Nej Mo a 1005987

original article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;9 nejm.org march 3, 2011842

Long-Acting Risperidone and Oral Antipsychotics in Unstable Schizophrenia

Robert A. Rosenheck, M.D., John H. Krystal, M.D., Robert Lew, Ph.D., Paul G. Barnett, Ph.D., Louis Fiore, M.D., M.P.H., Danielle Valley, M.P.H.,

Soe Soe Thwin, Ph.D., Julia E. Vertrees, Pharm.D., and Matthew H. Liang, M.D., M.P.H., for the CSP555 Research Group*

From the Veterans Affairs (VA) New Eng-land 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 Veter-ans Epidemiology and Research Informa-tion Center VA Cooperative Studies Pro-gram 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 Phar-macy 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 Health-care System/151D, 950 Campbell Ave., West Haven, CT 06516, or at robert [email protected].

* 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.

A bs tr ac t

Background

Long-acting injectable risperidone, a second-generation antipsychotic agent, may improve adherence to treatment and outcomes in schizophrenia, but it has not been tested in a long-term randomized trial involving patients with unstable disease.

Methods

We randomly assigned patients in the Veterans Affairs (VA) system who had schizo-phrenia or schizoaffective disorder and who had been hospitalized within the pre-vious 2 years or were at imminent risk for hospitalization to 25 to 50 mg of long-acting 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 hospital-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 received long-acting injectable risperidone than among those who received oral anti-psychotics (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 neuro-logic side effects were not significantly improved with long-acting injectable ris-peridone 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

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.)

The New England Journal of Medicine Downloaded from nejm.org on April 19, 2011. For personal use only. No other uses without permission.

Copyright 2011 Massachusetts Medical Society. All rights reserved.

Long-Acting Risperidone in schizophrenia

n engl j med 364;9 nejm.org march 3, 2011 843

The most common and potentially remediable cause of treatment failure in patients with schizophrenia is lack of ad-herence to prescribed oral medications.1,2 By en-suring sustained levels of drug in the blood, long-acting injectable delivery may improve adher-ence and symptom control and reduce the rate of relapse and hospitalization.2-5

In the United States, the first second-generation antipsychotic agent to be made available in a long-acting injectable delivery system was risperidone (Risperdal Consta, Ortho-McNeil Janssen). Long-acting injectable risperidone may cause fewer extrapyramidal symptoms than the long-acting injectable first-generation antipsychotic agents.6

A randomized trial showed the efficacy of long-acting injectable risperidone over placebo in patients with schizophrenia,7 and before-and-after studies have shown tolerability in switching from oral to long-acting injectable risperidone, with improved symptoms and reduced hospital use.8-11 These studies involved clinically stable patients and lacked randomized control groups. Three randomized trials that also involved pa-tients with stable disease showed no advantage of long-acting injectable risperidone therapy over oral treatment.12-14

In this trial involving patients with unstable disease, we hypothesized that long-acting inject-able risperidone would be superior in reducing the risk of hospitalization for up to 2 years as compared with a psychiatrists choice of an oral antipsychotic.

Me thods

Participants

Patients were eligible to participate in the study if they were 18 years of age or older, had a diag-nosis of schizophrenia or schizoaffective disor-der as assessed with the use of the Structured Clinical Interview based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disor-ders,15 and were at risk for psychiatric hospital-ization as evidenced by current psychiatric hospi-talization, hospitalization in the previous 2 years, or increased use of mental health services to pre-vent relapse as adjudicated by the study chairper-sons (the first two authors). The original entry criteria required hospitalization in the previous year but were extended to enhance recruitment (see the study protocol, available with the full text of this article at NEJM.org).

Randomization began in September 2006, and data collection continued for 3 years, with 209 of 369 patients (56.6%) randomly assigned in the first year, 140 patients (37.9%) assigned in the second year, and 20 patients (5.4%) assigned during the first 3 months of the third year. Follow-up continued for up to 2 years.

