In recent years, several antipsychotic medications have entered the market. These include clozapine, risperidone and olanzapine. In the next few years, 3 other drugs will probably become available to Australian prescribers: ziprasidone, quetiapine and sertindole. These drugs are sometimes called 'atypical antipsychotics' because, compared to the earlier drugs, they have reduced extra pyramidal adverse effects. However, these adverse effects may occur with all 'atypicals'; probably less with olanzapine and clozapine than risperidone.
The task for the prescriber is to decide if the recently introduced products result in improved outcomes for patients. These outcomes should include both 'narrow' and 'broad' perspectives. The narrow perspective has traditionally been influenced by pharmaceutical regulatory bodies, and includes key concepts such as a reduction in positive symptoms and an acceptable adverse effect profile. Clinicians and patients now desire a broader range of outcomes including improvements in a wider range of symptoms (negative symptoms, accompanying mood elements, cognitive performance), subjective measures, quality of life and prevention of relapse. As there are limited health resources, the pharmacoeconomics of the new drugs also needs consideration.
Patient outcomes may be improved by early treatment with drugs that are better tolerated. This is likely to increase compliance and allow maintenance of usual social networks.
Recently, several reviews by the Cochrane Collaboration have been completed. They allow us to assess the impact of the new antipsychotics on clinically relevant outcome measures. Readers should keep up-to-date as new reviews become available by checking the Cochrane Web page.
Clozapine has a superior efficacy for positive and negative symptoms compared to traditional antipsychotics. Overall, the other newer antipsychotics have equal efficacy for the treatment of positive symptoms; however, some of the company-sponsored trials report superiority on various outcome measures. In assessing these claims, clinicians need to remain mindful that 'statistically significant differences' do not necessarily mean clinically useful differences (large trials can detect small differences). Furthermore, the size of the effect identified in controlled clinical trials does not also translate into everyday clinical practice, where patients may be less compliant and have physical and psychiatric co-morbidity.
Clozapine
Clozapine has affinity for many receptors (including dopamine, serotonin, muscarinic and histamine receptors). It has had a major impact on a broad range of outcome variables for patients with treatment-resistant schizophrenia, but it has a particularly burdensome adverse effect profile. Patients may complain of sedation, hyper salivation and weight gain. Higher doses increase the risk of convulsions. Less frequently, but of greater clinical importance, clozapine is associated with a 1% risk of agranulocytosis. Patients taking this drug need to be enrolled in a monitoring program. This requires weekly blood tests for 18 weeks and then monthly blood tests while on clozapine. White blood cell and neutrophil counts are monitored, and if they fall below certain criteria, the drug is stopped. Re-challenge is not allowed.
It is a testament to the efficacy of clozapine that patients and prescribers are prepared to tolerate the problems associated with its use. A recently released Cochrane review1 has confirmed the favourable clinical impressions. The review included 29 studies involving 2490 participants (only a subset of whom were treatment-resistant). Several clinically important outcomes favoured clozapine. Compared to typical antipsychotics, patients taking clozapine had fewer relapses, a greater reduction in symptoms, fewer drop-outs and greater satisfaction. The clinical efficacy of clozapine for treatment-resistant patients was confirmed, with 31% of these patients showing a clinical improvement.
Risperidone
The receptor binding profile of risperidone is characterised by a higher affinity for serotonin receptors than dopamine receptors. Compounds with weaker dopaminergic affinity, if accompanied by stronger serotonergic affinity, may have antipsychotic properties and less extra pyramidal adverse effects.
A Cochrane review of risperidone versus traditional antipsychotic medications has recently been completed (data on 3401 patients drawn from 14 studies).2 The meta-analysis favoured risperidone for clinical improvement. While risperidone offered little or no additional effect on positive or negative symptoms, it did have a reduced risk of movement disorders. Fewer participants on risperidone dropped out of the studies. Those on risperidone had less sedation, but were more likely to gain weight.
Clinical experience and more recent trial data have shown that the initially recommended dose of risperidone may have been too high. Optimal antipsychotic and adverse event profiles can be achieved with doses of 2-6 mg/day.
The main problems with the use of risperidone are the risk of extra pyramidal adverse effects with higher doses, weight gain and occasional endocrine problems related to hyperprolactinaemia (e.g. amenorrhoea, galactorrhoea, impotence). As risperidone lacks anticholinergic properties, patients switched from older antipsychotics (which often required the co-prescription of anticholinergic drugs to reduce extra pyramidal adverse effects) can undergo cholinergic rebound (flu-like symptoms).
Olanzapine
Like clozapine, olanzapine has a wide range of receptor affinities. Several randomised controlled trials showed that olanzapine is an effective antipsychotic medication with a favourable adverse event profile compared to traditional antipsychotic drugs. In particular, olanzapine has lower rates of extra pyramidal adverse effects. Of interest, a recent post-hoc analysis of randomised controlled trials found that olanzapine was associated with a lower incidence of tardive dyskinesia than haloperidol.3 It has been listed on the Pharmaceutical Benefits Scheme as its cost-effectiveness, compared to risperidone, is acceptable.
Trial data and clinical experience suggest that olanzapine is relatively well tolerated, but drowsiness, weight gain and dizziness can occur. Transient elevation of liver enzymes has been associated with olanzapine4, but this does not appear to be of clinical significance. While sharing structural and receptor binding properties with clozapine, olanzapine does not have a similar risk of agranulocytosis.
Sertindole, ziprasidone and quetiapine
None of these drugs is currently available in Australia.
Sertindole has a distinct receptor binding profile, with high affinity for serotonin, dopamine and alpha adrenergic receptors. Data from early trials suggest that sertindole is an effective antipsychotic which is associated with a reduced risk of extra pyramidal adverse effects compared to traditional antipsychotic drugs. It is not associated with marked sedation, but there is an increased risk of QTc interval prolongation (1.7% of patients). While traditional antipsychotics can also be associated with cardiac arrhythmias, the manufacturer recommends baseline and regular ECG monitoring for patients taking sertindole. It should not be used in combination with medications known to prolong the QTc interval and is contraindicated in patients with clinically significant cardiovascular disease.
Like risperidone, ziprasidone has a receptor binding profile characterised by strong serotonergic affinity (agonist and antagonist) and weak to moderate dopaminergic affinity. Early trials suggest that ziprasidone, compared to traditional antipsychotics, is an effective antipsychotic with a reduced risk of extra pyramidal adverse effects. Ziprasidone is associated with sedation. Weight gain has not been a prominent adverse effect.
Quetiapine has a broad receptor binding profile, with weaker histamine and muscarinic binding properties than clozapine. Compared to older antipsychotic medications, quetiapine appears to be an effective antipsychotic medication which was associated with fewer extra pyramidal adverse effects; however, data are limited.5