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Long-Acting Risperidone and Oral Antipsychotics in Unstable Schizophrenia
Long-Acting Risperidone and Oral Antipsychotics in Unstable Schizophrenia
original article
A bs t r ac t
Background
From the Veterans Affairs (VA) New Eng- Long-acting injectable risperidone, a second-generation antipsychotic agent, may
land Mental Illness, Research Education improve adherence to treatment and outcomes in schizophrenia, but it has not been
and Clinical Center, VA Connecticut
Healthcare System, West Haven, and the tested in a long-term randomized trial involving patients with unstable disease.
Yale School of Medicine, New Haven, CT
(R.A.R., J.H.K.); the Massachusetts Veter- Methods
ans Epidemiology and Research Informa-
tion Center VA Cooperative Studies Pro- We randomly assigned patients in the Veterans Affairs (VA) system who had schizo-
gram Coordinating Center, Boston (R.L., phrenia or schizoaffective disorder and who had been hospitalized within the pre-
L.F., D.V., S.S.T., M.H.L.); the VA Health vious 2 years or were at imminent risk for hospitalization to 25 to 50 mg of long-
Economics Resource Center, Menlo Park,
CA (P.G.B.); and the VA Cooperative acting injectable risperidone every two weeks or to a psychiatrists choice of an oral
Studies Program Clinical Research Phar- antipsychotic. All patients were followed for up to 2 years. The primary end point
macy Coordinating Center, Albuquerque, was hospitalization in a VA or non-VA psychiatric hospital. Symptoms, quality of life,
NM (J.E.V.). Address reprint requests to
Dr. Rosenheck at the VA New England and functioning were assessed in blinded videoconference interviews.
Mental Illness, Research Education and
Clinical Center, VA Connecticut Health- Results
care System/151D, 950 Campbell Ave.,
West Haven, CT 06516, or at robert Of 369 participants, 40% were hospitalized at randomization, 55% were hospital-
.rosenheck@va.gov. ized 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
* The Cooperative Studies Program (CSP)
555 Research Group investigators are received long-acting injectable risperidone than among those who received oral anti-
listed in the Supplementary Appendix, psychotics (39% after 10.8 months vs. 45% after 11.3 months; hazard ratio, 0.87;
available at NEJM.org. 95% confidence interval, 0.63 to 1.20). Psychiatric symptoms, quality of life, scores
This article (10.1056/NEJMoa1005987) on the Personal and Social Performance scale of global functioning, and neuro-
was updated on March 7, 2011, at NEJM logic side effects were not significantly improved with long-acting injectable ris-
.org. peridone as compared with control treatments. Patients who received long-acting
N Engl J Med 2011;364:842-51. injectable risperidone reported more adverse events at the injection site and more
Copyright 2011 Massachusetts Medical Society. extrapyramidal symptoms.
Conclusions
Long-acting injectable risperidone was not superior to a psychiatrists choice of oral
treatment in patients with schizophrenia and schizoaffective disorder who were
hospitalized or at high risk for hospitalization, and it was associated with more local
injection-site and extrapyramidal adverse effects. (Supported by the VA Cooperative
Studies Program and Ortho-McNeil Janssen Scientific Affairs; ClinicalTrials.gov
number, NCT00132314.)
T
he most common and potentially Randomization began in September 2006, and
remediable cause of treatment failure in data collection continued for 3 years, with 209
patients with schizophrenia is lack of ad- of 369 patients (56.6%) randomly assigned in the
herence to prescribed oral medications.1,2 By en- first year, 140 patients (37.9%) assigned in the
suring sustained levels of drug in the blood, second year, and 20 patients (5.4%) assigned
long-acting injectable delivery may improve adher- during the first 3 months of the third year.
ence and symptom control and reduce the rate of Follow-up continued for up to 2 years.
relapse and hospitalization.2-5 Exclusion criteria were the following: detoxi-
In the United States, the first second-generation fication in the previous month; reported past
antipsychotic agent to be made available in a long- intolerance to risperidone or intramuscular injec-
acting injectable delivery system was risperidone tions; current treatment with long-acting inject-
(Risperdal Consta, Ortho-McNeil Janssen). Long- able antipsychotics, oral clozapine, warfarin, or
acting injectable risperidone may cause fewer a combination of these agents; serious medical
extrapyramidal symptoms than the long-acting conditions; unstable living arrangements; and a
injectable first-generation antipsychotic agents.6 history of assault or suicidal behavior requiring
A randomized trial showed the efficacy of urgent intervention.
