Antipsychotics Bring Little Long-Term Benefit in Alzheimer's

Second-generation antipsychotic medications appear to improve some specific clinical symptoms in patients with Alzheimer's disease but do not improve cognition, functioning, or quality of life.

Compared with placebo, patients treated with olanzapine or risperidone showed improvement on total scores on the Neuropsychiatric Inventory and on the hostile suspiciousness factor of the Brief Psychiatric Rating Scale (BPRS), according to an analysis of data from the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease (CATIE-AD).

In addition to those benefits, patients taking risperidone also showed improvement on the Clinical Global Impression of Change (CGIC) and on the BPRS psychosis factor. The CGIC is a global assessment of clinical change over time, based on the clinician's overall impression of change in cognitive, behavioral, and functional symptoms. Change over time is rated on a seven-point scale from “very much improved” to “very much worse.” The BPRS psychosis factor measures unusual thought content and hallucinations.

The report was posted online June 2 in AJP Advance. It will appear in print in the July American Journal of Psychiatry.

Patients in the trial were assigned randomly to flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks and could be randomly reassigned to a different medication at the clinician's discretion. The time of reassignment was defined as the end of phase 1 and the point at which change in symptoms was measured.

At week 12, investigators found no significant differences between patients treated with an antipsychotic medication and those treated with placebo in scores on measures of cognition, function, and quality of life.

The study underscores the less-than-desirable state of treatment for Alzheimer's patients who are agitated, hostile, and aggressive. Among psychotropic medication classes, the evidence for efficacy has been strongest for atypical antipsychotics, and they can be beneficial in an acute situation for patients who are dangerous to self or others. Their effects, however, are limited to discrete symptoms and have little or no impact on long-term functioning and quality of life, according to CATIE-AD.

“The results from this study support modest symptomatic benefit on some rating scales,” said David Sultzer, M.D., lead author of the report. “The CATIE-AD study does not show any impact on quality of life.”

Moreover, there are adverse effects associated with their use. A report in the Archives of Internal Medicine last month found that hospitalization and even death associated with use of antipsychotics in elderly patients with dementia were not uncommon (see Antipsychotics Linked to Serious Adverse Events in Some Elderly).

Only a minority (19 percent) of the 421 enrolled patients in the CATIE-AD study continued on their initial randomized treatment beyond 12 weeks, with some patients being switched to another medication as early as at two weeks.

An earlier analysis of CATIE-AD, whose primary endpoint was time to discontinuation, found no differences in time to discontinuation due to any cause between any of the treatment groups. A somewhat longer time to discontinuation due to lack of efficacy was seen for olanzapine and risperidone over quetiapine, but that was offset by more frequent discontinuation due to intolerability.

That report was published in the October 12, 2006, New England Journal of Medicine (Psychiatric News, November 3, 2006).

Study Demonstrates Upside of Treatment

Still, the new analysis focusing on clinical symptoms shows that antipsychotic medications do improve specific, discrete symptoms, especially symptoms—such as hostile suspiciousness—that can be most distressing to caregivers and family members.

“We know these medications have adverse effects, but in an individual patient we are weighing those risks against potential benefits,” Sultzer told Psychiatric News. “What CATIE-AD does is help us understand what the upside may be.”

And that upside can be most desirable when a patient has become suspicious of family members and caregivers and hostile or violent, he said. Nonpharmacologic behavioral measures for reducing agitation are important and should be considered as a first line of recourse. They can be difficult to implement, however, and when a patient has become dangerous to self or others, medication may be of value, Sultzer said.

He is a professor of psychiatry and biobehavioral sciences at UCLA and director of the Gero/Neuropsychiatry Division at the VA Greater Los Angeles Healthcare System.

Robert Roca, M.D., chair of APA's Council on Aging, said the appropriate use of antipsychotics in people with Alzheimer's will be a topic at the council's meeting during APA's fall component meetings.

In an interview with Psychiatric News, he expressed the dilemma of clinicians who have only imperfect tools for treating patients with Alzheimer's when they are dangerous to self or others. “The drugs seem to be helpful in those situations, but clinicians who use them have never been entirely satisfied that they are sufficiently effective and safe to make them comfortable with their use,” he said.

Paul Newhouse, M.D., chair of the Research Committee of the American Association of Geriatric Psychiatry, echoed that ambivalence. “They may not be very good tools, but they are the only ones we have for psychosis,” he told Psychiatric News.

Clinicians Switch Despite Improvement

The study involved 42 clinical sites and enrolled 421 patients, who were randomly assigned initially to masked treatment with olanzapine, quetiapine, risperidone, or placebo. At any time after the first two weeks of treatment, the clinician could discontinue the initially assigned medication for insufficient efficacy, adverse effects, or other reason.

At that point of discontinuation, phase 1 ended, and the patient could enter phase 2 and be assigned randomly to masked treatment with a second-generation antipsychotic that had not been assigned in phase 1 or with citalopram. Patients could also go directly to an open-choice treatment.

The following instruments were administered at study baseline and after two weeks, four weeks, eight weeks, 12 weeks, 24 weeks, and 36 weeks of treatment: Neuropsychiatric Inventory, BPRS, Cornell Scale for Depression in Dementia, and Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change Scale.

The benefits seen with olanzapine and risperidone on specific measures were not seen for quetiapine. Sultzer said he believes that may reflect the low dose that was used, although some side effects were seen; at the time of the study, the optimal dose of quetiapine was uncertain, and study authors were cautious about dosing.

Sultzer noted that since clinical symptoms were being measured at the last observation of the patient when he or she was still on the initial treatment, it represents a snapshot of the clinical picture at the time that clinicians had, for whatever reason, determined that a change in medication was indicated.

“The last observation was by definition when clinicians were ending phase 1, though the data show patients were actually getting better,” Sultzer said. “Our understanding of this is that clinicians were seeking more improvement than what was recorded on our rating scales or in some cases were concerned about side effects. It reflects an interesting treatment issue—the belief of what constitutes efficacy varies across caregivers, and clinicians probably felt the amount of benefit our scales show wasn't sufficient.”

The following instruments were administered at baseline and after 12 weeks, 24 weeks, and 36 weeks of treatment: Alzheimer's Disease Assessment Scale, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, Dependence Scale, Caregiver Activity Survey, and Alzheimer's Disease Related Quality of Life.

Improved clinical symptoms with antipsychotic treatment did not translate into functional benefits or improved quality of life on these measures, according to ratings at 12 weeks in those taking their originally assigned treatment.

“This may be due to additional factors that contribute to functional disability and poor life quality, such as progression of dementia, caregiver interactions, environmental factors, and perhaps adverse effects of the drugs,” the authors wrote.

“Clinical Symptom Responses to Atypical Antipsychotic Medications in Alzheimer's Disease: Phase 1 Outcomes From the CATIE-AD Effectiveness Trial” is posted at<http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.07111779v1>.▪