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Questions and Answers About the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease Study — Phase I Results

October 2006

1. What is the CATIE Alzheimer’s disease study?

A. The CATIE Alzheimer’s disease trial was a large-scale public health study using newer, atypical antipsychotic medications for the treatment of delusions, hallucinations, aggression and agitation that often accompany Alzheimer’s disease. Such symptoms affect more than 75 percent of the people who have Alzheimer’s disease.

The $16.9 million CATIE Alzheimer’s disease study was conducted at 42 sites with 421 participants and is one of two large-scale nationwide clinical trials funded by the NIH’s National Institute of Mental Health to examine the effectiveness of atypical antipsychotic medications. These medications were developed originally to treat symptoms (such as hallucinations and delusions) associated with schizophrenia, but they are widely used to treat similar symptoms in Alzheimer’s disease. For information relating to the CATIE Schizophrenia Study, visit the NIMH CATIE page.

2. Why is the CATIE Alzheimer’s study important?

A. Memory loss and disorientation are the most common symptoms of Alzheimer’s disease, but many people with the disease experience symptoms such as delusions, hallucinations, aggressive behavior, or agitation. These symptoms are associated with a rapid worsening of the illness and often result in the patient being placed in a nursing home or other specialized care institution.

The U.S. Food and Drug Administration (FDA) has not specifically approved antipsychotic medications for use in treating people with Alzheimer’s disease, but many doctors prescribe these medications “off label” when they believe a patient may benefit. Although many different antipsychotic medications have been used to treat these thinking and behavior symptoms in people with Alzheimer’s disease, doctors do not have data about how well they work, if some work better than others, and if they are safe. About 25 percent of Alzheimer’s patients living in nursing homes receive atypical antipsychotics.1 However, no data exist that indicate how many Alzheimer’s patients living outside of nursing home currently receive these medications.

The CATIE Alzheimer’s disease study was designed to evaluate the overall effectiveness of the newer antipsychotic medications in treating hallucinations, aggression and related symptoms. Specifically, it aimed to determine if these medications — overall — are beneficial, tolerable, and safe for use by Alzheimer’s patients. The study is unique for several reasons. Although studies of antipsychotic medications have been conducted, nearly all of those studies were conducted in nursing homes and therefore, are less relevant to the many people with Alzheimer’s disease cared for by family members in their own homes or in assisted-living facilities. Further, none of these earlier studies followed participants for longer than 12 weeks. Lastly, these earlier studies did not compare different antipsychotic medications to each other.

In contrast, the CATIE Alzheimer’s disease study included three of the most widely used antipsychotic medications and placebo (inactive pill) among patients in non-nursing home settings, who were experiencing delusions, hallucinations, aggression, or agitation. The study followed the participants over nine months and also included the involvement of caregivers.

3. Who participated in the study?

A. The 421 participants all had Alzheimer’s disease, and were geographically dispersed at 42 clinical sites across the United States. All were experiencing delusions, hallucinations, aggression, or agitation that disrupted their daily functioning, such that an antipsychotic medication was determined to be appropriate treatment. Participants were ambulatory and still living at home or in assisted living facilities. A family member, caregiver, or study partner who had regular contact with the patient also participated in the study to help with monitoring and assessments. Study staff worked closely with participants’ regular doctors to monitor co-occurring medical illnesses.

Patient Characteristics

Patients Enrolled: 421
Gender: 56 percent female
Average age: 78 years
Race: 21 percent non-white
Residence: 73 percent in own home; 16 percent in family member’s home;10 percent in assisted living

Caregiver characteristics

Among caregivers, 71 percent were women; 52 percent of caregivers were spouses and 33 percent were children or sons-in-law or daughters-in-law. The average ages of caregivers were 73.5 years for spouses and 51.2 years for children or their spouses. They spent 5.2 hours per day in specific caregiving activities

4. What treatments were given in the CATIE Alzheimer’s study and how was treatment chosen for each participant?

A. The CATIE Alzheimer’s study was designed with several phases. In phase 1, participants were randomly assigned to one of four treatment groups—three antipsychotic medications (olanzapine, quetiapine, and risperidone) or placebo (inactive pill). This means that they, their caregivers, and their doctors could not choose which one of the four treatments they would receive. Further, the study was “double-blinded,” meaning that neither the participant or caregiver, nor the medical staff knew which treatment the participant was taking. This type of “placebo-controlled, double-blind, randomized clinical trial” helps to ensure objective results because researchers, participants, and caregivers will not be biased by their expectations about how well a medication may work.

During Phase 1, doctors could adjust a participant’s dose based on the participant’s individual needs. Participants who benefited from their assigned treatment could continue on this treatment for up to 36 weeks. However, if after two weeks the participant was not benefiting from the treatment, then he or she could discontinue the medication and enter Phase 2 of the study, where he or she could receive on a random basis a different antipsychotic medication or citalopram, an antidepressant medication, also on a “double-blind” basis. Participants could leave the study at any time.

In addition to the medications in the study, patients and their caregivers received basic information about Alzheimer’s disease. The caregivers were offered two counseling sessions during the study and could speak with study staff as needed.

