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
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
David Sultzer, M.D.: "We know these medications have adverse
effects, but in an individual patient we are weighing those risks against
potential benefits. What CATIE-AD does is help us understand what the upside
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
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).
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
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.
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
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
"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
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
"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>.▪