Exclusion criteria were the following: detoxi-fication in the previous month; reported past intolerance to risperidone or intramuscular injec-tions; current treatment with long-acting inject-able antipsychotics, oral clozapine, warfarin, or a combination of these agents; serious medical conditions; unstable living arrangements; and a history of assault or suicidal behavior requiring urgent intervention.

The patients decisional capacity was assessed with the use of the MacArthur Competence As-sessment Tool.16 Guardian consent was allowed. Subjects received payment for their travel ex-penses and time: $25 for monthly and injection-only visits and $45 for extended quarterly assess-ment visits. The injectable-risperidone group thus had more planned paid visits than the oral-anti-psychotic group. After written informed consent had been obtained from the patient or guardian, testing for allergic reactions was performed with an oral test dose of 1 mg of risperidone. Long-acting injectable risperidone was provided free of charge by Ortho-McNeil Janssen Scientific Af-fairs, which had no role in the study.

The study and consent forms were approved by the institutional review boards of the 19 col-laborating centers. The analyses were conducted at the Veterans Affairs (VA) Cooperative Studies Program Coordinating Center, Boston, and the VA Health Economics Resource Center, Menlo Park, California. All authors designed the trial, inter-preted the findings, agreed to publication of the manuscript, and reviewed and approved the manu-script. The first author wrote the first draft of the manuscript. All authors vouch for the com-pleteness and accuracy of the data, the data analyses, and the fidelity of this report to the study protocol.

Randomization

Randomization was conducted centrally and strat-ified according to site because of potential prac-tice differences. Randomization was conducted with the use of randomly permuted blocks of variable size to ensure an approximate balance over time.





Treatment Groups

Patients randomly assigned to long-acting inject-able 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 ris-peridone was administered intramuscularly at an initial dose of 25 mg every 2 weeks. Dosage in-crements 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 restart-ing 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 anti-psychotics and mood stabilizers) and anticho-linergic medications were allowed.

Control-group participants continued to re-ceive 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

Concomitant Psychosocial Treatment

To ensure that no patient was randomly assigned to less than standard best practice an ethical imperative a short checklist of potentially use-ful ancillary psychosocial services available at the participating centers was provided to all partici-pants during follow-up visits.19

Measures

Blinded videoconference assessments were com-pleted every 3 months on measures of symptoms, quality of life, and functioning.

At a monthly unblinded meeting with the study nurse, the Clinical Global Impressions (CGI) scale20 was used to assess the patients global mental health status and the change from

baseline (on a scale of 1 to 7, with higher scores indicating poorer functioning or less improve-ment). Satisfaction with medication was measured with the use of the Drug Attitude Inventory (on a scale of 1 to 20, with higher scores indicating greater satisfaction).21

Retention on the assigned drug was measured according to the number of days until discontinu-ation of the assigned treatment or, among partici-pants assigned to the oral medication, days to crossover to any new oral or long-acting inject-able treatment. The use of long-acting injectable risperidone was documented according to study prescribing records, and the use of oral medica-tion was documented according to patient inter-views. Efforts were made to ensure that patients continued to receive the medications selected by their doctor if they discontinued the study drug.

Symptoms of schizophrenia were measured according to the total score on the Positive and Negative Syndrome Scale (PANSS, which ranges from 30 to 210, with higher scores indicating more symptoms), and its positive, negative, and general subscales.22 PANSS ratings were obtained from standardized videoconferences conducted by trained raters from MedAvante who were un-aware of the patients study-drug assignments. Psychiatric assessments by video conference are reliable in patients with schizophrenia and are well received.23

Subjective psychological distress was measured with the use of the depression and anxiety sub-scales of the Brief Symptom Index (on a scale of 0 to 4, with higher scores indicating greater distress).24

Quality of Life and Social FunctioningQuality of life was measured with the use of the HeinrichsCarpenter Quality of Life Scale (rang-ing from 0 to 120, with higher scores indicating better quality of life)25 and the Personal and So-cial Performance scale (ranging from 1 to 100, with higher scores reflecting better function-ing),26 the latter providing a global assessment of social functioning. Both were administered by videoconference assessors who were unaware of the study-drug assignments.

