31 August 2010
This meta-analysis found no significant differences between first generation (typical) antipsychotics (FGAs) and second generation (atypical) antipsychotics (SGAs) with regard to their effects on symptoms or discontinuation rates, when used to treat early psychosis. Patients taking SGAs gained more weight than those taking FGAs, whereas FGAs were associated with more extrapyramidal side effects than SGAs.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Practitioners should follow NICE guidance on schizophrenia. This does not give preference to FGAs or SGAs in people with newly diagnosed schizophrenia. Rather, NICE advise that the choice of antipsychotic should be made in partnership with the person (and carer if appropriate) taking into account the relative potential of individual antipsychotics to cause extrapyramidal side effects, metabolic side effects (such as weight gain), and other side effects. A patient decision aid is available on the schizophrenia section of NPC that includes a chart of the relative side effect profiles of different antipsychotics. This may be helpful when considering which antipsychotic is most appropriate for a person to try first. In view of the substantial differences in acquisition costs of FGAs and SGAs, prescribers and prescribing managers need to review their use of SGAs carefully and ensure that it is in line with NICE guidance.
What is the background to this?
Over a number of years, SGAs have been increasingly used in the treatment of psychosis in preference to FGAs. Previous NICE guidance on schizophrenia tended to support preferential use of SGAs, because of their perceived beneficial side effect profile. However, awareness of the different, but potentially equally undesirable side effects of SGAs has increased, and current NICE guidance (from 2009) does not give preference to SGAs over FGAs. People with newly diagnosed schizophrenia tend to be more likely to show a good response to antipsychotics, but they may also be more sensitive to extrapyramidal side effects. This meta-analysis (MA) considered results from 15 randomised controlled trials (RCTs) of 2,522 participants which compared FGAs and SGAs in treatment of the early phase of non-affective psychosis.
What does this study claim?
The MA found no statistically significant differences between SGAs and FGAs in rates of discontinuation for any cause at around 12 months (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.4 to 1.2) or effect on symptom scores at around 3 months (standardised mean difference [SMD] = –0.1, 95%CI –0.2 to 0.02). Participants on SGAs gained an average of 2.1 kg (95%CI 0.1 to 4.1) more weight than those on FGAs, whereas those on FGAs experienced more extrapyramidal side-effects (SMD = –0.4, 95%CI –0.5 to –0.2).
This study supports current NICE guidance on schizophrenia and the notion that, at a population level, there is little good reason to SGAs over FGAs routinely in early psychosis. There is no clear evidence of advantages in terms of symptom control or likelihood of discontinuation (due to intolerable side effects and/or lack of treatment efficacy). The differing propensity of individual drugs to cause particular side effects is more important in guiding choice for individual people. Finally, when there is not a compelling reason to choose a particular drug because of likely side effects, one cannot ignore the differences in cost. For example, haloperidol 5mg twice a day costs £4.04 per 28 days whereas olanzapine 10mg/day costs £79.45 per 28 days, nearly 20 times as much. In the quarter to December 2009, there were nearly 1.8million items for antipsychotics dispensed in primary care in England, of which about 1.3million (around 70%) were SGAs; SGAs accounted for well over 90% of the £65million spent on antipsychotics in English primary care that quarter. Some of those antipsychotics would have been prescribed for bipolar illness (for which only certain SGAs are licensed) and for behavioural and psychological symptoms of dementia (see our previous MeReC Stop Press). Nevertheless, pressures on public sector finances are increasing. Money spent on SGAs cannot be spent on other services including, for example, non-drug care. Prescribers and prescribing managers need to review their use of SGAs carefully and ensure that it is in line with NICE guidance.
What are the limitations of this analysis?
The results for effects on symptoms were consistent between studies, but the results for effects on discontinuation rates showed significant heterogeneity. That is, the results from different studies showed a greater dissimilarity than would be expected from chance alone. This probably arose from differences in the definition of ‘discontinuation’ used in the studies. This varied from taking lower doses of antipsychotic than prescribed in one study, to total discontinuation of the drug in another. The SGAs showed a clear advantage over FGAs in the MA with regard to extrapyramidal side effects. However, most studies used haloperidol as the FGA, albeit mostly at lower doses. ‘High potency’ FGAs such as haloperidol and trifluoperazine have a greater tendency to produce extrapyramidal effects than low potency FGAs such as chlorpromazine. It is possible that the differences between FGAs and SGAs seen in this MA would have been less marked if low potency FGAs had been used.
Design: Meta-analysis of RCTs obtained from searching Medline, Embase, PsycINFO and Cochrane CENTRAL plus hand searching of conference abstracts from the 3rd to 5th Conference on Early Psychosis and 8th to 14th Biennial Winter Workshop on Schizophrenia.
Patients: 2,522 patients from 15 RCTs. To be included, studies had to use a validated diagnostic system and explicitly define whether participants were antipsychotic-naïve, were experiencing a first episode of psychosis or were in the early phase of psychosis. It excluded studies of patients with affective psychosis, and of people who were younger than 13 or older than 65 years. Authors were contacted if insufficient data were presented in the published report.
Intervention and comparison: SGAs versus FGAs
Outcomes and results: The OR for discontinuation for any cause at 12 months (or where this was not reported, between 6 to 24 months) was 0.7 (95%CI 0.4 to 1.2, P=0.22). The SMD for symptoms scores at 12 weeks (or when this was not reported, between 6 to 18 weeks) was –0.1, 95%CI –0.2 to 0.02, P=0.12). Participants on SGAs gained an average of 2.1 kg (95%CI 0.1 to 4.1, P=0.04) more weight than those on FGAs, whereas those on FGAs experienced more extrapyramidal side-effects (SMD = –0.4, 95%CI –0.5 to –0.2, P<0.001).
Sponsorship: The first author is in receipt of an Academic Training Fellowship from the National Institute of Health Research, UK
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