April 5, 2006

Additional Background on the CATIE Studies

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) is the largest study of medications for the treatment of schizophrenia ever conducted.  Two articles representing Phase 2 of the landmark study have been released in the April, 2006 issue of the American Journal of Psychiatry.  Considered together, the studies affirm a core NAMI principal – that antipsychotic medications for the treatment of schizophrenia must be individually tailored based on the judgment of treating physicians, in partnership with consumers.  

CATIE I

In Phase I of CATIE, 1,493 individuals were assigned to one of five antipsychotic medications, one older (first generation) medicine perphenazine and four newer medicines, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), and ziprasidone (Geodon). 

In Phase I, the researchers did not find dramatic differences on the whole in the safety and efficacy of the various drugs studied.  The researchers did find that olanzapine (Zyprexa) is moderately more effective than the other medications studied.   These results, the researchers concluded, reinforced the importance of individualized clinical decision-making, taking into consideration factors such as past treatment history, co-morbid medical conditions, potential drug interactions, and other important clinical factors

NAMI’s analysis of CATIE I was that it raised more questions than answers. In its clarification of study results NIMH also warned against jumping to conclusions, emphasizing that "A one-size-fits-all policy for treating schizophrenia could be harmful, essentially turning the clock back 40 years when conventional antipsychotics were the only medications available for patients."

CATIE II Analysis

Phase II of CATIE was designed to inform decision-making for people who choose to stop their medications, or for whom the medicines were ineffective. This is a common clinical problem experienced by people with schizophrenia. 

Phase II was separated into two studies – one (known as the efficacy trial) that focused on people who stopped taking their medication during Phase I because it was not effectively reducing their symptoms, the second (known as the tolerability trial) that focused on people who stopped taking their medication during Phase I because of undesirable side effects.  

A. The Efficacy Trial

In the efficacy trial, the subjects from Phase I who had stopped their medication because it didn’t seem to be helping were assigned to one of five medication pathways.   One of the pathways was clozapine, which is the only FDA approved medicine for treatment resistant psychosis but which also has substantial side effects and monitoring requirements.

In this trial, researchers investigated whether people get symptom relief on clozapine after a randomly chosen antipsychotic medicine does not adequately address their symptoms and, if so, is the symptom relief from clozapine better than that from other second-generation atypical antipsychotic medications?  99 people participated in this arm of the study, many of whom had more than 4 hospitalizations.  The following results were obtained.

1. The compound clozapine (trade name Clozaril) worked better for people with schizophrenia than the other second generation (atypical) antipsychotics for research subjects who failed to respond to antipsychotic medications in phase one. This is a population with severe symptoms and clozapine provided the most symptom relief.
2. Clozapine was more likely to be taken for a longer time than the other medicines - an average of 10 months in the 18 month study, whereas the other medicines were taken for approximately 3 months.
3. One person on clozapine dropped out of the study due to the development of agranulocytosis, which is a loss of white blood cells that help to fight infection.  Clozapine has many noteworthy side effects, yet the paper reports that most people tolerated the medicine well.

Clozapine is a powerful medicine that differentially impacts symptoms for severely ill people with schizophrenia.  It also has noteworthy side effects (agranulocytosis, weight gain, risk of diabetes, myocarditis, drooling at night) which have made it difficult to get some physicians and consumers to try it.  The discussion part of the paper notes that "Given the superior effectiveness of clozapine relative to all other antipsychotics, efforts to develop models of service delivery that would encourage its use are warranted."

This arm of the study reinforces a growing knowledge base suggesting that clozapine is worth the risk for many people.  People should discuss specific risks with their doctor as part of the complex risk benefit assessment that should take place with all medicines.

B.  The Tolerability Trial

Another arm of the phase 2 study (Stroup et al)  looked at a larger group of  individuals who stopped their medicines because of side effects or requests during Phase I to change their medication.  For this arm of the study ziprasidone (Geodon) was compared to olanzapine (Zyprexa), risperidone (Risperdal) and quetiapine (Seroquel).  More people participated in this arm of the study than the efficacy arm -  444 total. Participants were randomly assigned to one of the medicines. The population had been ill for an average of 14 years, and first episode individuals were excluded from the study.  The following results were obtained.

1. Again there was a high rate of people not taking their medication for the 18 month duration of the study – 74% overall. More people on olanzapine and risperidone (35%) continued on their medication for the full 18 months, higher than the ziprasidone group (23%) or the quetiapine group(16%). 
2. People who stopped their medications in Phase I of CATIE because they were experiencing psychotic symptoms achieved better outcomes in terms of symptom relief from either olanzapine or risperidone.
3. People who stopped their medications in Phase I due to side effects showed no differences on the four medicines.

Significantly, side effects differ substantially from one medicine to another, and pre-existing risk factors are also important to consider in clinical decision-making.  For instance ziprasidone was associated with weight loss whereas olanzapine with weight gain and metabolic problems. Careful clinical assessments and individual tailoring of medications based on these assessments is very important.

Conclusion

Phase II of CATIE strongly reinforces the individualized nature of treatment for schizophrenia.  There are a multitude of clinical factors that impact on specific medications that should be prescribed to specific individuals.  Most importantly, access to a range of antipsychotic medications must be protected.  When it comes to the treatment of schizophrenia, there is no one size that fits all.

The results in Phase II also illustrate the critical need for a new generation of research to find medications for schizophrenia that are both more effective and have fewer side effects.  Although existing medications clearly benefit many people, there are also many who continue to struggle with symptoms despite taking medications and others who experience side effects so serious that they ultimately choose to stop treatment.

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