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n e w e ng l a n d j o u r na l
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original article
A bs t r ac t
Background
From the Veterans Affairs (VA) New England Mental Illness, Research Education
and Clinical Center, VA Connecticut
Healthcare System, West Haven, and the
Yale School of Medicine, New Haven, CT
(R.A.R., J.H.K.); the Massachusetts Veterans Epidemiology and Research Information Center VA Cooperative Studies Program Coordinating Center, Boston (R.L.,
L.F., D.V., S.S.T., M.H.L.); the VA Health
Economics Resource Center, Menlo Park,
CA (P.G.B.); and the VA Cooperative
Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque,
NM (J.E.V.). Address reprint requests to
Dr. Rosenheck at the VA New England
Mental Illness, Research Education and
Clinical Center, VA Connecticut Healthcare System/151D, 950 Campbell Ave.,
West Haven, CT 06516, or at robert
.rosenheck@va.gov.
* The Cooperative Studies Program (CSP)
555 Research Group investigators are
listed in the Supplementary Appendix,
available at NEJM.org.
This article (10.1056/NEJMoa1005987)
was updated on March 7, 2011, at NEJM
.org.
N Engl J Med 2011;364:842-51.
Copyright 2011 Massachusetts Medical Society.
We randomly assigned patients in the Veterans Affairs (VA) system who had schizophrenia or schizoaffective disorder and who had been hospitalized within the previous 2 years or were at imminent risk for hospitalization to 25 to 50 mg of longacting injectable risperidone every two weeks or to a psychiatrists choice of an oral
antipsychotic. All patients were followed for up to 2 years. The primary end point
was hospitalization in a VA or non-VA psychiatric hospital. Symptoms, quality of life,
and functioning were assessed in blinded videoconference interviews.
Results
Of 369 participants, 40% were hospitalized at randomization, 55% were hospitalized within the previous 2 years, and 5% were at risk for hospitalization. The rate of
hospitalization after randomization was not significantly lower among patients who
received long-acting injectable risperidone than among those who received oral antipsychotics (39% after 10.8 months vs. 45% after 11.3 months; hazard ratio, 0.87;
95% confidence interval, 0.63 to 1.20). Psychiatric symptoms, quality of life, scores
on the Personal and Social Performance scale of global functioning, and neurologic side effects were not significantly improved with long-acting injectable risperidone as compared with control treatments. Patients who received long-acting
injectable risperidone reported more adverse events at the injection site and more
extrapyramidal symptoms.
Conclusions
842
Me thods
Participants
Randomization was conducted centrally and stratified according to site because of potential practice differences. Randomization was conducted
with the use of randomly permuted blocks of
variable size to ensure an approximate balance
over time.
843
The
n e w e ng l a n d j o u r na l
Treatment Groups
m e dic i n e
Patients randomly assigned to long-acting injectable risperidone were seen clinically by a study
nurse every 2 weeks for the first month and then
monthly. All patients were seen monthly by their
psychiatrist and by the nurse. On the basis of
consensus guidelines,17 long-acting injectable risperidone was administered intramuscularly at an
initial dose of 25 mg every 2 weeks. Dosage increments of 12.5 mg were permitted every 4 weeks
at the discretion of the treating psychiatrist, up
to the maximum approved dose of 50 mg.
Steady-state drug levels are reached 6 to 8 weeks
after initiation of treatment with long-acting
injectable risperidone,17 and efforts to reduce
the use of oral antipsychotics subsequently were
encouraged in the injectable-risperidone group.
Previous oral antipsychotics were to be continued
for at least 3 weeks. Treatment interruptions
among patients randomly assigned to long-acting
injectable risperidone were addressed by restarting the intramuscular medication and providing
oral medication for 3 weeks if the interruption
occurred before the steady state was reached, or
if the interruption was longer than 6 weeks.
Concomitant psychotropic medications (i.e.,
antianxiety agents, antidepressants, and oral antipsychotics and mood stabilizers) and anticholinergic medications were allowed.
Control-group participants continued to receive oral antipsychotic therapy as prescribed by
their treating physician. Treating psychiatrists
were given a summary of optimal dosage ranges
for oral antipsychotic and anticholinergic agents,
based on published recommendations.18
Measures
of
Substance Use
Administrative data on service use, including hospitalizations, were available for all VA health services. Psychiatric inpatient admissions were identified through the VAs Patient Treatment File.
Non-VA admissions were identified according to
discharge summaries validated as psychiatric by
a physician who was unaware of the patients
study-drug assignments.
The primary outcome measure was the time
from randomization to psychiatric hospitalization (in both VA and non-VA hospitals) or, in the
case of patients who were hospitalized at randomization, the time from the date of discharge
from the initial stay to subsequent hospitalization. The key secondary outcome measure was the
change in the PANSS total score at 12 months.
Secondary analyses compared outcomes at all
time points up to 18 months, rather than the
difference between follow-up scores and baseline scores at one specific time point.