long-acting injectable risperidone over placebo The patients decisional capacity was assessed
in patients with schizophrenia,7 and before-and- with the use of the MacArthur Competence As-
after studies have shown tolerability in switching sessment Tool.16 Guardian consent was allowed.
from oral to long-acting injectable risperidone, Subjects received payment for their travel ex-
with improved symptoms and reduced hospital penses and time: $25 for monthly and injection-
use.8-11 These studies involved clinically stable only visits and $45 for extended quarterly assess-
patients and lacked randomized control groups. ment visits. The injectable-risperidone group thus
Three randomized trials that also involved pa- had more planned paid visits than the oral-anti-
tients with stable disease showed no advantage psychotic group. After written informed consent
of long-acting injectable risperidone therapy over had been obtained from the patient or guardian,
oral treatment.12-14 testing for allergic reactions was performed with
In this trial involving patients with unstable an oral test dose of 1 mg of risperidone. Long-
disease, we hypothesized that long-acting inject- acting injectable risperidone was provided free
able risperidone would be superior in reducing of charge by Ortho-McNeil Janssen Scientific Af-
the risk of hospitalization for up to 2 years as fairs, which had no role in the study.
compared with a psychiatrists choice of an oral The study and consent forms were approved
antipsychotic. by the institutional review boards of the 19 col-
laborating centers. The analyses were conducted
Me thods at the Veterans Affairs (VA) Cooperative Studies
Program Coordinating Center, Boston, and the VA
Participants Health Economics Resource Center, Menlo Park,
Patients were eligible to participate in the study California. All authors designed the trial, inter-
if they were 18 years of age or older, had a diag- preted the findings, agreed to publication of the
nosis of schizophrenia or schizoaffective disor- manuscript, and reviewed and approved the manu-
der as assessed with the use of the Structured script. The first author wrote the first draft of
Clinical Interview based on the fourth edition of the manuscript. All authors vouch for the com-
the Diagnostic and Statistical Manual of Mental Disor- pleteness and accuracy of the data, the data
ders,15 and were at risk for psychiatric hospital- analyses, and the fidelity of this report to the
ization as evidenced by current psychiatric hospi- study protocol.
talization, hospitalization in the previous 2 years,
or increased use of mental health services to pre- Randomization
vent relapse as adjudicated by the study chairper- Randomization was conducted centrally and strat-
sons (the first two authors). The original entry ified according to site because of potential prac-
criteria required hospitalization in the previous tice differences. Randomization was conducted
year but were extended to enhance recruitment with the use of randomly permuted blocks of
(see the study protocol, available with the full text variable size to ensure an approximate balance
of this article at NEJM.org). over time.
Substance Use agents, the hazard ratio was greater than or equal
At screening, physicians and patients were asked to 1.65 or less than or equal to 0.60. This hypoth-
whether substance abuse was a problem. Alcohol esis was derived from an assumption based on
and drug use in the previous 30 days was as- three studies in which baseline rates of relapse
sessed with the use of the alcohol and drug com- were approximately 41% in the oral-antipsychotic
posite indexes from the Addiction Severity Index group and approximately 25% in the intramuscu-
(on a scale of 0 to 1, with higher scores indicat- lar-medication group (i.e., a rate ratio of 1.64
ing more severe problems).29 [4125] corresponding to a difference of 16 per-
centage points [41%25%] in the annual rate of
Side Effects a first psychiatric hospitalization).2,33,34 The fol-
Neurologic side effects were measured with the low-up period for this outcome was up to 2 years,
use of three scales.30-32 Sexual dysfunction was terminating with hospitalization or discontinua-
measured with items from the Novel Antipsychot- tion of the assigned study medication.
ic Medication Experience Scale (ranging from Confirmatory Cox proportional-hazards analy-
0 to 4, with higher scores indicating worse side ses controlled for potential confounding factors.
effects) (Ames D: personal communication). These factors included prior use of risperidone,
history of substance abuse, and hospitalization
Hospitalization and Use of Other Medical Services at the time of enrollment.
