Article

844 Am J Psychiatry 165:7, July 2008 ajp.psychiatryonline.org

This article is featured in this months AJP Audio, is the subject of a CME course (p. 927), and is discussed in an editorial by Dr. Schultz (p. 787).
Clinical Symptom Responses to Atypical Antipsychotic
Medications in Alzheimers Disease: Phase 1 Outcomes
From the CATIE-AD Effectiveness Trial
David L. Sultzer, M.D.
Sonia M. Davis, Dr.P.H.
Pierre N. Tariot, M.D.
Karen S. Dagerman, M.S.
Barry D. Lebowitz, Ph.D.
Constantine G. Lyketsos, M.D.,
M.H.S.
Robert A. Rosenheck, M.D.
John K. Hsiao, M.D.
Jeffrey A. Lieberman, M.D.
Lon S. Schneider, M.D.
CATIE-AD Study Group
Objective: The study measured the ef-
fects of atypical antipsychotics on psychi-
atric and behavioral symptoms in pa-
ti ents wi th Al zheimers di sease and
psychosis or agitated behavior.
Method: The Clinical Antipsychotic Trials
of I nt er vent i on Ef f ect i venessAl z-
heimers Disease (CATIE-AD) Alzheimers
disease effectiveness study included 421
outpatients with Alzheimers disease and
psychosis or agitated/aggressive behavior.
Patients were assigned randomly to
masked, flexible-dose treatment with
olanzapine, quetiapine, risperidone, or
placebo for up to 36 weeks. Patients
could be randomly reassigned to a differ-
ent medication at the clinicians discre-
tion, which ended phase 1. Psychiatric
and behavioral symptoms, functioning,
cognition, care needs, and quality of life
were measured at regular intervals.
Results: In relation to placebo, the last
observation in phase 1 showed greater
improvement with olanzapine or risperi-
done on the Neuropsychiatric Inventory
total score, risperidone on the Clinical
Global Impression of Changes, olanzapine
and risperidone on the Brief Psychiatric
Rating Scale (BPRS) hostile suspiciousness
factor, and risperidone on the BPRS psy-
chosis factor. There was worsening with
olanzapine on the BPRS withdrawn de-
pression factor. Among patients continu-
ing phase 1 treatment at 12 weeks, there
were no significant differences between
antipsychotics and placebo on cognition,
functioning, care needs, or quality of life,
except for worsened functioning with
olanzapine compared to placebo.
Conclusion: In this descriptive analysis
of outpatients with Alzheimers disease in
usual care settings, some clinical symp-
toms improved with atypical antipsychot-
ics. Antipsychotics may be more effective
for particular symptoms, such as anger,
aggression, and paranoid ideas. They do
not appear to improve functioning, care
needs, or quality of life.
(Am J Psychiatry 2008; 165:844854)
Psychiatric and behavioral symptoms are common in
patients with Alzheimers disease and contribute substan-
tially to morbidity (13). Delusions or hallucinations ap-
pear in 30%50%, and as many as 70% demonstrate agi-
tated or aggressive behaviors. These symptoms contribute
to patient and caregiver distress (4, 5), can compromise
safety or lead to institutionalization (6, 7), and add to
health care costs (8, 9).
Optimal treatments for psychosis and agitated behavior
have been elusive. Interventions that address environ-
mental or interpersonal factors can be helpful (10, 11) and
should be attempted in all cases, although their overall ef-
fectiveness and applicability are not entirely clear. Cho-
linesterase inhibitor drugs and memantine may have
some beneficial impact on noncognitive symptoms in
Alzheimers disease (12, 13), although effects may not be
significant in those with active behavioral disturbances
(14). The majority of controlled medication trials for psy-
chosis and behavioral disturbances in Alzheimers disease
have examined the efficacy of atypical antipsychotic med-
ications over 6 to 12 weeks in patients with advanced dis-
ease. Several trials found modest efficacy of individual
atypical antipsychotic medications in relation to placebo
(15). However, efficacy is not seen in all trials or for all
symptoms, adverse events can occur, comparative efficacy
is not known, and overall effectiveness in usual clinical
populations is uncertain.
The National Institute of Mental Health (NIMH) Clinical
Antipsychotic Trials of Intervention EffectivenessAlz-
heimers Disease (CATIE-AD) project was designed to
compare the effectiveness of antipsychotic medications
and placebo in patients with Alzheimers disease and psy-
chosis or agitated/aggressive behavior (16). In contrast to
typical efficacy trials, CATIE-AD included outpatients in
usual care settings and assessed treatment effectiveness
on several clinical outcome measures over a 9-month in-
tervention period. Initial CATIE-AD treatment (olanza-
pine, quetiapine, risperidone, or placebo) was random-
ized and masked, yet the protocol allowed medication
dose adjustments or a switch to a different treatment on
Am J Psychiatry 165:7, July 2008 845
SULTZER, DAVIS, TARIOT, ET AL.
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the basis of the clinicians judgment. The primary CATIE-
AD phase 1 outcome was time to discontinuation of the
initially assigned medication for any reason, which was in-
tended as an overall measure of effectiveness that incor-
porated the judgments of patients, caregivers, and clini-
cians about therapeutic benefits in relation to undesirable
effects. The two primary hypotheses were that 1) there
would be pairwise differences between the three antipsy-
chotic treatment groups and the placebo group in the time
to discontinuation for any reason and 2) among the antip-
sychotics that were different from placebo, none would be
inferior to the others. The results revealed no pairwise
treatment differences in all-cause discontinuation. The
benefits of olanzapine and risperidone, i.e., longer times
to discontinuation for lack of efficacy in comparison to
placebo (Kaplan-Meier estimate of median time: olanza-
pine, 22.1 weeks; quetiapine, 9.1 weeks; risperidone, 26.7
weeks; placebo, 9.0 weeks), were offset by shorter times to
discontinuation due to adverse effects in the antipsy-
chotic groups (discontinuations due to intolerability:
olanzapine, 24%; quetiapine, 16%; risperidone, 18%; pla-
cebo, 5%) (17).
