Focus on Olanzapine
by Dr Ben Green MB ChB MRCPsych ILTM
Introduction
Olanzapine is a novel antipsychotic agent marketed by Lilly & Co. It has a pleotrophic pharmacology and affects dopaminergic, serotonergic, muscarinic and adrenergic activities. Clinical studies and trials suggest olanzapine is superior to haloperidol and also maybe superior to risperidone in terms of efficacy and side-effect profiles
The therapeutic advantage of recent antipsychotics (so-called atypical antipsychotics) has been attributed to alpha-2 adrenergic antagonist effects (Nutt, 1994).
The starting dose of olanzapine is a single evening dose of 10mg. The drug reaches peak plasma levels in 5-8 hours, and has a half-life of about 35 hours depending on metabolism. The usual maximum dose should be 20mg.
Abnormalities of the qt interval on ECG appear very infrequently and there is no need for a baseline ECG as with sertindole.
The most common side effects appear to be somnolence and weight gain. About 11% of patients gain weight -especially if on a high starting dose and if they were underweight pre-treatment.
Reported evidence to date suggests that olanzapine is relatively less likely to produce sexual dysfunction. In general weight gain and sexual dysfunction are of great concern to people taking antipsychotics.
Psychopharmacology
Olanzapine shows mesolimbic sensitivity, blocks conditioned avoidance at lower doses than those inducing catalepsy, substitutes for clozapine in a drug discrimination assay, produces a modest rise in prolactin, produces few extrapyramidal side effects and reduces positive and negative symptoms of schizophrenia as efficaciously as clozapine (Moore, 1995) However, despite this 'atypical' profile olanzapine has a weaker alpha-2 blockade than clozapine or risperidone. It has relatively high affinity for muscarinic, 5HT - 2, and D1, D2 and D4 receptors. Trials suggest a good response in schizophrenia with few extrapyramidal side effects (EPSEs) Administration is via the oral route. A rapid dissolving formulation is available.
Clinical Efficacy
In a clinical trial (Tran et al, Lilly - Published Data) 335 patients with schizophrenia were randomised to five treatment groups:
- placebo
- olanzapine low dose range (2.5-7.5mg)
- olanzapine medium dose range (7.5-12.5mg)
- olanzapine high dose range (12.5-17.5mg)
- haloperidol(10-20mg)
The trial lasted 6 weeks and involved weekly evaluations. Patients receiving olanzapine had few EPSEs, with no dystonic reactions - contrasted with 13% of the haloperidol group. It was the high dose treatment group that produced BPRS rating reductions significantly superior to haloperidol and placebo. SANS score comparison showed a similar statistically better reduction for the high dose olanzapine group compared to haloperidol and placebo. This apparent ability to affect negative symptoms is initially exciting.
On further testing in 152 patients in a double-blind multicentre six week study, the 10 mg olanzapine dosage was well tolerated and produced a significant effect against positive and negative symptoms compared to placebo (Beasley et al, 1995). Scales used included the BPRS, PANSS and CGI.
Tollefson et al (1997) demonstrated in a multicentre, double blind trial of 1,996 patients that olanzapine was superior to haloperidol at reducing overall BPRS and negative symptoms. A reduction in affective symptoms was also noted compared to haloperidol.
Negative symptoms are sometimes postulated to be attributable to permanent frontal lobe deficits, and therefore sometimes deemed irreversible. Tollefson and Sanger's study of negative symptoms (1997) looked at 335 patients comparing haloperidol and olanzapine over 52 weeks. A path analysis was used to determine to what extent the treatment on treatment symptoms was direct or indirect. Compared to haloperidol or placebo, olanzapine was significantly more likely to directly improve SANS scores, particularly with regard to affective blunting and apathy.
Maintenance therapy with olanzapine promises fewer relapses than with conventional agents such as haloperidol. The one year relapse rate with oral olanzapine was 19% whereas oral haloperidol's was 28% in a study by Tran et al (1998)
Comparisons with Other Novel Antipsychotics
Compared to risperidone:
- greater tolerability
- better at reducing affective symptoms
- possibly better at improving patient
- quality of life and interpersonal relationships
- statistically better improvements in PANSS
- scores and fewer relapses
fewer EPS and less sexual dysfunction
less likely to elevate prolactin levels
Olanzapine and risperidone are two 'atypical' antipsychotics, but they differ in terms of chemical structures, overall receptor binding affinity, animal neuropharmacology, pharmacokinetics and risk/benefit profiles. An international , randomized double-blind parallel study has been performed comparing risperidone and olanzapine in DSM-IV schizophrenia, schizophreniform disorder and schizoaffective disorder. The study involved an 8 week acute phase followed by a 20 week extension phase. The dose ranges of olanzapine were 5-20 mg/day and 4-12 mg/day for risperidone. Data is available to PoL from the interim analyses of the first 290 plus patients entered into the study. Statistically significantly more olanzapine-treated patients completed the 28 weeks than risperidone-treated patients. (68% versus 48%, p=.028). Both risperidone and olanzapine appeared to effective antipsychotics for positive and negative symptomatology. Olanzapine demonstrated a superiority over risperidone in reducing mood symptoms, providing high clinical response rates, maintaining response and improving patient quality of life and interpersonal relationships.