Administrative data on service use, including hos- A repeated-measures mixed-effects model was
pitalizations, were available for all VA health ser- used to compare the mean change from baseline
vices. Psychiatric inpatient admissions were iden- to 12 months in the PANSS score for injectable
tified through the VAs Patient Treatment File. and oral treatments. With a null hypothesis of
Non-VA admissions were identified according to no difference, the alternative hypothesis was
discharge summaries validated as psychiatric by that the difference was greater than or equal to
a physician who was unaware of the patients 5 units or less than or equal to 5 units. The
study-drug assignments. model had fixed effects for treatment group and
The primary outcome measure was the time time (a categorical variable); the interaction of
from randomization to psychiatric hospitaliza- treatment with time, site, and individual patients
tion (in both VA and non-VA hospitals) or, in the were treated as random effects. A first-order
case of patients who were hospitalized at ran- autocorrelation structure was used. The baseline
domization, the time from the date of discharge PANSS score was added to the model to assess
from the initial stay to subsequent hospitaliza- its effect on changes from baseline. Confirma-
tion. The key secondary outcome measure was the tory mixed models were run with the PANSS
change in the PANSS total score at 12 months. score.
Secondary analyses compared outcomes at all Further descriptive analysis of outcome and
time points up to 18 months, rather than the side-effect measures used mixed models of all
difference between follow-up scores and base- outcome data up to 18 months because of exten-
line scores at one specific time point. sive sample attrition after that time. Because of
the skewed distribution of service use, the sig-
Statistical Analysis nificance of differences was tested with the
The planned sample size of 450 patients (the Wilcoxon rank-sum test.
original sample size of 600 was resized because
of recruitment difficulties) provided 90% power R e sult s
for analyses of our primary outcome and second-
ary outcome, each with a two-sided test and a Study Participants
type I error of 2.5% (i.e., 1.25% in each tail). First, Altogether, 1045 patients were screened at 19 VA
a time-to-event analysis, with the use of the log- medical centers between 2006 and 2009, yielding
rank test, compared the hazard ratios associated a final analytic sample of 369 patients (Fig. 1).
with the time to the first psychiatric hospitaliza- Five sites discontinued the study because of in-
tion. With a null hypothesis that the hazard ratio sufficient recruitment. Participants were hospi-
would equal 1, the alternative hypothesis was that talized at the time of randomization (40%), had
for long-acting injectable risperidone versus oral been hospitalized within the previous 2 years
(55%), or had recent increased service use indi- per month. During the remainder of the trial,
cating a risk of hospitalization (5%). At screening, 17% of doses were 25 mg, 31% were 37.5 mg, and
problems with medication adherence were report- 50% were 50 mg, with an average of 1.5 injec-
ed for 64% of the patients; 43% of the patients tions per month (the percentages do not sum to
reported problems by themselves and in 60% of 100 because of rounding). During the first 6 weeks,
the cases, problems were reported by physicians. 40% of patients receiving long-acting injectable
Active problems with alcohol or drug use were risperidone received concomitant oral antipsy-
reported for 37% of the patients; 25% were re- chotics. During the remainder of the trial, 32%
ported by the participants and 36% were report- of injections were accompanied by prescriptions
ed by their physicians. There were no significant for oral antipsychotics during the same month.
differences between groups at baseline in this The follow-up interview rates in the intention-
sample of older male veterans (Table 1 in the to-treat analysis were as follows: 60% (223 pa-
Supplementary Appendix, available at NEJM.org). tients) at 1 year, 46% (170) at 18 months, and
29% (107) at 24 months, with no significant dif-
Treatment and Follow-Up Assessments ferences between groups at these time points
For patients assigned to and receiving long-acting (P=0.42 to 0.99). The mean (SD) duration of
injectable risperidone, at 6 weeks, 86% of injec- participation was 474235 days for long-acting
tion doses were 25 mg, 11% were 37.5 mg, and injectable risperidone versus 502226 days for
3% were 50 mg, with an average of 1.8 injections oral antipsychotics (P=0.22).