This report presents results on the CATIE-AD phase 1
clinical symptom measures. Here, the analysis examined
pairwise differences between antipsychotic treatment
groups and the placebo group on change in clinical symp-
toms at the last observation during the initially assigned
phase 1 treatment. Additional analyses explored clinical
symptom changes in the four treatment groups among
patients who continued the phase 1 treatment for up to 12
weeks. This approach can help to characterize treatment
effects on psychosis and behavioral symptoms, and it also
allows the principal CATIE-AD effectiveness outcome,
treatment discontinuation, to be viewed in the context of
symptom change.
Method
Study Design and Participants
The CATIE-AD research design and methods have been de-
scribed previously (16, 18); study group members are listed in the
online data supplement. Forty-two clinical sites enrolled 421 pa-
tients, who were randomly assigned initially to masked treatment
with olanzapine, quetiapine, risperidone, or placebo in a 2:2:2:3
ratio. The treating physician could adjust the dose, as indicated
clinically, over the 36 weeks of the trial. At any time after the first 2
weeks of treatment, the clinician could discontinue the initially
assigned (phase 1) medication for insufficient efficacy, adverse ef-
fects, or other reason. At that point, phase 1 ended and the patient
could enter phase 2 and be assigned randomly to masked treat-
ment with an atypical antipsychotic medication that had not
been assigned in phase 1 or with citalopram. Patients could also
go directly to an open-choice treatment.
To participate in the trial, patients had to meet the DSM-IV cri-
teria for dementia of the Alzheimers type or meet the criteria for
probable Alzheimers disease of the National Institute of Neuro-
logical and Communicative Disorders and Stroke and the Alz-
heimers Disease and Related Disorders Association (NINCDS-
ADRDA) (19) after a thorough history, physical and cognitive ex-
aminations, and laboratory assessments were completed. Each
enrolled patient was an outpatient living at home or in an assisted
living facility, had a knowledgeable informant, and was ambula-
tory. Patients in skilled nursing homes were not included. The
Mini-Mental State Examination (MMSE) (20) score was 5 to 26.
The entry criteria required that delusions, hallucinations, agita-
tion, or aggression had occurred nearly every day over the previ-
ous week or intermittently over 4 weeks. The symptoms had to
have been rated at least moderate in severity on the Brief Psychi-
atric Rating Scale (BPRS) conceptual disorganization, suspicious-
ness, or hallucinatory behavior item (21) or had to have occurred
at least weekly with moderate severity or greater on the delusion,
hallucination, agitation, or aberrant motor behavior item of the
Neuropsychiatric Inventory (22).
Patients could be taking stable cholinesterase inhibitor medi-
cation; memantine had not been approved in the United States
during the enrollment period. Patients were excluded if they were
taking antidepressants or anticonvulsants for mood stabilization.
The study was reviewed and approved by the institutional re-
view board at each site. Consent was documented according to
institutional review board guidelines.
Treatments
Medications were prepared in identically appearing low-dose
and high-dose capsules that contained olanzapine (2.5 mg or 5.0
mg), quetiapine (25 mg or 50 mg), risperidone (0.5 mg or 1.0 mg),
or placebo. The clinician selected the number of low- or high-
dose capsules for initial treatment and could subsequently adjust
the number of capsules prescribed according to clinical judg-
ment. If acute difficult behaviors emerged, the clinician could in-
crease the study medication, prescribe a benzodiazepine for
short-term use, or prescribe parenteral haloperidol for behavioral
emergency.
Patients and caregivers received basic information and educa-
tion about Alzheimers disease, behavioral symptoms, and behav-
ioral management strategies. Caregivers were offered two coun-
seling sessions and could speak with clinical staff as needed.
Clinical Outcome Measures: Psychiatric and
Behavioral Symptoms
The following instruments were administered at study baseline
and after 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, and 36
weeks of treatment.
Neuropsychiatric Inventory. The Neuropsychiatric Inventory
measures the frequency and severity of 12 psychiatric symptoms
on the basis of caregiver report (22). The items are delusions, hal-
lucinations, agitation/aggression, depression/dysphoria, anxiety,
elation, apathy/indifference, disinhibition, irritability/lability,
aberrant motor behavior, sleep disturbance, and appetite and
eating disorder.
BPRS. The BPRS measures the severity of 18 psychiatric and be-
havioral symptoms (21). Individual items were scored by a trained
clinician after a semistructured patient interview and collection
of additional information from the caregiver. Factor analysis in a
geropsychiatry sample (23) revealed a five-factor structure: 1) ag-
itation (anxiety, tension, excitement); 2) hostile suspiciousness
(hostility, suspiciousness, uncooperativeness); 3) psychosis (un-
usual thought content, hallucinations); 4) withdrawn depression
(emotional withdrawal, depressed mood, motor retardation,
blunted affect); and 5) cognitive dysfunction (disorientation, con-
ceptual disorganization).
Cornell Scale for Depression in Dementia. The Cornell scale
is a 19-item instrument that measures mood symptoms, ide-
ational disturbances of depression, and neurovegetative signs in
patients with dementia (24). The items are rated on the basis of
846 Am J Psychiatry 165:7, July 2008
CATIE-AD
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patient report, caregiver report, and the raters observations of the
patient.
Alzheimers Disease Cooperative StudyClinical Global Im-
pression of Change. The Alzheimers Disease Cooperative
StudyClinical Global Impression of Change (CGIC) is a global
assessment of clinical change over time, based on the clinicians
overall impression of change in cognitive, behavioral, and func-
tional symptoms (25). Change over time is rated on a 7-point
scale from very much improved to very much worse.
Clinical Outcome Measures: Cognitive Skills,
Functional Abilities, Care Needs, and Quality of Life
The following instruments were administered at baseline and
after 12 weeks, 24 weeks, and 36 weeks of treatment.
Alzheimers Disease Assessment Scale cognitive subscale
and MMSE. The 11-item cognitive subscale of the Alzheimers
Disease Assessment Scale assesses memory, language, visuocon-
structive skill, and ideational praxis (26). The MMSE is a brief 30-
item measure of global cognitive ability (20).
Alzheimers Disease Cooperative StudyActivities of Daily
Living Scale. The Alzheimers Disease Cooperative StudyAc-
tivities of Daily Living Scale is a 23-item, hierarchically scaled in-
ventory of basic (e.g., eating, toileting, bathing) and instrumental
(e.g., using the telephone, going shopping) functional skills and
abilities (27). Ratings are based on an informants observations.