Statistical Analysis
R e sult s
Study Participants
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The
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7 Declined participation
2 Declined participation
(55%), or had recent increased service use indicating a risk of hospitalization (5%). At screening,
problems with medication adherence were reported for 64% of the patients; 43% of the patients
reported problems by themselves and in 60% of
the cases, problems were reported by physicians.
Active problems with alcohol or drug use were
reported for 37% of the patients; 25% were reported by the participants and 36% were reported by their physicians. There were no significant
differences between groups at baseline in this
sample of older male veterans (Table 1 in the
Supplementary Appendix, available at NEJM.org).
Treatment and Follow-Up Assessments
Outcomes
1.0
Long-acting injectable treatment was not superior to oral treatment in the duration of adherence
to the randomized treatment (P=0.19) (Fig. 1 in
the Supplementary Appendix). Among participants receiving oral treatment, however, 21 of 182
(12%) switched to long-acting injectable risperidone an average of 153203 days after randomization. There were no significant differences with
respect to the initiation of concomitant psycho
tropic medications (Fig. 2 in the Supplementary
Appendix).
A total of 237 of 369 patients (64%) continued
to receive the study drug throughout their participation in the study. Reasons for medication
discontinuation were not significantly different
between groups (Table 2 in the Supplementary
Appendix).
With a mean follow-up of 11.3 and 10.8
months, respectively, 81 of 182 (45%) patients
receiving oral medication and 72 of 187 (39%)
receiving long-acting injectable risperidone were
hospitalized. Long-acting injectable risperidone
was not superior to oral treatment with respect
to the time to hospitalization (P=0.39 by the
log-rank test; hazard ratio, 0.87, 95% confidence
interval [CI], 0.63 to 1.20) (Fig. 2). An analysis
that excluded the 21 subjects who switched from
an oral antipsychotic to long-acting injectable
risperidone provided similar results (hazard ratio,
1.00; 95% CI, 0.71 to 1.40), as did an analysis
that was adjusted for covariates (hazard ratio,
0.82; 95% CI, 0.59 to 1.13).
The mixed-model analysis of the change from
baseline to 12 months in the PANSS total score
did not show superiority of long-acting injectable risperidone (P=0.72).
Further outcome comparisons across all time
points up to 18 months showed no significant
between-group differences in the PANSS total
score or subscales (Table 1, and Fig. 3 in the
Supplementary Appendix). No significant superiority of long-acting injectable risperidone was
observed on the blindly rated HeinrichsCarpenter
Quality of Life Scale or its subscales, the Personal and Social Performance scale or the selfreported Quality of Well-Being scale, the current
CGI functioning measure, or the Addiction Severity Index composite drug scores (Table 1). The
composite alcohol index of the Addiction Severity Index was higher in the oral-antipsychotic
group (P=0.04) and the Drug Attitude Inventory
0.8
Injectable risperidone
0.6
Oral antipsychotic
0.4
0.2
0.0
12
15
18
21
24
49
45
28
37
136
136
116
110
96
92
84
82
71
65
58
53
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Table 1. Follow-up Assessment Outcomes Based on Mixed Models with the Use of All Available Data over All Time
Points up to 18 Months.*
Variable
P Value
PANSS
Total score
74.690.92
74.100.91
0.591.27
0.65
General symptoms
37.170.46
36.890.45
0.270.64
0.67
Positive symptoms
18.840.38
18.120.38
0.720.48
0.13
Negative symptoms
18.690.35
19.030.35
0.350.37
0.36
2.860.06
2.780.06
0.080.07
0.28
Interpersonal relations
2.550.08
2.460.08
0.090.10
0.36
Instrumental functioning
2.660.05
2.650.05
0.01 0.06
0.81
Intrapsychic foundations
3.240.06
3.140.06
0.10 0.08
0.18
53.830.78
53.640.78
0.180.90
0.84
Body-mass index
30.690.50
30.070.51
0.620.72
0.39
Severity of illness
4.190.13
4.220.13
0.030.09
0.34
Change in condition
3.520.08
3.220.08
0.300.06
<0.001
0.130.03
0.070.03
0.060.03
0.04
0.0120.003
0.0180.003
0.0060.004
0.13
Drug use
0.670.62
0.640.62
0.030.06
0.55
0.660.02
0.670.02
0.010.01
0.63
0.260.04
0.210.04
0.060.03
0.11
SimpsonAngus Scale
0.230.05
0.220.05
0.010.03
0.60
0.440.09
0.450.09
0.010.06
0.80
1.060.10
1.010.10
0.050.10
0.61
1.100.11
0.930.11
0.170.11
0.13
7.960.13
8.270.13
0.310.13
0.02
NAMES***
Sexual interest
Sexual activities
Drug Attitude Inventory
*
Plusminus values are means SE. For all outcomes, the treatment comparison was a linear contrast based on a
mixed-effects model with three fixed effects (time, treatment, and timetreatment interaction), with site as a random effect and with autocorrelated repeated measures over time.
