Independently funded studies comparing marketed treatments are performed all too infrequently, according to Dr Jeffrey Lieberman, Principal Investigator of the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study.
“We need more studies that examine the effectiveness of marketed treatments in what might be called ecologically valid conditions – in real clinical settings, undertaken for sufficient lengths of time to enable clinically meaningful outcomes,” said Dr Lieberman, Chair of The Department of Psychiatry, Columbia University Medical Center and Director of the New York State Psychiatric Institute.
The $42.6 million CATIE trial, funded by US National Institute of Mental Health (NIMH), is the largest, longest, and most comprehensive independent trial ever undertaken to examine existing therapies for schizophrenia.
“The fact that NIMH sponsored CATIE study was an important statement. The successful conclusion of CATIE supports both the feasibility of doing such studies and the need for similar studies in other areas of medicine, particularly with the increasing flow of new medications into our pharmacopoeia,” he added.
In CATIE, a total of 1493 patients with schizophrenia were recruited at 57 US sites and randomly assigned to one of four newer, ‘atypical’ antipsychotics: olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon); or to the older, ‘typical’ medication, perphenazine (Trilafon).
Patients continued to take the randomised medication for the next 18 months, or until treatment could not control their symptoms adequately, or they developed an intolerable side effect, or they decided to stop the medication, or withdraw from the study for some other reason.
Overall, the treatments were comparably effective but all were associated with high rates of discontinuation due to side effects or failure to adequately control symptoms.
“CATIE showed that these treatments do clearly work: we did not have a placebo in the study, but if we did, you can be sure that the patients on placebo would have done far worse than any of the patients receiving study medications,” said Dr Lieberman. “However, almost three quarters of patients changed treatments – so although treatments work, but there are clear limitations in their effectiveness.”
“Olanzapine was slightly better than the other drugs in terms of symptom control and prevention of relapse, but it did so at a substantial cost in terms of side effects. It had the highest rate of discontinuation for side effects, particularly weight gain and metabolic disturbances,” he added.
According to Dr Lieberman, the major surprise of the initial results (New England Journal of Medicine 2005:353;1209-1223) was that perphenazine was comparably effective to three of the four new medications studied and did not produce substantially greater rates of EPS.
“This spurred something of a rush to judgement, with some commentators saying that we should use the older medicine more, or that patients should have to be treated with one of the older medicines first, or there should be some restriction on the choice of medicines in a formulary – that is not a justified or supported policy based on this initial report of the CATIE data. If the data at this stage of the reporting process speak for anything, they speak of the need for choices of treatment,” said Dr Lieberman.
The published results underscore the considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients should carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication: “What works for one person may not work for another. This comes as no surprise to experienced clinicians – switching medicines to find the best treatment for a given patient is a common practice,” he added.
When published, the full data from CATIE should provide clearer guidance for clinicians on optimal choice of antipsychotic agent for a specific patient. Over the next six to nine months further data will begin to be published concerning the effects of the study antipsychotics on cognitive functioning, co-morbidity (psychiatric and medical), rates of recovery, effects on violence and aggressive behaviour, and cost effectiveness.
A further practical finding from CATIE is that many clinicians switch antipsychotic medication prematurely: “In some cases, clinicians are switching patients before they have explored the full dose range of the initial medication. Although there was a 74 per cent switching rate, of which about a third was for lack of efficacy, in only half of these cases had patients been switched at the maximum dose of their assigned treatment,” said Dr Lieberman.
Overall he is confident that the full CATIE results will support and justify NIMH’s effort to conduct ‘practical’ clinical trials in real world settings, and that the results will help doctors and patients choose the most appropriate medication according to the patients' individual needs.