Dependence Scale. The Dependence Scale is a 13-item mea-
sure of the amount of caregiver assistance needed by the patient
to accomplish daily activities (28) and has been used as a predic-
tor of nursing home placement (7). On the basis of the Depen-
dence Scale interview with an informant, the clinician rates the
patients level of equivalent institutional care. Level 1 indicates
limited home care (needs some help with activities such as shop-
ping or housekeeping), level 2 represents supervised adult home
care (supervised setting with constant companionship and regu-
lar help with cooking and housekeeping), and level 3 indicates a
health-related facility (24-hour supervision for personal care and
safety).
Caregiver Activity Survey. The Caregiver Activity Survey mea-
sures the time that caregivers spend providing care for a patient
with Alzheimers disease (29). The time spent by care providers
over the past 24 hours is recorded for each of five domains of care
needs: using transportation, dressing, eating, looking after ones
appearance, and general supervision. Caregiving time was the
sum of time for the four specific domains, excluding general su-
pervision.
Alzheimers Disease Related Quality of Life. Thi s i ns t r u-
ment measures health-related quality of life in patients with
Alzheimers disease on the basis of a structured interview with the
caregiver (30). Its items assess behaviors that reflect social inter-
action, maintained interests, participation in activities, cheerful-
ness, and freedom from distress. Forty-seven items in five do-
mains (social interaction, awareness of self, feelings and mood,
enjoyment of activities, response to surroundings) are rated, and
the total score is a weighted sum of the item scores.
Data Analysis
The intent-to-treat group included the patients who were as-
signed randomly to a treatment group (N=421) and received at
least one dose of study medication (N=416). Discontinuation of
phase 1 occurred when the study physician judged that the pa-
tients response to the assigned medication was not adequate be-
cause of insufficient efficacy, adverse effects, or other reason or
TABLE 1. Baseline Clinical Status of Randomly Assigned Patients in Phase 1 of the CATIE Alzheimers Disease Effectiveness
Study
Clinical Measure
Olanzapine
(N=100)
Quetiapine
(N=94)
Risperidone
(N=85)
Placebo
(N=142)
Total
(N=421)
Mean SD Mean SD Mean SD Mean SD Mean SD
Neuropsychiatric Inventory total
score
a
31.8 16.3 37.6 18.4 38.3 20.2 39.1 17.8 36.9 18.3
BPRS scores
Total 27.0 11.8 28.0 12.3 27.7 13.6 28.2 12.0 27.8 12.3
Hostile suspiciousness factor 2.1 1.2 2.2 1.3 2.2 1.3 2.3 1.2 2.2 1.3
Psychosis factor 1.7 1.5 2.0 1.4 2.0 1.6 1.8 1.5 1.9 1.5
Agitation factor 1.7 1.2 1.7 1.1 1.6 1.3 1.7 1.1 1.7 1.2
Withdrawn depression factor 1.3 0.9 1.2 0.9 1.3 1.0 1.2 0.9 1.2 0.9
Cognitive dysfunction factor 2.6 1.1 2.7 1.2 2.7 1.3 2.7 1.2 2.7 1.2
Cornell Scale for Depression in
Dementia score
8.8 5.4 9.8 5.5 10.3 5.4 10.6 5.6 9.9 5.5
Alzheimers Disease Assessment
Scale cognitive subscale score
34.6 12.7 36.1 13.6 31.1 13.6 35.7 13.2 34.6 13.3
Mini-Mental State Examination
score
15.0 5.4 14.9 6.1 15.7 6.1 14.7 5.8 15.0 5.8
Alzheimers Disease Cooperative
StudyActivities of Daily Living
Scale total score
39.4 17.4 39.0 17.8 40.0 18.1 38.2 16.3 39.0 17.2
Alzheimers Disease Related
Quality of Life total score
69.2 14.6 66.9 13.2 68.1 16.3 65.7 14.6 67.3 14.7
Caregiver Activity Survey score
(hours spent by care providers
over past 24 hours), excluding
supervision domain
5.1 4.7 4.8 3.1 5.0 6.4 5.7 4.6 5.2 4.8
N % N % N % N % N %
Equivalent institutional care
(level of care needed)
Limited home care 30 30 27 29 23 27 30 21 110 26
Supervised adult home 47 47 52 55 51 60 91 64 241 57
Health-related facility 23 23 15 16 11 13 21 15 70 17
a
Significant overall difference among treatment groups (one-way ANOVA: F=3.45, df=3, 410, p=0.02).
Am J Psychiatry 165:7, July 2008 847
SULTZER, DAVIS, TARIOT, ET AL.
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when the patient or family chose to discontinue the treatment.
This report presents the clinical outcome measures during phase
1 treatment.
Psychiatric and behavioral symptoms. The primary analysis
for these measures was the difference in change scores between
the antipsychotic treatment groups and the placebo treatment
group at the last observation in phase 1. The last-observation
analysis was chosen because of the substantial percentage of pa-
tients who discontinued phase 1 treatment, in order to provide a
concise summary of patient status immediately before discontin-
uation. We performed pairwise comparisons of each antipsy-
chotic with placebo by using an analysis of covariance (ANCOVA),
adjusting for the site and for the baseline rating scale score. Pair-
wise comparisons used a Hochberg modification of the Bonfer-
roni adjustment for multiple comparisons (31), in which the larg-
est of the p values is compared to 0.05 and the smallest is
compared to 0.05/3=0.017. An additional descriptive analysis also
compared the active treatments to one another. If a test with 2 de-
grees of freedom comparing the three antipsychotic treatment
groups had p<0.05, then pairwise comparisons among the active
treatments were performed, also using the Hochberg adjustment
for multiple comparisons. A further sensitivity analysis for key
outcomes also adjusted for the duration of treatment in phase 1,
since patients discontinued phase 1 at various times, and the
Neuropsychiatric Inventory baseline score, which was found to
be different across the groups at baseline. ANCOVA analyses for
the CGIC were confirmed by an analysis of the distribution of or-
dinal scores at the last observation using a Mantel-Haenszel
mean score chi-square test for ordinal data.
