Review: Results of Phase 3 of the CATIE Schizophrenia Trial

The article reviewed here is ‘Results of Phase 3 of the CATIE Schizophrenia Trial’ by Stroup and colleagues. The authors place the CATIE trial in the context of other studies including the CUtlass Study (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and the EuFEST study (European First-Episode Schizophrenia Trial as well as other phases of the CATIE study that had already been reported*. Part of the methodology was described elsewhere but essentially the CATIE is a multi-centre trial with random assignment to Ziprasidone, Risperidone, Quetiapine, Olanzapine and Perphenazine with follow-up for 18 months and then some complicated pathways in which medications can be discontinued before participants are randomised to further treatment arms. In the third phase, the phase being reported here, paticipants could choose from one of 9 treatment pathways

1. Clozapine

2. Olanzapine

3. Perphenazine

4. Quetiapine

5. ‘Antipsychotic monotherapy with Aripiprazole’

6. Risperidone

7. Ziprasidone

8. Long-acting injectable fluphenazine

9. A combination of two of the above

There were many exclusion criteria which need to be considered in interpreting the results. Participants were aged 18-65 with a DSM-IV diagnosis of schizophrenia determined by Structured Clinical Interview. Some of the exclusion criteria were schizoaffective disorder, first-episode of schizophrenia, ‘treatment resistance defined by persistence of severe symptoms despite an adequate trial of one of the proposed treatments or prior treatment with clozapine for treatment resistance’, ‘serious and unstable medical condition’. Looking at these exclusion criteria more closely it seems that the participants should not have a new onset, nor should they still have severe symptoms after a trial of one of the antipsychotics above. So it seems as though the type of participants are those who have passed through the initial stages of the illness and settled on a medication without severe symptoms. I was curious as to why some of the exclusion criteria exist. For instance if a group with ‘serious and unstable medical condition’ is included then they could be analysed separately if it is thought that this group might influence the overall results (although it might be argued that analysing this group separately might require a suitable sample size). By the time the participants have been randomised to the individual arms in the third phase, the numbers in each arm is relatively small ranging from just 4 in the perphenazine group to 41 in the Olanzapine group. The discontinuation rates in the arms range from 33% (Aripiprazole, combination and fluphenazine) to 50% (perphenazine). There was flexible dosing in the third phase and choice of medication was based on previously trialled medication in a way which maintained the blinding within the trial since the data had already been collected. The primary outcome measure was the discontinuation rate which is influenced by a number of important practical factors. A large number of secondary outcome measures were also examined including PANSS scores. There are several tables showing an extensive list of baseline characteristics for the different treatment options above as well as adverse effects associated with medication. The statistics are descriptive as the primary outcome measure was discontinuation rate alone so the remainder of outcome measures are in effect included in a secondary analysis. 39% of the patients discontinued treatment with a mean duration of treatment of 7.7 months. Although this is a secondary analysis there are p-values for the outcome measures by safety and the method used to calculate these values varies according to the outcome measure. Those reaching the highest level of significance were Sialorrhoea (38% in the clozapine group), hesitancy (36% in the Quetiapine group), weight change (10.5 lbs in the Perphenazine group) and Prolactin (24.2ng/mL in the Risperidone group). It’s useful to have some comparative data on the adverse events although with small sample sizes for individual antipsychotics there are difficulties in interpretation as the authors have noted and perhaps a meta-analysis of adverse-events from other trials for individual antipsychotics might be interesting to see.

The main finding for me seemed to be the discontinuation rate of 39% as this was the primary outcome measure.  There were some trends towards choosing second generation antipsychotics although that might well result from the study design in which the majority of choices are second generation antipsychotics. The PANSS score changes from baseline at 3 and 6 months seem to all be significant at the 5% level apart from 2 antipsychotics at each of 3 and 6 months which is difficult to interpret given that this is a secondary analysis.

* There are also Conflict of Interest Declarations at the end of the article.

References

Stroup TS, Lieberman JA, McEvoy JP, Davis SM, Swartz MS, Keefe RS, Miller AL,Rosenheck RA, Hsiao JK; CATIE Investigators.Schizophr Res. 2009 Jan;107(1):1-12. Results of phase 3 of the CATIE schizophrenia trial.

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Disclaimer

The comments made here represent the opinions of the author and do not represent the profession or any body/organisation. The comments made here are not meant as a source of medical advice and those seeking medical advice are advised to consult with their own doctor. The author is not responsible for the contents of any external sites that are linked to in this blog.

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