Background Information of the Condition
Bipolar disorder Type I is characterized by at least one manic episode, with or without major depression. Patients are often symptomatically ill for nearly half of the time and their most frequent symptoms are depression, followed distantly by mania/hypomania, and then mixed episodes.1 Drugs used for treatment of acute mania are: lithium, valproate (valproic acid or valproate divalproex sodium), haloperidol, carbamazepine and antipsychotics (risperidone, quetiapine, olanzapine, ziprasidone).
In clinical trials, the efficacy of anti-manic drugs is measured using the Young Mania Rating Scale (YMRS). The score ranges from 0-602. Efficacy is measured either as a mean change in YMRS score from baseline; or as clinical response, defined as 50% reduction from baseline; or as symptomatic remission, defined as an endpoint score < 12. The YMRS score has good reliability (r = 0.93) and validity, associated with the number of days of continued stay in hospital (r = 0.66). Limitations of this score include subjectivity, lack of assessment of depressed mood, and double rating of 4 items (irritability, speech, content and disruptive-aggressive behaviour).
Other outcome measures used in clinical trials are – 21-item Hamilton Depression Rating Scale (HAM-D-21), the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression bipolar version (CGI-BP), Brief Psychiatric rating Scale (BPRS), Global Assessment Functioning Scale (GAF), and Health Related Quality of Life Assessment SF- 36 (HRQOL).
Drug (Product Monograph) 3
Category: Antipsychotic and an anti-manic drug
Mechanism of Action: Olanzapine, a thienobenzodiazepine, works across a number of receptor systems: dopamine D1, D3, D4, 5-HT2A/C, 5-HT3, 5-HT6, muscarinic M1-M5, adrenergic α1 and histamine H1.
Indications: “for the acute treatment of manic or mixed episodes in bipolar I disorder, either as monotherapy or cotherapy with other agents (e.g., lithium or divalproex sodium)”.
Dose: The recommended starting dose in adults is 15mg once a day as monotherapy and 10 mg once a day as combination therapy. Daily dosage (5-20 mg) should be adjusted in response to clinical assessment.
Duration: Not specified. If the patient responds to acute treatment and continues on with maintenance therapy, the dose should initially remain unchanged.
Methodology of Systematic Review
- In double-blind randomized controlled trials (DBRCTs), does maintenance with olanzapine monotherapy provide a therapeutic advantage in terms of mortality, morbidity and preventing relapse compared with placebo or other anti-manic drugs in adult patients with remission of Bipolar I disorder (manic or mixed episode)?
- In double-blind randomized controlled trials, does maintenance therapy with olanzapine in combination with other drugs provide a therapeutic advantage in terms of mortality, morbidity and preventing relapse compared with placebo or other anti-manic drugs in adult patients with remission of Bipolar I disorder (manic or mixed episode)?
Assessment principles: DBRCTs that compare olanzapine monotherapy (or in combination with other drugs) to appropriate comparators, in adult patients with remission of Bipolar I disorder (manic or mixed episode) will be critically appraised. Therapeutic effect will be assessed according to the following hierarchy of health outcome measures – all-cause mortality, non-fatal serious adverse events, general health and quality of life, remission or response of manic symptoms, decrease in depression symptoms, withdrawals due to adverse events, and other adverse events such as movement disorders, cardiovascular effects, weight gain, sedation and abnormal laboratory values.
Search strategy: Databases searched include MEDLINE (1966 to February 2007), EMBASE (1988-February 2007), and the Cochrane database (issue 4, 2006).
Search Findings: Two DBRCTs were identified for monotherapy: one comparing olanzapine with lithium4, and one with placebo5. One combination therapy trial compared olanzapine versus placebo in addition to lithium or valproate6.
Olanzapine vs lithium
One DBRCT4 studied 431 adult patients achieving symptomatic remission on open-label combination therapy with olanzapine and lithium; followed by 52 weeks of double-blind monotherapy with either olanzapine (N = 217) or lithium (N =214). The withdrawal rate of 68.5% of total randomized patients invalidates study findings as reported (last observation carried forward in the intention-to-treat analysis).
Olanzapine vs Placebo
One DBRCT5 studied 361 adult patients with olanzapine compared to placebo for 48 weeks. The withdrawal rate of 79% of randomized patients in the olanzapine group and 93% in the placebo group invalidates study findings as reported (last observation carried forward in the intention-to-treat analysis). Withdrawal due to adverse events were significantly higher in the olanzapine group as compared to the placebo group (p<0.001) ARI = 7.6%, NNH = 12.
Olanzapine in combination with lithium or valproate
One DBRCT6 studied 99 adult patients with olanzapine compared to placebo in patients on lithium or valproate for18 months. The withdrawal rate of 69% of randomized patients in the olanzapine group and 90% in the placebo group invalidates study findings as reported.
Critical appraisal Issues:
The studies reported last observation carried forward (LOCF) on a limited number of randomized patients (drop out rates ranging from 68 to 93%). Reporting results as LOCF does not compensate for the incomplete patient follow-up. A modified study design is required to produce scientifically valid results whereby patients are followed after withdrawal from active therapy, for the full trial period.
- There is insufficient evidence that olanzapine monotherapy provides a therapeutic advantage versus lithium or placebo as maintenance therapy in patients with acute mania.
- There is insufficient evidence that olanzapine combination therapy provides a therapeutic advantage versus valproate or lithium monotherapy.
- Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry. June 2002; 59(6):530-537.
- Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: Reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429-435.
- Zyprexa (olanzapine) Product Monograph.
- Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: A 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005;162:1281-1290.
- Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163:247-256.
- Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer v. mood stabilizer alone. Br J Psychiatry. 2004;184:337-345.