A confirmatory mixed-model repeated-measures analysis was
also performed for change from baseline on two measures: the
Neuropsychiatric Inventory total score and BPRS total score. This
strategy compared treatment groups across all time points to-
gether; it assumed that missing data from subjects who discon-
tinued could be represented by subjects who remained in the
phase at that visit. The model had fixed effects for treatment,
baseline value, classification of time (weeks 2, 4, 8, and 12), and
the interactions between baseline value and time and between
treatment and time, if significant, and it used a random patient
intercept and spatial power covariance structure to account for
the correlation of the repeated measurements within a subject.
The mixed model excluded visits after week 12 because the group
sizes declined substantially at later visits.
Finally, a secondary set of ANCOVA analyses compared treat-
ment groups at each of weeks 2, 4, 8, and 12 (observed cases), in
order to further characterize the response patterns for the pa-
tients who had not yet discontinued by that visit. The distribution
of ordinal scores on the CGIC across the treatment groups for ob-
served cases at week 12 was also assessed by using a Mantel-
Haenszel mean score chi-square test for ordinal data. For descrip-
tive purposes, the proportions of responders in the treatment
groups were calculated; those with CGIC designations of much
improved or very much improved at week 12 were considered
responders. This approach is different from the previous analysis
(17), which included the entire intent-to-treat group, defined re-
sponse as at least minimal improvement on the CGIC, and con-
sidered all patients who ended phase 1 before week 12 to be non-
responders. The current analysis of observed cases of patients
who continued with phase 1 treatment at week 12 used the higher
threshold for response because this group tended to have fewer
symptoms, since those with more symptoms were more likely to
have ended phase 1 before week 12.
Cognition, functional skills, and care needs. Thes e mea-
sures were completed only at weeks 12, 24, and 36. Change scores
were examined with ANCOVA only for patients who were con-
tinuing the phase 1 assigned treatment at week 12. Scores on
these measures at the last observation during phase 1 were often
not available because a high proportion of patients discontinued
phase 1 before week 12 and thus had no postbaseline assessment.
Results
Patient Characteristics and Treatment
Patient characteristics, treatments prescribed, time to
phase 1 discontinuation, and adverse events were re-
ported previously (17, 32). The mean age of the partici-
pants was 77.9 years (SD=7.5); 56% were female, and 21%
were nonwhite. Overall, 77%85% of the patients discon-
tinued the phase 1 medication before the end of the 36-
week study period. The median duration of phase 1 treat-
TABLE 2. Change in Clinical Symptoms From Baseline to Last Observation in Phase 1 of the CATIE Alzheimers Disease
Effectiveness Study
Symptom Measure
Olanzapine
(N=99)
a
Quetiapine
(N=94)
a
Risperidone
(N=84)
a
Placebo
(N=139)
a
Overall Comparison of
Treatment Groups
(F test, df=3) (p) Mean SD Mean SD Mean SD Mean SD
Change in Neuropsychiatric Inventory
total score
b
7.0 18.1 7.3 20.2 11.6 15.4 4.2 20.0 0.004
Alzheimers Disease Cooperative
StudyClinical Global Impression
of Change score
3.9 1.5 3.8 1.5 3.5 1.4 4.2 1.3 0.005
Change in BPRS scores
b
Total 2.9 11.8 4.2 9.2 4.3 9.2 2.9 10.0 0.39
Hostile suspiciousness factor 0.6 1.3 0.5 1.3 0.7 1.2 0.3 1.2 0.01
Psychosis factor 0.3 1.6 0.4 1.2 0.7 1.3 0.2 1.3 0.08
Agitation factor 0.4 1.2 0.3 1.0 0.2 1.1 0.1 1.0 0.09
Withdrawn depression factor 0.2 1.0 0.1 0.8 0.1 0.9 0.1 0.8 0.01
Cognitive dysfunction factor 0.1 0.9 0.0 0.9 0.1 0.9 0.1 1.0 0.15
Change in Cornell Scale for Depres-
sion in Dementia score
b
0.9 5.8 0.8 5.5 2.0 5.3 1.2 4.5 0.65
a
Number of subjects is the number who received at least one dose of the medication. Some patients discontinued treatment before assess-
ment, so the actual numbers of subjects used in the last-observation analysis are lower (olanzapine, N=97; quetiapine, N=84; risperidone,
N=77; placebo, N=130). The numbers vary slightly by score; the numbers reported here are for the Clinical Global Impression of Change. The
ranges of numbers of subjects per treatment are as follows: olanzapine, range=9497; quetiapine, range=8284; risperidone, range=7678;
placebo, range=129130.
b
Negative value reflects improvement.
848 Am J Psychiatry 165:7, July 2008
CATIE-AD
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ment was 7.1 weeks and did not differ significantly across
the treatment groups (median duration ranged from 5.3 to
8.1 weeks in the four groups). The mean last prescribed
medication dose was 5.5 mg/day of olanzapine, 56.5 mg/
day of quetiapine, and 1.0 mg/day of risperidone. There
was no difference in the numbers or sizes of capsules pre-
scribed across treatments. Rescue medications were pre-
scribed rarely, and there were no significant differences
among treatment groups: of the 421 patients, three re-
ceived a conventional antipsychotic and 21 received a
benzodiazepine (olanzapine, N=3; quetiapine, N=8; ris-
peridone, N=3; placebo, N=7).
Clinical Symptoms at Baseline
The baseline scores on clinical symptom measures are
shown in Table 1. The only difference in baseline symptom
scores across the treatment groups was for the total score
on the Neuropsychiatric Inventory.
Change From Baseline to Last Observation
Global symptoms. Symptom changes from baseline to
the last phase 1 observation are shown in Table 2. Differ-
ences between placebo and the active drugs appear in Ta-
ble 3. On the Neuropsychiatric Inventory total score, pa-
tients treated with olanzapine or risperidone showed
greater improvement from baseline to the last phase 1 ob-
servation than those treated with placebo. On the CGIC,
the patients treated with risperidone had greater global
improvement than those in the placebo group. Overall
group differences were confirmed in an analysis of the dis-
tribution of ordinal scores on the CGIC at the last observa-
tion in phase 1 (Mantel-Haenszel mean score chi-square
test for ordinal data:
2
=12, 11, df=3, p=0.007). Improve-
ment on the BPRS total score at last observation was not
significantly different between those treated with antipsy-
chotic medication and those treated with placebo. Includ-
ing baseline Neuropsychiatric Inventory total score and
the duration of phase 1 treatment as additional covariates
in the ANCOVA model did not affect these results.
