n engl j med 355;15 www.nejm.org october 12, 2006
1525
The new england
journal
of medicine
established in 1812
october 12, 2006
vol. 355 no. 15
Effectiveness of Atypical Antipsychotic Drugs
in Patients with Alzheimer’s Disease
Lon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M. Davis, Dr.P.H.,
John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz, Ph.D., Constantine G. Lyketsos, M.D., M.H.S.,
J. Michael Ryan, M.D., T. Scott Stroup, M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D.,
and Jeffrey A. Lieberman, M.D., for the CATIE-AD Study Group*
ABSTRACT
From the Keck School of Medicine, Uni-
versity of Southern California, Los Ange-
les (L.S.S., K.S.D.); the Banner Alzheimer’s
Institute, Phoenix, AZ (P.N.T.); Quintiles,
Research Triangle Park, NC (S.M.D.); the
National Institute of Mental Health, Na-
tional Institutes of Health, Bethesda, MD
(J.K.H.); the University of Rochester
Medical Center, Rochester, NY (M.S.I.,
J.M.R.); the School of Medicine, University
of California, San Diego, La Jolla (B.D.L.);
the Department of Psychiatry, Johns
Hopkins Bayview, Johns Hopkins Univer-
sity, Baltimore (C.G.L.); the School of
Medicine, University of North Carolina at
Chapel Hill, Chapel Hill (T.S.S.); Veter-
ans Affairs Greater Los Angeles Health-
care System, University of California, Los
Angeles, Los Angeles (D.L.S.); the School
of Medicine, University of Pennsylvania,
Philadelphia (D.W.); and the College of
Physicians and Surgeons, New York
(J.A.L.). Address reprint requests to Dr.
Schneider at the Keck School of Medi-
cine, University of Southern California,
1510 San Pablo St., HCC 600, Los Ange-
les, CA 90033, or at lschneid@usc.edu.
*Members of the Clinical Antipsychotic
Trials of Intervention Effectiveness–
Alzhei mer’s Disease (CATIE-AD) Study
Group are listed in the Appendix.
N Engl J Med 2006;355:1525-38.
Copyright © 2006 Massachusetts Medical Society.
Background
Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis,
aggression, and agitation in patients with Alzheimer’s disease, but their benefits
are uncertain and concerns about safety have emerged. We assessed the effective-
ness of atypical antipsychotic drugs in outpatients with Alzheimer’s disease.
Methods
In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzhei-
mer’s disease and psychosis, aggression, or agitation were randomly assigned to re-
ceive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per
day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as
needed, and patients were followed for up to 36 weeks. The main outcomes were
the time from initial treatment to the discontinuation of treatment for any reason
and the number of patients with at least minimal improvement on the Clinical
Global Impression of Change (CGIC) scale at 12 weeks.
Results
There were no significant differences among treatments with regard to the time to
the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks),
quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median,
8.0 weeks) (P = 0.52). The median time to the discontinuation of treatment due to a
lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as
compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P = 0.002). The time
to the discontinuation of treatment due to adverse events or intolerability favored
placebo. Overall, 24% of patients who received olanzapine, 16% of patients who re-
ceived quetiapine, 18% of patients who received risperidone, and 5% of patients who
received placebo discontinued their assigned treatment owing to intolerability
(P = 0.009). No significant differences were noted among the groups with regard to
improvement on the CGIC scale. Improvement was observed in 32% of patients as-
signed to olanzapine, 26% of patients assigned to quetiapine, 29% of patients as-
signed to risperidone, and 21% of patients assigned to placebo (P = 0.22).
Conclusions
Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for
the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s dis-
ease. (ClinicalTrials.gov number, NCT00015548.)
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1526
D
elusions, hallucinations, aggres-
sion, and agitation affect more than half
of patients with Alzheimer’s disease and
related dementias.
1-4
Antipsychotic drugs are used
to treat these behaviors and symptoms and are
among the most frequently used psychotropic drugs
in Alzheimer’s disease.
