who met DSM-IV-TR criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features). In this flexible-dosage trial, outpatients and inpatients were randomized to receive either olanzapine 2.5-20 mg daily (mean modal dosage of 10.7 mg daily; mean dosage of 8.9 mg daily) or placebo. Olanzapine was found to be more effective than placebo as demonstrated by substantially greater reduction in the total score on the Adolescent Structured Y-MRS, which was the primary efficacy measure in this study. However, the olanzapine-treated adolescents had substantially greater weight gain and elevations in serum transaminases, prolactin, fasting glucose, fasting total cholesterol, and uric acid compared with those receiving placebo.
The efficacy and safety of oral olanzapine in combination with fluoxetine hydrochloride for the acute treatment of depressive episodes associated with bipolar I disorder in pediatric patients 10-17 years of age were established in a randomized, double-blind, placebo-controlled trial of 8 weeks' duration in 255 patients who met the DSM-IV-TR criteria for bipolar I disorder, depressed episode. Patients randomized to receive olanzapine and fluoxetine were initially given 3 mg of olanzapine with 25 mg of fluoxetine and force-titrated to the maximum dosage of 12 mg of olanzapine with 50 mg of fluoxetine over 2 weeks; after 2 weeks, patients received flexible dosages of olanzapine 6-12 mg with fluoxetine 25-50 mg daily. At week 8, olanzapine in combination with fluoxetine was found to be substantially more effective than placebo in reducing the Children's Depression Rating Scale-Revised (CDRS-R) total score, which was the primary efficacy measure in this study. The average daily dosage was 7.7 mg of olanzapine and 37.6 mg of fluoxetine. The pediatric patients who received olanzapine in combination with fluoxetine had substantially greater weight gain and elevations in serum transaminases, serum lipids, and prolactin compared with those receiving placebo. The recommended initial dosage of the olanzapine/fluoxetine combination is lower in children and adolescents than in adults. In addition, the manufacturer states that flexible dosing is recommended in such patients instead of the forced-titration dosing initially used in this study.
(See Bipolar Disorder under Dosage: Oral Dosage, in Dosage and Administration.) Although there is no body of evidence available to determine how long adolescent patients with bipolar disorder treated with olanzapine should be maintained on the drug, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. If olanzapine is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.
Based on the observed efficacy and tolerability of mood stabilizers and atypical antipsychotic agents in clinical trials in adults and the available clinical experience in pediatric patients, the American Academy of Child and Adolescent Psychiatry (AACAP) currently states that mood stabilizers (e.g., lithium, valproic acid, carbamazepine) and atypical antipsychotics (e.g., olanzapine, aripiprazole, risperidone, quetiapine, ziprasidone) are among drugs of first choice in the acute management of pediatric patients with bipolar I disorder experiencing manic or mixed episodes with or without psychosis. Additional controlled studies are necessary to more clearly establish the efficacy and safety of atypical antipsychotics in pediatric patients with bipolar disorder, particularly during long-term therapy.
-
Acute Agitation
Short-acting olanzapine injection (e.g., Zyprexa IntraMuscular) is used IM for the management of acute agitation in patients with bipolar I disorder for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with their diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). According to DSM-IV, psychomotor agitation is excessive motor activity associated with a feeling of inner tension.
The efficacy of short-acting IM olanzapine for the management of acute agitation in adults with bipolar mania was established in a short-term (single-day), double-blind, placebo-controlled trial in agitated, hospitalized patients who met the DSM-IV criteria for bipolar I disorder and who displayed an acute manic or mixed episode with or without psychotic features. The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (''moderate'') or greater using a 1-7 scoring system where scores of 1 or 7 indicate absent or extreme agitation, respectively. An active comparator treatment arm using IM lorazepam was included in this study. The primary measure used for assessing efficacy in managing agitation in this trial was the change from baseline in the PANSS Excited Component at 2 hours post-injection of a fixed, 10-mg IM dose of olanzapine. Patients in this study could receive up to 3 injections of IM olanzapine; however, patients could not receive the second injection until after the initial 2-hour period when the efficacy was assessed. IM olanzapine was found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours and at 24 hours following the initial injection. An analysis of this study as well as 2 additional controlled studies conducted in agitated patients with schizophrenia for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.
-
-
Treatment-resistant Depression
Oral olanzapine is used in combination with fluoxetine hydrochloride for the acute and maintenance therapy of treatment-resistant depression (i.e., major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dosage and duration in the current episode).
The efficacy and safety of oral olanzapine in combination with fluoxetine for the acute treatment of treatment-resistant depression were demonstrated in 3 clinical studies conducted in 579 adults 18-85 years of age. Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine. In the first study, efficacy of the fixed combination of olanzapine and fluoxetine (Symbyax) was evaluated in 300 patients who met DSM-IV criteria for major depressive disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode. Patients enrolled in this study entered an open-label fluoxetine lead-in phase in which the nonresponders were randomized to receive the fixed combination of olanzapine and fluoxetine, olanzapine alone, or fluoxetine alone for 8 weeks. The fixed combination of olanzapine and fluoxetine was flexibly dosed between 6-18 mg of olanzapine daily; all patients received 50 mg of fluoxetine daily. A substantially greater reduction in mean total MADRS scores from baseline to end point was observed in patients receiving olanzapine in fixed combination with fluoxetine compared with those receiving either fluoxetine or olanzapine alone. A second, smaller study with the same treatment-resistant depressed patient population also demonstrated a substantially greater reduction in MADRS scores in patients treated with the fixed combination compared with patients receiving fluoxetine or olanzapine monotherapy (when analyzed with change in MADRS score as the outcome measure). A third study demonstrated a substantially greater reduction in total MADRS scores in patients receiving the fixed combination of olanzapine and fluoxetine compared with those treated with fluoxetine or olanzapine alone, when data were analyzed in a subpopulation of 251 depressed patients who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dosage and duration in the current episode).
The efficacy of oral olanzapine in combination with fluoxetine in the maintenance therapy of treatment-resistant depression was demonstrated in a 47-week study in 892 adults (18-65 years of age) who met DSM-IV criteria for major depressive disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode. Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine. Patients were initially treated with open-label olanzapine and fluoxetine in fixed combination (Symbyax). Patients who responded to and were stabilized on the fixed combination over approximately 20 weeks were randomized to continue receiving fixed-combination olanzapine and fluoxetine treatment or to receive fluoxetine alone for another 27 weeks. A total of 15.8% of patients receiving olanzapine and fluoxetine in fixed combination relapsed compared with 31.8% of patients receiving fluoxetine monotherapy; this difference was statistically significant. In addition, patients who continued to receive olanzapine and fluoxetine in fixed combination experienced a substantially longer time to relapse over the 27-week period compared with those receiving fluoxetine alone. If combined olanzapine and fluoxetine therapy is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.
The manufacturer states that olanzapine monotherapy is not indicated for the treatment of treatment-resistant depression.