Individual symptoms. Patients treated with olanzapine
or risperidone showed greater improvement on the BPRS
hostile suspiciousness factor at the end of phase 1 than
those treated with placebo (Table 3). Patients treated with
risperidone had greater improvement on the BPRS psy-
chosis factor than those treated with placebo. On the BPRS
withdrawn depression factor, patients treated with olan-
zapine showed worsening of symptoms compared to pla-
cebo. There was no significant difference between those
treated with antipsychotic medication and those receiving
placebo on the BPRS cognitive dysfunction factor or the
Cornell Scale for Depression in Dementia.
Repeated-Measures Analysis
The mixed-model analysis of change in both the Neu-
ropsychiatric Inventory and BPRS total scores for time
points between baseline and week 12 showed no overall
TABLE 3. Difference Between Effects of Placebo and Active Drugs on Clinical Symptoms From Baseline to Last Observation
in Phase 1 of the CATIE Alzheimers Disease Effectiveness Study
Symptom Measure
Comparison With Placebo (N=139)
a,b
Olanzapine (N=99)
b
Quetiapine (N=94)
b
Risperidone (N=84)
b
Difference
in Least-
Squares
Means
c
95% CI p
Difference
in Least-
Squares
Means
c
95% CI p
Difference
in Least-
Squares
Means
c
95% CI p
Neuropsychiatric
Inventory total
6.3 10.8 to 1.7 0.007
d
4.0 8.7 to 0.7 0.10 8.2 13.0 to 3.4 <0.001
d
Alzheimers Disease
Cooperative Study
Clinical Global
Impression of Change
0.36 0.73 to 0.01 0.06 0.43 0.81 to 0.04 0.04 0.70 1.10 to 0.30 <0.001
d
BPRS
Total 0.6 3.0 to 1.8 0.63 1.6 4.1 to 0.9 0.21 2.0 4.5 to 0.6 0.13
Hostile suspiciousness
factor
0.4 0.7 to 0.1 0.006
d
0.3 0.6 to 0.0 0.08 0.5 0.8 to 0.2 0.003
d
Psychosis factor 0.2 0.5 to 0.1 0.20 0.2 0.5 to 0.2 0.36 0.5 0.8 to 0.1 0.01
d
Agitation factor 0.3 0.5 to 0.0 0.03 0.2 0.5 to 0.0 0.08 0.2 0.5 to 0.0 0.09
Withdrawn depression
factor
0.3 0.1 to 0.5 0.003
d
0.0 0.2 to 0.2 0.99 0.2 0.0 to 0.4 0.09
Cognitive dysfunction
factor
0.2 0.0 to 0.4 0.04 0.1 0.2 to 0.3 0.61 0.0 0.2 to 0.2 0.94
Cornell Scale for
Depression in Dementia
0.4 1.5 to 0.8 0.54 0.1 1.4 to 1.1 0.85 0.8 2.0 to 0.5 0.22
a
Least-squares mean difference and p value are based on ANCOVA models with adjustment for site and baseline value.
b
Number of subjects is the number who received at least one dose of the medication. Some patients discontinued treatment before assess-
ment, so the actual numbers of subjects used in the last observation analysis are lower (olanzapine, N=97; quetiapine, N=84; risperidone,
N=77; placebo, N=130). The numbers vary slightly by score; the numbers reported here are for the Clinical Global Impression of Change. The
ranges of numbers of subjects per treatment are as follows: olanzapine, range=9497; quetiapine, range=8284; risperidone, range=7678;
placebo, range=129130.
c
Negative values reflect greater improvement with active drug.
d
Significant at 0.05 in accordance with the Hochberg adjustment for multiple comparisons (31).
Am J Psychiatry 165:7, July 2008 849
SULTZER, DAVIS, TARIOT, ET AL.
ajp.psychiatryonline.org
FIGURE 1. Change in Clinical Symptoms for Observed Cases
a
in Phase 1 of the CATIE Alzheimers Disease Effectiveness
Study
b
a
For patients continuing to take the assigned phase 1 medication at each time point.
b
Pairwise comparisons of least-squares mean change scores for each antipsychotic and placebo at each time point are shown here for descrip-
tive purposes (ANCOVA, adjusted for baseline score and site, no adjustment for multiple comparisons). Significant pairwise comparisons with
the antipsychotic treatment groups are provided in the text. Discrepancies between the magnitude of between-group differences shown in
the graphs and the results of antipsychotic-placebo pairwise comparisons are due to differences between observed means and least-squares
means, which adjust for baseline score and site variations.
c
Change scores less than 0 reflect clinical improvement.
*p<0.05. **p<0.01.
BPRS hostile suspiciousness factor
Risperidone (RIS)
Placebo
Olanzapine (OLZ)
N= 93 80 52 42 31
N= 98 90 72 48 40
N= 82 71 61 40 32
N=138 126 94 67
47
0 2 4 6 8 10 12
2
4
6
8
10
12
14
16
18
20
*
*
Quetiapine (QUE)
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
Weeks
1.0
0
0
2 4 6 8 10 12
OLZ
OLZ
QUE
0.2
0.4
0.6
0.8
1.2
1.4
1.6
**
*
**
**
**
**
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
Weeks
Neuropsychiatric Inventory total
0
0 2 4 6 8 10 12
2
4
6
8
10
12
*
*
*
*
Weeks
BPRS total
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
**
**
0.0
0 2 4 6 8 10 12
0.2
0.4
0.6
0.8
1.2
1.4
1.0
*
*
Weeks
BPRS psychosis factor
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
0.2
0.0
0.2
0.4
0.6
1.0
0.8
*
Weeks
BPRS withdrawn depression factor BPRS agitation factor
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
Q
0.0
0 2 4 6 8 10 12
0.2
RIS
RIS
0.4
0.6
0.8
1.2
1.0
*
*
Weeks
S
c
o
r
e

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e
c
0 2 4 6 8 10 12
*
* *
OLZ
0
850 Am J Psychiatry 165:7, July 2008
CATIE-AD
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time-by-treatment interaction. The reduced model with-
out this interaction term, which compared the treatment
groups across the average of all time points, revealed an
overall effect of treatment group (mixed-model, repeated-
measures analysesNeuropsychiatric Inventory: F=3.15,
df=3, 349, p=0.03; BPRS: F=2.80, df=3, 377, p=0.04), with
significant pairwise differences between risperidone and
placebo treatment on the Neuropsychiatric Inventory (es-
timated mean difference=5.7, SE=1.9; t=3.03, df=345, p=
0.003) and on the BPRS (estimated mean difference=2.9,
SE=1.1; t=2.71, df=373, p=0.007).