5,6
Second-generation (atypical) antipsychotic
drugs have been considered to be at least as ef-
fective as conventional antipsychotic agents such
as haloperidol, with a lower risk of most adverse
effects,
7
and are used as first-line pharmacologic
treatments for patients with dementia.
5,8
How-
ever, there is a dearth of placebo-controlled and
active-drug–controlled, randomized trials and lon-
ger-term data from controlled trials regarding
the effectiveness of atypical antipsychotic drugs.
Moreover, the available data on efficacy have been
inconsistent, rates of response to placebo have
been high, and patients have been required to re-
ceive drugs for the 6-week to 12-week study pe-
riods, whether or not they benefited, an artificial
situation that does not address effectiveness.
9
New safety issues have emerged with respect
to atypical antipsychotic drugs. Increased risks
of cerebrovascular adverse events
10-12
and death
13,14
have complicated their use. Antidepressant med-
ications such as citalopram have been suggest-
ed as alternatives to antipsychotic drugs,
15
at least
for aggression or agitation,
16
despite the lack of
data from adequate trials.
17
We conducted a double-blind, placebo-con-
trolled trial to determine the effectiveness of olan-
zapine, quetiapine, and risperidone as compared
with placebo in outpatients with Alzheimer’s dis-
ease and psychosis, aggression, or agitation.
Methods
Study Setting and Design
The trial was part of the National Institute of
Mental Health (NIMH) Clinical Antipsychotic
Trials of Intervention Effectiveness. Such trials
address broad outcomes in settings and with in-
terventions that reflect usual practices. The ra-
tionale, design, and methods of this study —
Clinical Antipsychotic Trials of Intervention
Effectiveness–Alzheimer’s Disease (CATIE-AD)
— have been described previously.
18
The trial was
conducted between April 2001 and November
2004 at 45 sites in the United States (26 univer-
sity clinics, 7 Veterans Affairs medical centers,
and 12 private-practice sites [3 sites did not ran-
domly assign any patients]).
In phase 1 of the study, patients were randomly
assigned under double-blind conditions to receive
olanzapine, quetiapine, risperidone, or placebo in
a 2:2:2:3 ratio. Doses were adjusted as clinically
indicated by study physicians. If the physicians
judged that the patient’s response was not ade-
quate at any time after the first 2 weeks, then treat-
ment could be discontinued. Patients with an ad-
equate response continued treatment for up to
36 weeks. Patients whose initial treatment was
discontinued during phase 1 could be enrolled in
phase 2 and randomly assigned under double-
blind conditions to receive one of the antipsy-
chotic drugs to which they were not initially as-
signed or to receive citalopram.
18
This report is
limited to phase 1 results.
Participants
Eligible participants fulfilled criteria for demen-
tia of the Alzheimer’s type (according to the Diag-
nostic and Statistical Manual of Mental Disorders, fourth
edition)
19
or probable Alzheimer’s disease
20
on the
basis of the history, physical examination, results
of structural brain imaging, and the score on the
Mini–Mental State Examination (MMSE)
21
; the
MMSE score had to be between 5 and 26 (on a
scale from 0 to 30, with lower scores indicating
poorer performance). To be eligible, patients had
to be ambulatory and living at home or in an as-
sisted-living facility. Eligible patients had delu-
sions, hallucinations, aggression, or agitation that
developed after the onset of dementia and was
severe enough to disrupt their functioning and, in
the opinion of the study physicians, to justify treat-
ment with antipsychotic drugs. Signs and symp-
toms of psychosis, aggression, or agitation had to
have occurred nearly daily during the previous
week or at least intermittently for 4 weeks. During
the week before they were randomly assigned to
treatment, eligible patients also had a severity
rating of at least “moderate” for conceptual dis-
organization, suspiciousness, or hallucinatory
behavior on the Brief Psychiatric Rating Scale
(BPRS).
