CATIE Raises More Questions than It Answers

Individualized Clinical Decision-making Must be Protected

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study is a first step in developing a comprehensive understanding of the comparative effects of medications in the treatment of schizophrenia.The results of Phase I of CATIE raise many additional questions that must be addressed in future studies.

Although major, multi-site studies have been conducted in many other medical disciplines, this is the first time that the National Institute of Mental Health (NIMH) has funded a study of this magnitude.  The CATIE results reported recently in the New England Journal of Medicine are the first in a series of studies that will shed comprehensive light on the safety and efficacy of medications for schizophrenia.     

The CATIE study provides extensive evidence that antipsychotic medications are not interchangeable.  An antipsychotic medication that works for one person may not work for another person.

Although the CATIE researchers concluded that as a whole, olanzapine (Zyprexa) is moderately more effective than the other medications (three new, one old) studied, the principal investigator in the study, Jeffrey Lieberman, M.D., emphasized that differences in the way individuals respond to specific medications are still not adequately understood.  “There is considerable variation in the therapeutic and side effects of antipsychotic medications” Lieberman explained.  “Doctors and patients must evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication.  What works well for one person may not work for another.”

The results of Phase I of the CATIE study do not justify the conclusion that there are no differences in the way individuals with schizophrenia respond to the older antipsychotic medications and the newer atypical antipsychotic medications.

As stated above, although Phase I of the CATIE study did not show dramatic differences on a whole in the safety and efficacy of the various drugs studied, these results should not be used to conclude that there are no differences at the individual level.  The CATIE researchers emphasized that there are significant differences in the way individuals with schizophrenia respond to specific medications.  For many consumers, finding the medication that works best has been a key ingredient in recovery.  Decisions about specific medications to prescribe in individual cases must be made through careful consultation between the consumer and his/her treating psychiatrist, taking into consideration factors such as past treatment history, co-morbid medical conditions, potential drug interactions, and other important clinical factors.  

Phase I of the CATIE study did not include a number of commonly prescribed antipsychotic medications ¾thus, the effects of these medications were not considered in the conclusions drawn by the researchers.

A number of commonly prescribed anti-psychotic medications, including clozapine (Clozaril) and haloperidol (Haldol) were excluded from phase I of the CATIE study.   Had they been included, the overall conclusions drawn by the researchers may have been different.  For example, clozapine has achieved remarkable results with many previously treatment refractory (treatment resistant) individuals with schizophrenia ¾for some, it has meant the difference between a life in the back wards of hospitals and a life of dignity and independence in the community.  However, clozapine was not included in Phase I of the CATIE study.  (The effects of clozapine on safety and efficacy will be incorporated into Phase II of the study).

Haloperidol (Haldol) was also excluded from the CATIE study because it has frequently been associated in previous studies with high rates of extrapyramidal symptoms (EPS) such as stiffness and akathesia, and movement disorders, such as Tardive Dyskinesia (TD). Although haloperidol may have been excluded for laudable reasons, the fact is that the inclusion of halperidol in the study may well have produced different conclusions with regard to the relative impact of side effects, particularly neurological side effects, produced by the various medications included in the study.

The primary outcome measure studied in the CATIE study, discontinuation of treatment, is not necessarily an indicator in all cases that a specific medication is not working or is causing intolerable side effects.

A decision by an individual with schizophrenia to discontinue treatment does not necessarily indicate that he or she has determined that the medication is not working or is causing intolerable side effects.  Some people with schizophrenia discontinue medications because they are feeling better and believe that they no longer require pharmacological treatment.  Others discontinue treatment because of lack of insight.  In fact, the study results indicate that fewer than 50% of those who discontinued olanzapine, quetiapine, risperidone, and ziprasidone did so because these drugs were either not effective or intolerable.  Only the results for perphenazine (Trilafon) showed a discontinuation rate of more than 50% due to lack of efficacy or intolerability.   

Drug formularies in public and private insurance plans must allow vulnerable individuals with schizophrenia to have access to medications that have worked for them in the past.

At the least, these formularies must:

• allow individuals who are doing well on specific anti-psychotic medications to continue taking these medications; and
• allow physicians to make medication choices based on what’s worked in the past or is in the best clinical interests of the individual with schizophrenia, even if the individual is not currently on a medication regimen.
• NAMI does not believe that prior authorization procedures are appropriate in determining whether antipsychotic medications will be covered in private or public insurance.   However, if prior authorization procedures are required for drugs that do not have “preferred” status within a drug formulary, these procedures must include:
• requirements that decisionsbe made within 24 hours of the time requests for exceptions are initiated, and quicker in emergencies
• provision of a three day emergency supply of the selected medication for treatment until the prior authorization request is reviewed
• a co-pay structure that does not place burdens on consumers who are prescribed medications not on the preferred drug list; and
• procedures that are easy and transparent for consumers, family members, treatment providers and advocates.

The CATIE study has notable limitations.  For example,

• Clinical best practice suggests that medication decisions are best made through a collaborative process between the physician and consumer.  In CATIE, patients were randomized to medications without being given the opportunity to make an informed choice, in consultation with their physician, about the medications they preferred.  While this may have been necessary to protect the integrity of the research, it may have also contributed to the high rates of medication discontinuation by participants in the study.   In the real world, patients who are given opportunities to participate meaningfully in the selection of medications may be less inclined to discontinue those medications.  
• The CATIE study only lasted for 18 months.  Tardive Dyskinesia, a side effect routinely linked to the older, first-generation of antipsychotic medications such as haloperidol and perphenazine, typically does not develop until after several years of treatment with these medications.
• The researchers excluded people with pre-existing movement disorders from the perphenazine arm of the study because of their concern that this would expose them to unnecessary risks. There are no indications that people with a pre-disposition to obesity or metabolic disorders were similarly excluded from the arms of the study involving the administration of olanzapine or other atypical antipsychotic medications.  While the exclusion of people with pre-existing movement disorders from the perphenazine arm may have been the right thing to do, it may also have skewed the results with respect to side effects associated with this arm of the study.
• There is no discussion in the CATIE study of the impact of psychosocial interventions on adherence to treatment.  Given the importance of these interventions in adherence to treatment, an assessment of that factor is essential to completely understanding the results.

Some research has documented that the newer atypical antipsychotic medications show higher rates of improvement in cognition, which is crucial to employment, recovery and independence.  However, the comparative effects of the medications on cognition were not included in Phase I of the CATIE study.

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