5. What were the results of phase 1?

A. To determine both the benefits and the risks associated with each treatment, the researchers used the length of time patients stayed on their assigned treatments as the primary measure of treatment success. After a minimum two-week period, a medication could be discontinued if it was not benefiting the patient, if he or she was experiencing intolerable side effects, such as dizziness, or for any other reason. This “all cause discontinuation” or “time in treatment” benchmark integrated patients’, caregivers’ and clinicians’ judgments of efficacy, safety and tolerability into an overall measure of effectiveness that reflected therapeutic benefits in relation to undesirable effects.

In phase 1, there were no differences in the length of time in treatment among any of the four treatment groups. Patients stayed on their assigned medication for an average of about eight weeks, regardless of their specific treatments. In other words, the participants who took placebo benefited just as much as those who took any of the three antipsychotic medications.

When the researchers examined the reasons for discontinuation, they found some differences between placebo and the medications. Those taking olanzapine and risperidone were less likely to cite lack of benefit as a reason to discontinue use. However, those taking any of the three antipsychotic medications were more likely to discontinue use because of intolerable side effects than those taking placebo.

The dosage levels of olanzapine and risperidone used in this study were similar to those used in previous studies, but the quetiapine dose was lower than what was used in other studies. It is possible that the quetiapine dose was too low to have a therapeutic effect, but the physicians were free to raise it, and the dose was still high enough to cause side effects.

6. Were there differences in side effects among the treatment groups?

A. Although some participants in the study benefited from the treatments, those who received the antipsychotic medications experienced more side effects and discontinued their treatment because of side effects more than those who received placebo. All three antipsychotic medications were more likely to cause sleepiness and weight gain than placebo. There were some differences among the three medication treatments with respect to movement problems (less likely with quetiapine), confusion (more likely with olanzapine), and psychotic symptoms (more likely with olanzapine).

7. What do these results mean for clinicians who treat people affected by Alzheimer’s disease, and their caregivers?

A. For the first time, doctors, patients, and their caregivers have extensive and clinically relevant information on antipsychotic medications from a large, long-term study directly comparing the medications to each other and to placebo. The results from this first phase of the study indicate that the overall benefit of these medications is offset by intolerability to associated side effects. Doctors pondering whether to prescribe atypical antipsychotic medications for their Alzheimer’s patients need to consider the risks, benefits and individual needs of a given patient. Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer’s patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer’s patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

The results from subsequent phases of the study will provide further information to help guide practice.

8. What other information will doctors and patients be able to learn from CATIE-AD in the future?

A. CATIE-AD will determine whether people who discontinue treatment during phase I can be helped by switching to a different antipsychotic or to an antidepressant. The study will also show which treatments, if any, will help improve symptoms, quality of life, and functioning, as well as caregiver burden, thereby delaying nursing home placement.

9. Who conducted the CATIE Alzheimer’s disease study?

A. The CATIE AD study was led by Drs. Lon Schneider at the University of Southern California (USC), Los Angeles and Pierre Tariot (Banner Alzheimer’s Institute in Phoenix, AZ). Co-authors included: Karen Dagerman (USC Los Angeles); Sonia Davis (Quintiles, Research Triangle Park, NC); M. Saleem Ismail and J. Michael Ryan (University of Rochester, NY); John K. Hsiao (NIMH) and Barry D. Lebowitz (University of California, San Diego; formerly NIMH); Constantine G. Lyketsos (Johns Hopkins University, Baltimore, MD); T. Scott Stroup (The University of North Carolina (UNC), Chapel Hill); David L. Sultzer (Veteran’s Affairs Greater Los Angeles Healthcare System, University of California, Los Angeles); Daniel Weintraub (University of Pennsylvania, Philadelphia); and Jeffrey A. Lieberman (College of Physicians and Surgeons, Columbia University, NY).

The University of North Carolina was the primary contractor for the CATIE project, led by Dr. Jeffrey Lieberman, (formerly of UNC, Chapel Hill). Quintiles, a private contract research organization (CRO), assisted with study implementation and data analysis of the trial.

For a listing of the clinical sites involved in the study, visit ClinicalTrials.gov .

10. What role did the pharmaceutical companies have in CATIE?

A. The pharmaceutical companies donated the medications used in this study. They had no input into the planning of the study but were presented with an overview of the design. They had no input into its implementation or conducting of the data analysis, and did not participate in preparing manuscripts for publication. The medications used in the study and their manufacturers included:

  • Olanzapine (Zyprexa®), manufactured by Eli Lilly and Company
  • Quetiapine (Seroquel®), manufactured by Astra Zeneca Corporation
  • Risperidone (Risperdal®), manufactured by Janssen Pharmaceuticals
  • Citalopram (Celexa®), manufactured by Forest Laboratories in the United States, was used in phase 2 of the study to be reported later

Reference

1. The Quality of Antipsychotic Drug Prescribing in Nursing Homes, Becky A. Briesacher; M. Rhona Limcangco; Linda Simoni-Wastila; Jalpa A. Doshi; Suzi R. Levens; Dennis G. Shea; Bruce Stuart, Arch Intern Med. 2005;165:1280-1285.