A recent meta-analysis concludes that all antipsychotic drugs differ in their efficacy and adverse effects and they are not a homogeneous group. This supports an individualised approach to treatment, taking into account the patient’s (or carer’s) views and based on relative efficacy, likelihood of adverse effects (e.g. extrapyramidal and metabolic side effects, including weight gain) and cost of treatment.
This meta-analysis does not provide us with good quality evidence to guide our practice in this area. Better quality and more pragmatic studies such as CATIE and CUTLASS are more useful. They support the view that trials of two or more drugs are likely to be needed to control symptoms of schizophrenia and switching will be necessary in most people before the most suitable treatment can be identified. Perhaps what this meta-analysis does support is that although second-generation agents are recommended as first-line options for patients with newly-diagnosed schizophrenia in the current NICE guidance, first-generation agents, such as perphenazine, should also be considered. Many are as effective, they are similarly tolerated, and they are generally far less costly than the newer second-generation agents.
What does this study claim?
This large meta-analysis of patients with schizophrenia (150 mostly short-term RCTs, n=21,533) compared the efficacy and adverse effects of nine second-generation antipsychotic drugs with first-generation drugs (haloperidol in 95 of these studies). It found that amisulpiride, clozapine, olanzapine and risperidone were significantly more effective for controlling overall symptoms, compared with first-generation antipsychotic drugs. The number needed to treat (NNT) for one additional person to respond ranged from 6 (95% CI 4 to 10) for amisulpiride to 15 (95% CI 9 to 36) for risperidone. Aripiprazole, quetiapine, sertindole, ziprasidone and zotepine were not significantly different from first-generation drugs, for overall efficacy or for the treatment of negative symptoms.
All nine second-generation antipsychotic drugs induced fewer extrapyramidal side effects than haloperidol, even at low doses (<12mg per day haloperidol). The NNT to prevent extrapyramidal side effects in one patient ranged from 2 for clozapine to 5 for zotepine. However, only clozapine, olanzapine and risperidone were shown to be significantly less likely than low-potency first-generation antipsychotics (600mg per day chlorpromazine or equivalent) to cause extrapyramidal side effects. Amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, and zotepine were associated with significantly more weight gain (in varying degrees) than haloperidol, whereas aripiprazole and ziprasidone were not. However there was no significant difference between second-generation and low-potency first-generation drugs in terms of weight gain.
How does this fit with other evidence?
NICE guidance on schizophrenia (December 2002) recommends that medication should be used as part of a package of care and that second-generation antipsychotics should be considered in the choice of first-line agents, mainly because of a lower risk of extrapyramidal symptoms. They advise that second-generation agents at the lower end of the standard dose range are the preferred treatments for a person experiencing a first episode of schizophrenia. The choice of antipsychotic drug should be made jointly by the individual and the clinician responsible for treatment based on an informed discussion of the relative benefits of the drugs and their side-effect profiles. The individual’s advocate or carer should be consulted where appropriate. This guidance is currently being updated, with publication anticipated in March 2009.
In the consultation draft of the updated full NICE guideline on schizophrenia, NICE conclude that, in 72 RCTs involving 16,556 participants with an acute exacerbation or recurrence of schizophrenia, there was no evidence that any particular antipsychotic had a superior risk/benefit profile, when compared to any other antipsychotic.
The limitations of the studies included in the meta-analysis should be considered when interpreting its results. It is difficult to assess response to treatment in schizophrenia and many studies rely on rating scales for symptom scores, using an arbitrary cut-off to imply efficacy. Patient oriented outcomes such as quality of life and relapse rate have seldom been reported: of the 150 RCTs included in the meta-analysis only 17 studies considered quality of life and only 14 long-term studies considered relapse. As patients with schizophrenia are likely to require long-term treatment, it is also of concern that only 81% of the studies included in the meta-analysis lasted for over 12 weeks.
A commentary accompanying the meta-analysis considers how the RCTs included may have been biased in favour of the second-generation antipsychotic drug. For example, in 95 of the 150 RCTs reviewed, the second-generation agent was compared with haloperidol, a high-potency first-generation agent, which is associated with a high-rate of extrapyramidal adverse effects. Medium potency first-generation drugs, such as perphenazine, may have been more appropriate comparators as they appear to be effective and associated with a lower rate of side effects.
The CATIE and CUTLASS studies were large pragmatic, independently funded studies, which had minimal exclusion criteria, and allowed co-existing conditions and the use of other medication, thereby enabling better comparison with patients seen in clinical practice. The main outcome measures were patient oriented e.g. all-cause treatment discontinuation, quality of life and the use of less potent comparator drugs than haloperidol was allowed (e.g. sulpiride, perphenazine). Both studies found that the superiority of any particular second-generation antipsychotic over another second- or first-generation antipsychotic was not supported. While olanzapine showed some benefit, it was also associated with significant metabolic-related adverse effects, in particular weight gain. Furthermore, there was little difference in the rates of extrapyramidal side effects between first- and second-generation agents.
In summary, both first- and second-generation antipsychotic classes are very broad and include some distinctly different agents. Evidence suggests that there appears to be little to choose in terms of efficacy between first- and second-generation agents and differences in the overall tolerability of the different types of antipsychotic may be far less than was previously thought. Second-generation antipsychotics are generally associated with fewer parkinsonian-like extrapyramidal side effects and most are associated with some degree of weight gain, but otherwise they are a heterogeneous group and have different side-effect profiles.
Initial choice of antipsychotic should be determined on an individual basis, taking into account patient preference, the relative efficacy of each drug, the likelihood of adverse effects (e.g. extrapyramidal side effects and metabolic side effects, including weight gain) and cost of treatment. Trials of two or more drugs are likely to be needed and switching will be necessary in most people before the most suitable treatment can be identified. Although second-generation agents are recommended as first-line options for patients with newly-diagnosed schizophrenia in the current NICE guidance, this meta-analysis suggests that first-generation agents, such as perphenazine, should also be considered. Many are as effective, they are similarly tolerated, and they are generally far less costly than the newer second-generation agents.
Design: meta-analysis of 150 double-blind, mainly short-term, RCTs. Open label and single-blind studies were excluded because they systematically favoured second-generation antipsychotics.
Patients: 21,533 participants with schizophrenia or related disorders
Comparison: the safety and efficacy of second-generation (amisulpiride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) vs. first-generation antipsychotic drugs (haloperidol, chlorpromazine, perphenazine, fluphenazine, flupenthixol, perazine etc.).
Outcomes: the primary outcome was mean overall change in symptom scores. Other efficacy outcomes included negative, positive and depressive symptoms, response rate, and overall quality of life. Adverse effects analysed were extrapyramidal side effects, weight gain and sedation.
Results: Four of the second-generation antipsychotic drugs were significantly better than first-generation drugs for overall efficacy, with small to medium effect sizes (amisulpiride −0·31 [95% CI −0·44 to −0·19, p<0·0001], clozapine −0·52 [−0·75 to −0·29, p<0·0001], olanzapine −0·28 [−0·38 to −0·18, p<0·0001], and risperidone −0·13 [−0·22 to −0·05, p=0·002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms.
Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol, and most of them even when haloperidol was used at doses less than 12 mg per day. Compared with haloperidol (but not low-potency first-generation antipsychotic drugs), clozapine, olanzapine, sertindole, and zotepine induced the most weight gain, quetiapine and risperidone caused intermediate weight gain, amisulpiride had little effect, and aripiprazole and ziprasidone had no significant effect. Clozapine, quetiapine, and zotepine were significantly more sedating than haloperidol, whereas aripiprazole was significantly less sedating.
Sponsorship: National Institute of Mental Health