Outcomes
Long-acting injectable treatment was not superi- 1.0 P=0.39 by the log-rank test
or to oral treatment in the duration of adherence
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.*
* 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 ran-
dom 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 in-
dicating worse side effects.
Scores on the Drug Attitude Inventory range from 1 to 20, with higher scores indicating greater satisfaction.
Oral Injectable
Antipsychotic Risperidone
Type of Use (N=182) (N=187) P Value
Inpatient care
Acute medical or surgical hospital stays
Days 1.04.1 1.04.0 0.95
Patients with any hospitalization (%) 15.4 15.0 0.91
Total acute psychiatric hospital stays after randomization
Total days 20.343.4 19.259.7 0.80
Patients with any hospitalization (%) 62.1 64.7 0.60
Hospitalization at time of randomization
Patients hospitalized (%) 35.2 45.5 0.04
Days from hospitalization at randomization to discharge 2.77.4 8.453.0 0.02
Hospitalizations subsequent to the original stay
Patients with new hospitalization after randomization (%)* 42.9 36.4 0.20
Days in subsequent stays 17.641.1 10.828.0 0.21
No. of subsequent stays among patients with any stays 2.62.5 2.21.5 0.60
Residential treatment, nonhospital
Patients with any residential treatment admission (%) 23.6 19.3 0.31
Days 26.486.4 18.171.3 0.49
Outpatient care
Outpatient visits after randomization (no.)
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
Other psychiatry 1.02.9 0.62.0 0.33
Medical and surgical 15.115.9 16.124.3 0.22
Other ancillary care 22.433.3 23.140.5 0.77
Total outpatient visits 136.5137.0 122.4130.9 0.26
Visits to administer long-acting injectable risperidone (no.) 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).
diction Severity Index and the Drug Attitude In- tients, and some injections were missed, but this
ventory were not significant after adjustment for reflects the real-world practice that was the focus
multiple comparisons. Although the current CGI of this effectiveness study.
scores assigned by raters who were aware of the Third, decisions regarding hospitalization
patients study-drug assignments did not differ were unblinded, and the direction of any bias is
between groups, the CGI improvement scores as- unknown. If physicians thought there was less
signed by these raters indicated significantly need to hospitalize patients, knowing that they
greater improvement in the group of patients who were receiving ample medication, the bias could
received long-acting injectable risperidone, sug- favor long-acting injectable risperidone. On the
gesting an unblinded rater bias favoring long- other hand, if admitting physicians knew that
acting injectable risperidone. patients receiving long-acting risperidone were
Taken together, these findings are consistent symptomatic in spite of being adequately medi-
with three efficacy trials that also showed no cated, the bias could favor oral treatment.
superiority of long-acting injectable risperidone Fourth, this sample involved older, primarily
over oral regimens in patients with stable schizo- male veterans, and results may not be generaliz-
phrenia.12-14 Two studies have suggested that able to other populations.
unintended intramuscular injections into fat tis- Finally, although our revised target sample
sue may decrease pharmacologic effectiveness, was 450 subjects, we enrolled only 382 subjects,
but this was not assessed in our study.35,36 and data were available for only 369 because of
Our study had several limitations. First, 12% early dropouts. Dropout patterns and sample
of control patients received long-acting injectable sizes were similar to those of previous schizo-
risperidone treatment an average of 5 months phrenia trials.36,37 Our study did not show the
into the trial. This may have biased the results superiority of long-acting injectable risperidone,
in favor of oral treatment in the intention-to- but the confidence intervals for the time to hos-
treat analysis. Replication of the analyses of hos- pitalization were fairly wide (hazard ratio, 0.87;
pitalization risk and blinded outcomes excluding 95% CI, 0.63 to 1.20), and the study was not
observations after these crossovers or discontinu- large enough to exclude modest differences
ation of long-acting injectable risperidone yield- between the groups.
ed no significant findings favoring long-acting Supported by the Veterans Affairs Cooperative Studies Pro-
injectable treatment. gram and an unrestricted grant from Ortho-McNeil Janssen
Scientific Affairs.
Second, the dose of long-acting injectable ris- Disclosure forms provided by the authors are available with
peridone may have been inadequate in some pa- the full text of this article at NEJM.org.
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