NHS Evidence Health Information Resources formerly National Library for Health

Expensive modern drugs for people with schizophrenia are no better than cheaper medicines that have been used for decades, reported The Guardian (24 November 2006). This was a reasonably accurate summary of a randomised trial that found no significant differences between first and second generation anti-psychotic drugs for schizophrenia after one year.

The Guardian on the 24 November 2006 (1) reported that a study found second generation anti-psychotic drugs (SGAs) to have no clear benefit over first generation anti-psychotics (FGAs), despite costing at least 10 times more.
The report is based on a randomised study, comparing the effect of FGAs with SGAs in people with schizophrenia requiring a change in treatment (2). The findings of the study suggested there were no significant differences between the two classes of treatment in terms of quality of life and a range of other clinical measures.
The Guardian article provided a concise and generally accurate summary of the research study, though the statement that SGAs cost "at least 10 times more" does not appear to be derived from the research findings, which reported more modest differences in cost between the two drug classes.

Evaluation of the evidence base for first- versus second-generation antipsychotic drugs in schizophrenia

Where does the evidence come from?

The research was conducted by Dr. Peter Jones and colleagues from the University of Cambridge, Imperial College London, University of Manchester and the Institute of Psychiatry, London. The study was funded by the UK NHS Health Technology Assessment Programme.

What were the authors' objectives?

To test the hypothesis that in people with schizophrenia requiring a change in treatment, second generation anti-psychotic drugs (SGAs) other than clozapine are associated with improved quality of life across one year, compared with first-generation antipsychotics (FGAs).

What was the nature of the evidence?

The study was a pragmatic multi-centre randomised controlled trial of 227 patients with schizophrenia, aged between 18 and 65 years, who were assessed for medication review because of an inadequate response or due to adverse effects of their current treatment, and had positive psychotic symptoms for at least one month. The primary outcome was the total score on the Quality of Life Scale (QLS) at 12, 26 and 52 weeks. Other outcomes measured (using the relevant scales) included: positive and negative symptoms, depression, attitudes and adherence to treatment, global functioning, adverse effects and patient satisfaction.

What interventions were examined in the research?

Patients were randomised to receive either an FGA or an SGA. Prior to randomisation, the responsible psychiatrist chose which specific drug to administer. FGAs were: chlorpromazine, flupenthixol, haloperidol, loxapine, sulpiride, trifluoperazine, zuclopenthixol, and depot antipsychotics (fluphenazine, zuclopenthixol, flupentixol and haloperidol decanoate, and pipothiazine palmtate). Thioridazine and droperidol were removed from licence during the course of the trial. SGAs were: risperidone, olanzapine, amisulpride, zotepine and quetiapine.

Psychiatrists were encouraged to keep patients in their randomised treatment arm for a minimum of 12 weeks (preferably for 52 weeks) and to choose a drug from the same class if a treatment change was needed. Nevertheless, patients were allowed to change from FGAs to SGAs and vice-versa.

What were the findings?

At 52 weeks, 85% of the FGA arm and 78% of the SGA arm were interviewed. There was no difference in QLS scores between the FGA and SGA groups (53.2 and 51.3, respectively). Neither were there statistically significant differences between the treatment groups in terms of symptoms (positive or negative), depression, attitudes and adherence to treatment, global functioning, or adverse effects. Participants reported no clear preference for either class of drug at any stage.

What were the authors' conclusions?

In people whose medication is changed for clinical reasons, there is no disadvantage across one year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than non-clozapine SGAs.

How reliable are the conclusions?

The study used appropriate methods to randomise the patients and to conceal the allocation sequence by using a remote telephone randomisation service. As participants were not blinded to treatment, the risk of bias may have been increased. However, the outcome assessors were blind to which treatment the patients had received.

Demographic and clinical characteristics that could potentially have influenced outcomes were similar for each of the two groups, and all patients were accounted for as the trial progressed over time.

The authors report intention-to-treat (ITT) effects at 52 weeks as their main analyses. ITT analysis compares patients' outcomes on the basis of the treatment they were randomised to, rather than the treatment they actually received. If patients switch from one treatment group to the other (as was the case in this study), ITT analysis can diminish any differences in outcomes between the two treatment groups. However, the authors of this study did conduct a 'per protocol' analysis (where patients were analysed according to the actual treatment received) at 12-weeks and found that there was still no difference between FGAs and SGAs in terms of QLS score.

The research was accompanied by two commentaries (3, 4) which discuss the trial in its broader context.

Systematic reviews

Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.

There was one related systematic review identified on the Cochrane Database of Systematic Reviews (CDSR) (5) and two on the Database of Abstracts of Reviews of Effects (DARE) (6,7). Two HTA reports were also identified (8,9).

References and resources

1. NHS study questions use of new schizophrenia drugs. The Guardian, 24 Novermber 2006, p12.

2. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Archives of General Psychiatry 2006;63(10):1079-87.

3. Lieberman JA. Comparative effectiveness of antipsychotic drugs. A commentary on: Cost Utility Of The Latest Antipsychotic Drugs In Schizophrenia Study (CUtLASS 1) and Clinical Antipsychotic Trials Of Intervention Effectiveness (CATIE). Archives of General Psychiatry 2006;63(10):1069-72.

4. Rosenheck RA. Outcomes, costs, and policy caution. A commentary on: the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Archives of General Psychiatry 2006;63(10):1074-6.

5. Tuunainen A, Wahlbeck K, Gilbody SM. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD000966. DOI: 10.1002/14651858.CD000966.

6. Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizophrenia Research 1999;35(1):51-68. [DARE Abstract]

7. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003;361:1581-9. [DARE Abstract]