Scores on the Positive and Negative Syndrome Scale (PANSS) range from 30 to 210, with higher scores indicating
more symptoms.
Scores on the HeinrichsCarpenter Quality of Life Scale range from 0 to 120, with higher scores indicating better
quality of life.
Scores on the Personal and Social Performance Scale range from 1 to 100, with higher scores reflecting better functioning.
Body-mass index is the weight in kilograms divided by the square of the height in meters.
Scores on the Clinical Global Impressions scale range from 1 to 7, with higher scores indicating poorer functioning
or less improvement.
** Scores on the Addiction Severity Index range from 0 to 1, with higher scores indicating more severe problems.
Scores on the Brief Symptom Index range from 0 to 4, with higher scores indicating greater distress.
Scores on the Quality of Well-Being scale range from 0 to 1, with higher scores indicating better well-being.
Scores on the Abnormal Involuntary Movement Scale range from 0 to 4, with higher scores indicating more severe
tardive dyskinesia.
Scores on the SimpsonAngus Scale range from 0 to 4, with higher scores indicating more severe extrapyramidal
symptoms.
Scores on the Barnes Akathisia Scale range from 0 to 5, with higher scores indicating more severe akathisia.
*** Scores on the Novel Antipsychotic Medication Experience Scale (NAMES) range from 0 to 4, with higher scores indicating worse side effects.
Scores on the Drug Attitude Inventory range from 1 to 20, with higher scores indicating greater satisfaction.
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Discussion
This randomized, controlled trial showed that in
high-risk patients with schizophrenia or schizo
affective disorder, long-acting injectable risperidone was not superior to oral antipsychotics with
respect to the primary outcome of time to hospitalization, or multiple standard measures of
symptoms, quality of life, side effects, or service
use. Greater numbers of adverse events were reported by the injectable-risperidone group. These
events primarily included injection-site phenom-
Type of Use
Oral
Antipsychotic
(N=182)
Injectable
Risperidone
(N=187)
P Value
1.04.1
1.04.0
0.95
15.4
15.0
0.91
20.343.4
19.259.7
0.80
62.1
64.7
0.60
Inpatient care
Acute medical or surgical hospital stays
Days
Patients with any hospitalization (%)
Total acute psychiatric hospital stays after randomization
Total days
Patients with any hospitalization (%)
Hospitalization at time of randomization
Patients hospitalized (%)
Days from hospitalization at randomization to discharge
35.2
45.5
0.04
2.77.4
8.453.0
0.02
42.9
36.4
0.20
17.641.1
10.828.0
0.21
2.62.5
2.21.5
0.60
23.6
19.3
0.31
26.486.4
18.171.3
0.49
Individual psychiatry
58.965.8
52.056.2
0.67
Group psychiatry
30.163.5
24.556.6
0.36
Vocational rehabilitation
5.415.4
3.815.3
0.25
Telephone psychiatry
3.66.6
2.44.8
0.05
1.02.9
0.62.0
0.33
15.115.9
16.124.3
0.22
0.77
Days
Outpatient care
Outpatient visits after randomization (no.)
Other psychiatry
Medical and surgical
Other ancillary care
Total outpatient visits
Visits to administer long-acting injectable risperidone (no.)
22.433.3
23.140.5
136.5137.0
122.4130.9
0.26
1.24.9
19.714.7
<0.001
* These data pertain to hospitalizations at Veterans Affairs (VA) hospitals only and thus the percentages are somewhat
smaller than the total proportion of patients who were hospitalized (i.e., at either VA or non-VA hospitals).
849
The
n e w e ng l a n d j o u r na l
diction Severity Index and the Drug Attitude Inventory were not significant after adjustment for
multiple comparisons. Although the current CGI
scores assigned by raters who were aware of the
patients study-drug assignments did not differ
between groups, the CGI improvement scores assigned by these raters indicated significantly
greater improvement in the group of patients who
received long-acting injectable risperidone, suggesting an unblinded rater bias favoring longacting injectable risperidone.
Taken together, these findings are consistent
with three efficacy trials that also showed no
superiority of long-acting injectable risperidone
over oral regimens in patients with stable schizophrenia.12-14 Two studies have suggested that
unintended intramuscular injections into fat tissue may decrease pharmacologic effectiveness,
but this was not assessed in our study.35,36
Our study had several limitations. First, 12%
of control patients received long-acting injectable
risperidone treatment an average of 5 months
into the trial. This may have biased the results
in favor of oral treatment in the intention-totreat analysis. Replication of the analyses of hospitalization risk and blinded outcomes excluding
observations after these crossovers or discontinuation of long-acting injectable risperidone yielded no significant findings favoring long-acting
injectable treatment.
Second, the dose of long-acting injectable risperidone may have been inadequate in some paReferences
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Copyright 2011 Massachusetts Medical Society.
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