The introduction of clozapine, risperidone and olanzapine has improved the outcomes for patients with psychoses. The reduced extrapyramidal adverse effects of the new antipsychotic medications, compared with standard antipsychotics, make them the drugs of choice for patients with a recent onset of psychosis. A trial of a new antipsychotic medication should also be considered in patients who have had a suboptimal response and/or disabling adverse events while taking older antipsychotic medication. Clozapine should be reserved for use in treatment-resistant patients. Three other antipsychotic medications may soon be available: ziprasidone, quetiapine and sertindole.
Antipsychotic medications are effective in the management of acute psychotic symptoms arising from a variety of psychiatric and neuropsychiatric conditions. In particular, antipsychotic medications (also known as neuroleptics) are effective in reducing symptoms such as delusions, hallucinations and disorganised communication. After the acute phase, maintenance treatment with antipsychotic medications plays a key role in reducing the risk of relapse in schizophrenia and related conditions (e.g. delusional disorder, schizoaffective disorder).
How good are we at treating schizophrenia?
While many patients with psychosis show a moderate to substantial reduction in symptoms after treatment with antipsychotic medications, about 30% have little or no improvement. While agitation may settle promptly with treatment, symptoms such as hallucinations, delusions and disorganised communication may take several weeks to settle. The negative symptoms of schizophrenia (such as lack of speech, blunted affect) are less responsive to medication. However, the major limitation of the older medications is their disabling adverse effects. Extra pyramidal adverse effects (Parkinsonism, dystonia, akathesia, tardive dyskinesia) and sedation are particularly common.
Medication is a central feature of the treatment of schizophrenia, but as with many chronic illnesses, patient and carer education is also needed in order to optimise longer-term outcomes. A variety of educational programs have proven efficacy in reducing relapses.
While antipsychotic medications reduce relapse and are relatively effective for some of the more prominent symptoms of psychoses, the current treatment of schizophrenia remains suboptimal. Many patients do not respond, many have adverse effects and many relapse. The ideal treatment would be the immediate, complete and sustained remission of all symptoms of psychoses. Clearly, there is a substantial gap between current and ideal treatment.
Do the new medications result in better patient outcomes?
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 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.
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).
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
Who should receive the new antipsychotics?
Most clinicians believe that the reduced risk of extra pyramidal adverse events associated with products such as risperidone and olanzapine make these drugs the first choice for treating new patients. Clinical experience and consumer feedback suggest that compliance is improved for individuals on drugs such as risperidone and olanzapine because of their more favourable adverse event profile.
For patients who have responded to traditional antipsychotics but who have been disabled by extra pyramidal adverse effects, there is a strong case for a trial of risperidone or olanzapine. In addition, there is a case for offering patients, who have made a partial response to traditional antipsychotics, a trial of the newer antipsychotic medications to try to improve the clinical outcomes.
When 'switching' from one antipsychotic to another, care should be taken to educate the patient about the potential risks and benefits. A crossover phase of several weeks (lowering the dose of the previous medication in concert with increasing the dose of the new antipsychotic) is generally recommended. Reducing the dose of pre-existing depot medications is not required in light of the gradual reduction in serum levels for such preparations. Apart from the risk of cholinergic rebound in those switching to risperidone, no major drug interactions have been reported in such crossovers. Patients should be educated about the potential of the newer antipsychotics to cause sedation and/or postural hypotension in the early phases of prescribing. Patients and their carers need to be alert for early signs of breakthrough psychosis (the 'relapse signature'). All parties need to set the desired goals of treatment (e.g. reduction in symptoms, improved adverse effect profile) in order to decide when to continue or stop the trial of the new medication.6
After several years' experience with clozapine, there is now a strong consensus that it is currently the most effective drug for treatment-resistant patients. However, the majority of these patients will not even respond to clozapine. The key issue for clinicians relates to balancing the proven efficacy of the product against the burden of adverse events and monitoring. Patients who have failed to respond to adequate trials of traditional and newer antipsychotic medications should be offered a trial of clozapine.
As parenteral preparations of olanzapine and risperidone are not available, traditional antipsychotics may be needed for the management of acute psychosis with agitation. The co-prescription of a benzodiazepine is often required for sedation.
The introduction of clozapine has allowed us to reject the myth that all antipsychotics are essentially equal with respect to efficacy and adverse effects. The introduction of drugs such as risperidone and olanzapine has reduced the adverse effect burden for people with psychoses. While we are still a long way from ideal treatment (immediate, complete and sustained remission of all symptoms of psychoses in all treated patients), the introduction of several new antipsychotic medications has narrowed the gap between current best practice and optimal practice.
Abstracts for the Cochrane Library can be accessed at the following web page: http://som.flinders.edu.au/fusa/cochrane/cochrane/cdsr.htm
Carr VJ. The role of the general practitioner in the treatment of schizophrenia: general principles. Med J Aust 1997;166:91-4.
Carr VJ. The role of the general practitioner in the treatment of schizophrenia: specific issues. Med J Aust 1997;166:143-6.
The following statements are either true or false.
1. Clozapine, olanzapine and risperidone can all cause patients to gain weight.
2. Patients taking clozapine require regular full blood counts.
Answers to self-test questions
- Wahlbeck K, Cheine M, Essali MA, Rezk E. Clozapine versus `typical' neuroleptic medication for schizophrenia (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. Oxford: Update software.
- Kennedy E, Song F, Hunter R, Gilbody S. Risperidone versus `typical' antipsychotic medication for schizophrenia (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. Oxford: Update software.
- Tollefson GD, Beasley CM, Tamura RN, Tran PV, Potvin JH. Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997;154:1248-54.
- Beasley CM, Tollefson GD, Tran PV. Safety of olanzapine. J Clin Psychiatry 1997;58 Suppl 10:13-7.
- Srisurapanont M, Disayavanish C, Taimkaew K. Quetiapine for schizophrenia (Cochrane Review). In: The Cochrane Library, Issue 3, 1998. Oxford: Update software.
- Weiden PJ, Aquila R, Dalheim L, Standard JM. Switching antipsychotic medications. J Clin Psychiatry 1997;58 Suppl 10:63-72.