After 28 weeks of therapy Olanzapine showed statistically better improvements in PANSS scores and fewer relapses than risperidone.At 6 months the rates of relapse were 11% for olanzapine and 29% for risperidone. Olanzapine patients has statistically fewer EPS and sexual dysfunction, measured by subjective and objective rating scales. Olanzapine patients were less likely to have elevated prolactin levels than the risperidone group.
Side Effects
The most common side effects appear to be somnolence and weight gain. About 11% of patients gain weight -especially if on a high starting dose and if they were underweight pre-treatment.
| Side Effect | Olanzapine |
Haloperidol |
| Postural Hypotension | 2% | 1% |
| Constipation | 5% | 4% |
| Dry Mouth | 7% | 4% |
| Somnolence | 16% | 15% |
| Hostility | 6% | 5% |
| Rash | 2% | 1% |
| Headache | 11% | 13% |
| Diarrhoea | 3% | 3% |
| Agitation | 8% | 9% |
| Akathisia | 6% | 21% |
| Anxiety | 6% | 8% |
| Confusion | 1% | 2% |
| Dyskinesia | 0% | 2% |
| Tremor | 3% | 13% |
Sexual dysfunction is a problem for many patients, although sexual dysfunction in schizophrneia does not appear to be primarily attributable to drugs. Untreated patients with schizophrneia have more sexual problems than controls (Aizenberg et al,1995).
Data from Lilly's clinical trials of olanzapine have yielded the following data:
| Event | Number of reports Total N=2,500 |
Percentage Reporting |
| Decreased libido | 23 | 0.9% |
| Increased libido | 18 | 0.7% |
| Impotence | 11 | 0.7% |
| Abnormal Ejaculation | 3 | 0.2% |
| Priapism | 1 | 0.1% (Denominator=only males) |
| Anorgasmia | 1 | 0.0% |
Recent published data
Position in Psychiatry On-Line Prescribers' survey.
| Month and Year | For new patients | For enduring illness |
|---|---|---|
| October 1996 | Launch | Launch |
| November 1996 | 1.0% | 1.0% |
| May 1997 | No. 3 Olanzapine (6.2%) |
No. 4 Olanzapine(5.9%) |
| June 1997 | No. 3 Olanzapine (7.1%) |
No. 3 Olanzapine(7.3%) |
Recent work by Tollefson et al (1997) from an international multicentre, double blind parallel trial looks at olanzapine versus haloperidol in first episode psychosis. Olanzapine was significantly better than haloperidol in reducing average BPRS total scores, BPRS negative scores, PANSS total scores and PANSS positive scores. Haloperidol patients had significantly more EPS.
Conclusion
Olanzapine is an atypical antipsychotic which was launched in October 1996. The initial impression is of a useful antipsychotic with few EPS and with a potential to reduce positive and negative symptoms to a better degrees than some conventional antipsychotics and some other 'atypical' antipsychotics. There is good tolerability in humans.
References
Aizenberg, D, Zemishlany, Z, Dorfman-Etrog P, Weizman, A. (1995) Sexual dysfunction in male schizophrenic patients. J Clin Psychiatry, 56(4): 137-141.
Beasley, CM, Satterlee, WG, Sanger, T &
Tollefson, GD. (1995) Additional Clinical Experience with Olanzapine: an atypical
antipsychotic. (Lilly Published Material)
Moore, N A. (1995) Letter to the Editor, J
Psychopharmacology, 9, 155.
Nutt, D J (1994) Putting the 'A' in atypical:
does alpha-2 adrenoceptor antagonism account for the therapeutic advantage of new
antipsychotics? J Psychopharmacol., 8, 193-5.
Tollefson GD et al. (1997) Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders, results of an international collaborative trial. Am J Psychiatry; 154:4 457-465.
Tollefson G D and Sanger, T M. (1997) Negative Symptoms: a path analytic aapproach to a double-blind, placebo- and haloperidol-controlled clinicaltrial with olanzapine.l. Am J Psychiatry; 154:4 466-473.
Tollefson, G D Sanger, T M, Lieberman, J A. (1997) Olanzapine versus haloperidol in the treatment of first episode psychosis. Schizophrenia Research; 24 Nos.1-2.
Tran, PV, Beasley CM, Tollefson, GD et al. (1995) Clinical efficacy & Safety of Olanzapine (Lilly Published Material)
Tran, PV,
Dellva, MA, Tolefson, G D, Wentley, A L, Beasley C M. (1998) Oral olanzapine versus
oral haloperidol in the maintenence treatment of schizophrenia and related psychoses. B
J Psychiatry , 172, 499-505.
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