22
Alternatively, a frequency rating of “of-
ten” or “more frequently” and a severity rating
of at least “moderate” were required for delusions,
hallucinations, agitation, or “aberrant motor
behavior” in the Neuropsychiatric Inventory.
23
atypical antipsychotic drugs in alzheimer’s disease
n engl j med 355;15 www.nejm.org october 12, 2006
1527
A study partner or caregiver who had regular
contact with the patient was required to partici-
pate in the assessments.
18
Patients were excluded if they had received a
diagnosis of a primary psychotic disorder (e.g.,
schizophrenia), delirium, other dementia such as
vascular dementia
24
or Lewy-body dementia,
25
or
psychosis, agitation, or aggression that could be
better accounted for by another medical condition,
medication, or substance abuse. Patients were also
excluded if they required psychiatric admission,
were suicidal, were going to receive treatment with
a cholinesterase inhibitor or antidepressant medi-
cation, had previously been treated with two of the
three atypical antipsychotic drugs under study, or
had contraindications to any of the study drugs.
The study was approved by the NIMH data
and safety monitoring board and by the institu-
tional review board at each site. Written informed
consent was obtained from the patients or their
legally authorized representatives and from the
partners or caregivers who participated with the
patients.
Interventions
The trial design encouraged prescribing that re-
flected clinical practice while maintaining the
randomized and double-blind treatment assign-
ment. The study physicians determined the start-
ing doses and adjusted the doses on the basis of
their clinical judgment and patients’ responses.
Medications were dispensed at each visit in the
form of identically appearing small and large cap-
sules containing lower and higher doses of olan-
zapine (Zyprexa, Eli Lilly; 2.5 mg or 5.0 mg), que-
tiapine (Seroquel, AstraZeneca; 25 mg or 50 mg),
risperidone (Risperdal, Janssen Pharmaceutica;
0.5 mg or 1.0 mg), or placebo.
To treat difficult behaviors during the trial,
study physicians could increase the dose of the
421 Underwent randomization
in phase 1
521 Patients screened
100 Excluded
50 Did not meet inclusion criteria
14 Declined to participate
36 Were excluded for other reasons
94 Assigned to quetiapine
0 Did not take drug
77 Discontinued phase 1
50 For lack of efficacy
15 For intolerability
12 For other reasons
17 Completed phase 1
54 Entered phase 2
23 Did not enter phase 2
85 Assigned to risperidone
1 Did not take drug
66 Discontinued phase 1
37 For lack of efficacy
15 For intolerability
14 For other reasons
19 Completed phase 1
49 Entered phase 2
17 Did not enter phase 2
100 Assigned to olanzapine
1 Did not take drug
80 Discontinued phase 1
39 For lack of efficacy
24 For intolerability
17 For other reasons
20 Completed phase 1
57 Entered phase 2
23 Did not enter phase 2
142 Assigned to placebo
3 Did not take drug
121 Discontinued phase 1
97 For lack of efficacy
7 For intolerability
17 For other reasons
21 Completed phase 1
93 Entered phase 2
28 Did not enter phase 2
Figure 1. Enrollment and Outcomes.
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1528
study medication or prescribe a benzodiazepine or
oral or parenteral haloperidol.
All patients and caregivers were given basic
information about Alzheimer’s disease.
26
Caregiv-
ers were offered two counseling sessions during
the first 18 weeks and could speak with staff mem-
bers as needed.
Outcomes
The primary outcome measure was the time until
discontinuation of treatment for any reason in
phase 1. This outcome integrates the judgments
of patients, caregivers, and clinicians regarding ef-
ficacy, safety, and tolerability into a global measure
of effectiveness that reflects therapeutic benefits
in relation to undesirable effects.
The two primary hypotheses in phase 1 were,
first, there would be pairwise differences between
the three groups given atypical antipsychotic agents
and the placebo group in the time until discon-
tinuation of treatment for any reason, and second,
that among those antipsychotic drugs that were
found to be different from placebo, none would be
inferior to the others.