Change From Baseline to Week 12 for Observed
Cases
Mean change scores on the Neuropsychiatric Inventory
total, BPRS total, and BPRS factors over 12 weeks of phase
1 treatment are shown in Figure 1. Only patients continu-
ing the assigned phase 1 treatment were included at each
time point, so the group sizes declined over the 12-week
period. Change over time among the observed cases seen
on these curves generally supports the results of the last-
observation and mixed-model analyses.
The distribution of scores on the CGIC in observed
cases after 12 weeks of treatment (Figure 2) did not signif-
icantly differ among the groups (p=0.14, Mantel-Haenszel
mean score chi-square test for ordinal data). The propor-
tions of patients with a rating of much improved or very
much improved were 45%, 52%, 61%, and 40% in the
olanzapine, quetiapine, risperidone, and placebo groups,
respectively.
Structured ratings of functional abilities, care needs,
cognitive skills, and quality of life were assessed only at
baseline and at week 12 during the CATIE-AD early treat-
ment period. On the Activities of Daily Living Scale, pa-
tients in the olanzapine treatment group showed worsen-
ing of functional ability compared to those in the placebo
group at week 12 (Table 4). We found no significant differ-
ences between patients treated with an antipsychotic
medication and those treated with placebo in change
scores at week 12 on the Alzheimers Disease Assessment
Scale cognitive subscale, MMSE, Alzheimers Disease Re-
lated Quality of Life, or Caregiver Activity Survey. On the
rating of equivalent institutional care, there was no overall
difference among the treatment groups in change in the
level of care from baseline to week 12.
Active Drug Comparisons
At the last observation in phase 1, there were no differ-
ences among the three antipsychotic treatment groups on
any clinical outcome measure except the BPRS withdrawn
depression factor (overall comparison: F=3.52, df=2, 376,
p=0.04). In the pairwise comparisons, the olanzapine
group showed worsening of symptoms compared to the
quetiapine group (least-squares mean difference=0.3, 95%
CI=0.1 to 0.5, p=0.009).
In the analysis of observed cases at weeks 2, 4, 8, and 12,
there were only two significant differences among the
three antipsychotic treatment groups on the clinical out-
come measures. First, on the BPRS withdrawn depression
factor at week 8 there was a significant overall group effect
(F=4.51, df=2, 176, p=0.02), and the olanzapine group
showed worsening of symptoms compared to the quetia-
pine group (least-squares mean difference=0.4, 95% CI=
0.1 to 0.8, p=0.01) and the risperidone group (least-
squares mean difference=0.4, 95% CI=0.1 to 0.8, p=0.02).
Second, on the Activities of Daily Living scale at week 12
there was a significant overall group effect (F=4.36, df=2,
130, p=0.02), and the olanzapine group showed a greater
decline (worsening) than the quetiapine group (least-
squares mean difference=5.2, 95% CI=9.3 to 1.0, p=
0.02) and the risperidone group (least-squares mean dif-
ference=5.4, 95% CI=9.5 to 1.2, p=0.02).
Discussion
Several clinical outcome measures in CATIE-AD indi-
cate that patients may benefit symptomatically from treat-
ment with atypical antipsychotic medications. Beneficial
effects of olanzapine and risperidone were apparent on
the Neuropsychiatric Inventory total score, a summary
measure of psychiatric and behavioral symptoms. Im-
provement on the clinician-rated CGIC in the risperidone
group provides convergent support for the improvements
in symptom scores.
The magnitude of the difference in mean global score
improvements between active medication and placebo
FIGURE 2. Distribution of Improvement Ratings for Ob-
served Cases
a
at 12 Weeks in Phase 1 of the CATIE Alzhei-
mers Disease Effectiveness Study
a
For patients continuing to take the assigned phase 1 medication at
12 weeks.
P
e
r
c
e
n
t

o
f

O
b
s
e
r
v
e
d

C
a
s
e
s

a
t

W
e
e
k

1
2
0
10
20
30
50
40
Very Much
Improved
Much
Improved
Rating on Alzheimers Disease Cooperative
StudyClinical Global Impression of Change
Minimally
Improved
Minimally
Worse
Placebo (N=48)
Olanzapine (N=40)
Quetiapine (N=31)
Risperidone (N=33)
Much
Worse
No
Change
Am J Psychiatry 165:7, July 2008 851
SULTZER, DAVIS, TARIOT, ET AL.
ajp.psychiatryonline.org
was usually small. Significant group differences were not
seen on the BPRS total score at the last observation, al-
though the mixed-model analysis revealed a significantly
greater effect with risperidone than with placebo, with a
larger estimated mean difference in the mixed model than
was measured at the last phase 1 observation. Some analy-
ses revealed pairwise group differences that were near the
statistical threshold for significance after adjustment for
multiple comparisons, suggesting that while group differ-
ences cannot be excluded, their magnitude is small. In
contrast, other group differences were probably clinically
meaningful. For example, the baseline total score on the
Neuropsychiatric Inventory (overall mean=36.9) was im-
proved at the last observation in phase 1 by 11.6 points in
the risperidone group and 7.0 points in the olanzapine
group, compared to 4.2 points in the placebo group. Also,
the CGIC ratings at the last observation in phase 1 and at 12
weeks indicate that some individuals were likely benefiting
from antipsychotic treatment. Greater benefit from que-
tiapine than from placebo did not appear on most CATIE-
AD symptom outcomes, although Figure 1 indicates that a
quetiapine effect cannot be entirely ruled out. Limited
quetiapine impact on symptoms may have been due to the
low dose of quetiapine prescribed. However, sedation oc-
curred in this group at rates comparable to those for the
other drugs (17), suggesting at least some medication ef-
fect. Use of rescue medication (haloperidol, lorazepam)
likely did not contribute to clinical outcomes, since these
medications were prescribed rarely and equally across the
treatment groups (17).