The main secondary outcome measure was
the attainment of minimal or greater improve-
ment on the Clinical Global Impression of Change
(CGIC)
27
scale at week 12 while the patients con-
tinued to receive the phase 1 drug. The other sec-
ondary outcomes were the time to the discontinu-
ation of treatment in phase 1 because of lack of
efficacy and the time to the discontinuation of
treatment because of adverse events, intolerability,
or death. Safety was assessed by eliciting infor-
mation about the occurrence of adverse events.
The patients’ weight and prolactin, glucose, cho-
lesterol, and triglyceride levels were measured at
weeks 12, 24, and 36.
Statistical Analysis
Patients who underwent randomization and re-
ceived at least one dose of the study medication
were included in the intention-to-treat sample.
Randomization was performed with the use of
permuted blocks of nine per site without stratifi-
cation and was implemented with the use of an
interactive voice-response telephone system.
A total of 421 patients underwent randomiza-
Table 1. Baseline Characteristics of Patients Who Underwent Randomization.*
Characteristic
Olanzapine Group
(N = 100)
Quetiapine Group
(N = 94)
Risperidone Group
(N = 85)
Placebo Group
(N = 142)
Total
(N = 421)
Demographic
Age — yr 78.8±7.3 77.3±8.7 78.4±7.1 77.3±7.1 77.9±7.5
Female sex — no. (%) 55 (55) 50 (53) 49 (58) 81 (57) 235 (56)
Race — no./total no. (%)†
White 80/99 (81) 76/94 (81) 68/85 (80) 107/141 (76) 331/419 (79)
Black 14/99 (14) 15/94 (16) 15/85 (18) 31/141 (22) 75/419 (18)
Other 5/99 (5) 3/94 (3) 2/85 (2) 3/141 (2) 13/419 (3)
Education — no. (%)
Did not complete high school 28 (28) 21 (22) 15 (18) 37 (26) 101 (24)
General equivalency diploma or high-
school diploma
35 (35) 33 (35) 28 (33) 46 (32) 142 (34)
<4 yr of college 16 (16) 16 (17) 22 (26) 36 (25) 90 (21)
≥4 yr of college 15 (15) 21 (22) 17 (20) 20 (14) 73 (17)
Unknown 6 (6) 3 (3) 3 (4) 3 (2) 15 (4)
Married — no. (%) 63 (63) 56 (60) 49 (58) 81 (57) 249 (59)
Residence — no. (%)
Own home 77 (77) 69 (73) 61 (72) 100 (70) 307 (73)
Family’s home 11 (11) 13 (14) 14 (16) 28 (20) 66 (16)
Assisted-living facility 9 (9) 10 (11) 10 (12) 12 (8) 41 (10)
Other 3 (3) 2 (2) 0 2 (1) 7 (2)
atypical antipsychotic drugs in alzheimer’s disease
n engl j med 355;15 www.nejm.org october 12, 2006
1529
tion (from a target sample of 450 patients), yield-
ing a statistical power of 99% to identify a differ-
ence of 33% in the rates of discontinuation of
treatment by 36 weeks between any one of the
drugs and placebo and a power of 80% to detect
a difference of 20%, assuming a 60% rate of dis-
continuation in the placebo group.
We used Kaplan–Meier survival curves to esti-
mate the time to the discontinuation of treatment
for all patients in the intention-to-treat population.
The treatment groups were compared with the
use of Cox proportional-hazards regression mod-
els,
28
stratified according to site. Sites with 17 or
fewer patients were grouped according to the size
and type of site (i.e., university clinic, private prac-
tice, or Veterans Affairs medical center) for a total
of 15 sites (8 pooled and 7 with 18 or more ran-
domly assigned patients).