These clinical symptom ratings in CATIE-AD comple-
ment and extend the findings from the primary effective-
ness analysis, which showed benefits of olanzapine and
risperidone in terms of longer times to discontinuation
due to lack of efficacy, which were offset by discontinua-
tions due to adverse effects (17). The clinical symptom rat-
ings reported here also show some antipsychotic efficacy
during phase 1, yet these improved last-observation rat-
ings occurred at or very near the time when the clinician
decided that phase 1 treatment was not optimal and in-
tended to change the treatment, except for the 19% of pa-
tients who completed the entire study while taking the
phase 1 medication. Notably, phase 1 discontinuations
were due predominantly to insufficient efficacy. Thus, the
clinical symptom ratings reveal some beneficial antipsy-
chotic effects, despite the frequent coincident decision to
change treatment. This distinction suggests that clinicians
were seeking a level of clinical improvement that was
greater than the change detected on the clinical scales,
were mindful of possible placebo assignment in phase 1,
or were balancing symptom change with other clinical
considerations, such as adverse effects. Treatment expec-
tations and patient circumstances likely contributed to
the perception of effectiveness. As applied to clinical prac-
tice, these findings support an individualized approach,
where the value of an individual patients symptomatic
improvement needs to be assessed in the context of that
persons particular clinical circumstances.
The analyses that used the last clinical rating in phase 1
are conceptually different from the descriptive analyses
that used scores from observed cases of continued phase 1
treatment through week 12. The last-observation analysis
includes a preponderance of data from patients who, for a
variety of reasons, were not doing particularly well while
taking the assigned treatment. By contrast, the results from
observed patients continuing phase 1 treatment apply to
those who were doing reasonably well with their first pre-
scribed medication, because phase 1 would have ended
earlier for these patients had the clinicians felt the assigned
treatment was not effective overall. This is reflected in the
larger improvement from baseline generally seen in all
treatment groups among observed cases at week 12 com-
pared to the last-observation study group. Despite this im-
portant difference, the results from using the two analytic
approaches are not substantially different.
The BPRS factor scores provide a view of antipsychotic
treatment effects on distinct symptoms. Patients treated
with risperidone or olanzapine showed improvement on
TABLE 4. Change in Cognition, Functioning, Care Needs, and Quality of Life for Observed Cases
a
at 12 Weeks in Phase 1 of
the CATIE Alzheimers Disease Effectiveness Study
Clinical Measure
Change in Score
Olanzapine (N=40) Quetiapine (N=31) Risperidone (N=33) Placebo (N=47)
Mean SD Mean SD Mean SD Mean SD
Alzheimers Disease Cooperative Study
Activities of Daily Living Scale total
b
6.1
c
8.2 1.0 7.7 1.1 8.8 0.5 8.4
Alzheimers Disease Assessment Scale
cognitive subscale
d
0.7 6.1 0.8 6.9 1.7 5.2 1.3 5.7
Mini-Mental State Examination
b
0.1 3.7 0.8 3.8 0.8 3.2 0.7 2.7
Alzheimers Disease Related Quality of Life
total
b
6.4 12.6 6.7 11.7 2.1 12.1 4.1 15.8
Caregiver Activity Survey (hours spent by
care providers over past 24 hours),
excluding supervision domain
d
0.2 4.8 0.7 4.3 1.1 4.7 0.6 4.1
a
For patients taking the assigned phase 1 medication at week 12.
b
Change score greater than 0 reflects clinical improvement.
c
Significantly different from placebo (p<0.001, ANCOVA model with adjustment for site and baseline score).
d
Change score less than 0 reflects clinical improvement.
852 Am J Psychiatry 165:7, July 2008
CATIE-AD
ajp.psychiatryonline.org
the BPRS hostile suspiciousness factor, which assesses
hostility, aggression, mistrust, and uncooperativeness.
This subscale had the highest mean score at baseline
among noncognitive measures, and the mean score im-
proved by more than 50% among risperidone-treated pa-
tients continuing phase 1 treatment at week 12. The BPRS
psychosis factor score also improved with risperidone
treatment. In contrast, antipsychotic treatment effects on
the BPRS agitation factor score, which includes excitabil-
ity, tension, and anxiety, were not as robust. This observa-
tion conforms to some clinical opinion that antipsychot-
ics might be particularly useful for suspicious thoughts,
paranoid delusions, and hostile or aggressive behaviors,
which occur commonly in Alzheimers disease.
On measures of depression or cognition, the magnitude
of changes was small and there were no differences across
treatments except for increased scores in the olanzapine
group on the BPRS withdrawn depression factor at the last
observation in phase 1. Taken together, these findings sug-
gest that antipsychotic medication may have differential
effects on specific symptoms in Alzheimers disease. Better
understanding of specific effects can help clinicians to se-
lect optimal pharmacotherapy.
Beneficial effects were not apparent on measures of
functional abilities, quality of life, or caregiving time
needed. Thus, improved clinical symptoms with antipsy-
chotic treatment did not translate into functional benefits
or improved quality of life in the context of the CATIE-AD
effectiveness design. This may be due to additional factors
that contribute to functional disability and poor life qual-
ity, such as progression of dementia, caregiver interac-
tions, environmental factors, and perhaps adverse effects
of the drugs. Nonetheless, improved psychiatric and be-
havioral symptoms may be clinically meaningful for indi-
vidual patients without affecting function.
There are several limitations to the study design and
analyses. CATIE-AD did not follow a usual clinical efficacy
trial design, and while the effectiveness design has several
advantages, the results of these analyses should be inter-
preted carefully. For example, the end of phase 1 was de-
fined not by a specific time point but by the clinicians
judgment that continued treatment with the assigned
medication was not optimal. The protocol invited medica-
tion switches based on clinical judgment and, in fact,
phase 1 treatment was often discontinued relatively
quickly. In this respect, CATIE-AD results reflect clinician
expectations and behaviors as well as pharmacologic effi-
cacy. Also, the brief treatment exposure for many patients
may not have captured all beneficial or adverse medica-
tion effects. Moreover, mild sedation may have contrib-
uted to behavioral improvement with antipsychotic treat-
ment, but its specific role cannot be defined. Finally, the
data analyses included many measures and comparisons,
and there was no adjustment to statistical testing for the
number of variables evaluated overall.
The results presented here are predominantly group
mean scores on clinical rating instruments, and this ap-
proach can obscure important treatment effects in indi-
vidual patients. Subgroups of participants may respond to
individual treatments particularly well or particularly
poorly, as a result of distinct neurobiological factors (33),
baseline symptom patterns, or sensitivity to treatment.
Additional research is needed to clarify patient- or symp-
tom-specific responses in order to maximize benefit and
minimize harm of any available treatment.
The clinical outcomes in CATIE-AD contribute to the
evolving understanding of psychopharmacological inter-
ventions for psychiatric symptoms in Alzheimers disease.
Some antipsychotic efficacy trials and the analyses re-
ported here indicate that clinical symptoms may improve.
However, the extent of mean improvement on rating
scales is modest, it is not apparent for all symptoms or in
all treatment studies, and beneficial effects on mean rat-
ings of functional ability, quality of life, or cost-effective-
ness (34) were not seen in CATIE-AD. Because of the
unique design, the results of CATIE-AD are probably more
generalizable to usual outpatient clinical settings than are
results from efficacy trials. Whether the potentially benefi-
cial effects of symptom reduction with antipsychotic
treatment outweigh other undesirable clinical or adverse
effects depends on an individual patients circumstances,
including severity of symptoms, vulnerability to adverse
effects, and the effectiveness or opportunity for behavioral
interventions. Additional studies to understand better the
risk-benefit profile and effectiveness of specific treat-
ments in individual patients will be valuable.
Received Nov. 17, 2007; revision received Feb. 22, 2008; accepted
March 1, 2008 (doi: 10.1176/appi.ajp.2008.07111779). From the De-
partment of Psychiatry and Biobehavioral Sciences, David Geffen
School of Medicine, UCLA, and the Gero/Neuropsychiatry Division, VA
Greater Los Angeles Healthcare System, Los Angeles; Quintiles, Re-
search Triangle Park, N.C.; the Banner Alzheimers Institute, Phoenix;
the Department of Psychiatry and Behavioral Sciences, Keck School
of Medicine, University of Southern California, Los Angeles; the Divi-
sion of Geriatric Psychiatry, University of California, San Diego, School
of Medicine, La Jolla; the Department of Psychiatry, Johns Hopkins
Bayview Medical Center, Baltimore; the Department of Psychiatry,
Yale University School of Medicine and VA Connecticut Health Care
System, New Haven, Conn.; the Division

of Services and Intervention
Research, NIMH, Bethesda, Md.; and the Department of Psychiatry,
College of Physicians and Surgeons, Columbia University, and New
York State Psychiatric Institute, New York. Address correspondence
and reprint requests to Dr. Sultzer, Psychiatry, 3-South, 116AE, 11301
Wilshire Blvd., Los Angeles, CA 90073; dsultzer@ucla.edu (e-mail).
Dr. Sultzer has received research funding from Forest and Pfizer,
has received lecture honoraria from Forest, and has served as a con-
sultant to Eli Lilly and AstraZeneca. Dr. Davis is employed by Quin-
tiles, Inc. Dr. Tariot has received consulting fees from AC Immune, As-
traZeneca, Avid, Baxter Healthcare, Eisai, Epix, Forest, Memory,
Myriad, Pfizer, and Sanofi-Aventis; research support from Elan, Mit-
subishi Pharma, Neurochem, Ono, the National Institute on Aging,
NIMH, the Alzheimers Association, the Arizona Department of
Health Services, and the Institute for Mental Health Research; con-
sulting fees and research support from Abbott, GlaxoSmithKline,
Merck, Merz, Takeda, and Wyeth; and educational fees from Lund-
beck; he is also a contributor to the patent Biomarkers of Alzhei-
mers Disease. Dr. Lyketsos has received research funding from For-
est, GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Eli Lilly, Ortho-McNeil,
Am J Psychiatry 165:7, July 2008 853
SULTZER, DAVIS, TARIOT, ET AL.
ajp.psychiatryonline.org
Bristol-Myers Squibb, Novartis, NIMH, the National Institute on Aging,
and the Associated Jewish Federation of Baltimore; has received lec-
ture honoraria or travel support from Pfizer, Forest, GlaxoSmithKline,
and Monitor; and has served as consultant/adviser to AstraZeneca,
GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda,
and Wyeth. Dr. Rosenheck has received research support from Eli
Lilly, Janssen, AstraZeneca, and Wyeth, and he has been a consultant
for GlaxoSmithKline, Bristol-Myers Squibb, Janssen, and Organon. Dr.
Lieberman has received research funding from Acadia, Bristol-Myers
Squibb, GlaxoSmithKline, Janssen, Merck, Organon, and Pfizer; has
participated as consultant or advisory board member for AstraZen-
eca, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, and Pfizer; and
holds a patent related to work with Repligen. Dr. Schneider has been
a consultant for Pfizer, Eli Lilly, Johnson & Johnson, AstraZeneca, and
Bristol-Myers Squibb. Ms. Dagerman, Dr. Lebowitz, and Dr. Hsiao re-
port no competing interests.
Supported in part by NIMH research contract N01 MH-9001 and by
the U.S. Department of Veterans Affairs. Medications for this study
were provided by AstraZeneca Pharmaceuticals, Forest Pharmaceuti-
cals, Janssen Pharmaceutica, and Eli Lilly.
The content of this article does not necessarily reflect the views or
policies of the U.S. Department of Health and Human Services, nor
does mention of trade names, commercial products, or organiza-
tions imply endorsement by the U.S. government.
ClinicalTrials.gov number: NCT00015548.
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