In the Cox model, the overall difference among
the treatment groups was evaluated with the use
of a test with 3 degrees of freedom. If the differ-
ence was significant at a P value of less than 0.05,
then each drug was compared with placebo by
means of a Hochberg adjustment for multiple
comparisons.
29
Any antipsychotic drug found to be signifi-
Table 1. (Continued.)
Characteristic
Olanzapine Group
(N = 100)
Quetiapine Group
(N = 94)
Risperidone Group
(N = 85)
Placebo Group
(N = 142)
Total
(N = 421)
Clinical
MMSE total score 15.0±5.4 14.9±6.1 15.7±6.1 14.7±5.8 15.0±5.8
Alzheimer’s Disease Assessment Scale (cogni-
tive) total score
34.6±12.7 36.1±13.6
31.1±13.6 35.7±13.2 34.6±13.3
Criteria met for psychosis of Alzheimer’s dis-
ease — no./total no. (%)
73/100 (73)
73/93 (79) 71/85 (84) 106/142 (75) 323/420 (77)
BPRS total score 27.0±11.8 28.0±12.3 27.7±13.6 28.2±12.0 27.8±12.3
NPI total score‡ 31.8±16.3 37.6±18.4 38.3±20.2 39.1±17.8 36.9±18.3
Delusions — no./total no. (%) 77/98 (79) 76/93 (82) 74/84 (88) 112/140 (80) 339/415 (82)
Hallucinations — no./total no. (%) 41/98 (42) 47/93 (51) 47/83 (57) 67/139 (48) 202/413 (49)
Agitation or aggression — no./total no. (%) 82/98 (84) 80/93 (86) 71/83 (86) 125/140 (89) 358/414 (86)
Depression — no./total no. (%) 55/98 (56) 58/93 (62) 51/83 (61) 88/140 (63) 252/414 (61)
Alzheimer’s Disease Cooperative Study–
Activities of Daily Living Inventory
39.4±17.4 39.0±17.8 40.0±18.1
38.2±16.3
39.0±17.2
Medications — no. (%)§
Antidepressant or antipsychotic
27 (27) 19 (20) 23 (27) 35 (25) 104 (25)
Antidepressant 19 (19) 9 (10) 18 (21) 18 (13) 64 (15)
Conventional antipsychotic 5 (5) 7 (7) 1 (1) 6 (4) 19 (5)
Atypical antipsychotic 11 (11) 7 (7) 10 (12) 16 (11) 44 (10)
Cholinesterase inhibitor 67 (67) 54 (57) 50 (59) 82 (58) 253 (60)
Mean weight — lb¶ 148.9±36.6 153.3±30.5 151.7±31.4 148.3±28.0 150.3±31.4
Mean body-mass index∥ 25.3±5.7 25.5±3.9 25.9±4.8 25.2±4.0 25.4±4.6
* Plus–minus values are means ±SD. MMSE scores range from 0 to 30, with higher scores indicating better mental status; scores on the
Alzheimer’s Disease Assessment Scale range from 0 to 70, with lower scores indicating milder disease; BPRS scores range from 0 to 108,
with lower scores indicating milder symptoms; scores on the Neuropsychiatric Inventory (NPI) range from 0 to 144, with lower scores indi-
cating milder symptoms; and scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory range from 0 to 78,
with higher scores indicating better functioning. Because of rounding, percentages may not total 100. Treatment groups were compared
for baseline differences with the use of analysis of variance or chi-square tests.
† Race was reported by the patient or caregiver. “Other” includes Native American or Native Alaskan (<1% of patients), Asian (2%), Native
Hawaiian or other Pacific Islander (<1%), and more than one race (2%).
‡ P = 0.02 for the overall comparison of the treatment groups.
§ Trazodone accounted for 47% of antidepressant use, and donepezil accounted for 72% of cholinesterase-inhibitor use.
¶ To convert values to kilograms, divide by 2.2.
∥ The body-mass index is the weight in kilograms divided by the square of the height in meters.