Health-related quality of life was assessed with the use of the Quality of Well-Being scale (ranging from 0 to 1, with higher scores indicat-ing greater well-being),27 which has been vali-dated for use in schizophrenia.28





Substance UseAt screening, physicians and patients were asked whether substance abuse was a problem. Alcohol and drug use in the previous 30 days was as-sessed with the use of the alcohol and drug com-posite indexes from the Addiction Severity Index (on a scale of 0 to 1, with higher scores indicat-ing more severe problems).29

Side EffectsNeurologic side effects were measured with the use of three scales.30-32 Sexual dysfunction was measured with items from the Novel Antipsychot-ic Medication Experience Scale (ranging from 0 to 4, with higher scores indicating worse side effects) (Ames D: personal communication).

Hospitalization and Use of Other Medical ServicesAdministrative data on service use, including hos-pitalizations, were available for all VA health ser-vices. Psychiatric inpatient admissions were iden-tified 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 hospitaliza-tion (in both VA and non-VA hospitals) or, in the case of patients who were hospitalized at ran-domization, the time from the date of discharge from the initial stay to subsequent hospitaliza-tion. 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 base-line scores at one specific time point.

Statistical Analysis

The planned sample size of 450 patients (the original sample size of 600 was resized because of recruitment difficulties) provided 90% power for analyses of our primary outcome and second-ary outcome, each with a two-sided test and a type I error of 2.5% (i.e., 1.25% in each tail). First, a time-to-event analysis, with the use of the log-rank test, compared the hazard ratios associated with the time to the first psychiatric hospitaliza-tion. With a null hypothesis that the hazard ratio would equal 1, the alternative hypothesis was that for long-acting injectable risperidone versus oral

agents, the hazard ratio was greater than or equal to 1.65 or less than or equal to 0.60. This hypoth-esis was derived from an assumption based on three studies in which baseline rates of relapse were approximately 41% in the oral-antipsychotic group and approximately 25% in the intramuscu-lar-medication group (i.e., a rate ratio of 1.64 [41 25] corresponding to a difference of 16 per-centage points [41% 25%] in the annual rate of a first psychiatric hospitalization).2,33,34 The fol-low-up period for this outcome was up to 2 years, terminating with hospitalization or discontinua-tion of the assigned study medication.

Confirmatory Cox proportional-hazards analy-ses controlled for potential confounding factors. These factors included prior use of risperidone, history of substance abuse, and hospitalization at the time of enrollment.

A repeated-measures mixed-effects model was used to compare the mean change from baseline to 12 months in the PANSS score for injectable and oral treatments. With a null hypothesis of no difference, the alternative hypothesis was that the difference was greater than or equal to 5 units or less than or equal to 5 units. The model had fixed effects for treatment group and time (a categorical variable); the interaction of treatment with time, site, and individual patients were treated as random effects. A first-order autocorrelation structure was used. The baseline PANSS score was added to the model to assess its effect on changes from baseline. Confirma-tory mixed models were run with the PANSS score.

Further descriptive analysis of outcome and side-effect measures used mixed models of all outcome data up to 18 months because of exten-sive sample attrition after that time. Because of the skewed distribution of service use, the sig-nificance of differences was tested with the Wilcoxon rank-sum test.

R esult s

Study Participants

Altogether, 1045 patients were screened at 19 VA medical centers between 2006 and 2009, yielding a final analytic sample of 369 patients (Fig. 1). Five sites discontinued the study because of in-sufficient recruitment. Participants were hospi-talized at the time of randomization (40%), had been hospitalized within the previous 2 years





(55%), or had recent increased service use indi-cating a risk of hospitalization (5%). At screening, problems with medication adherence were report-ed 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 re-ported by the participants and 36% were report-ed 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

For patients assigned to and receiving long-acting injectable risperidone, at 6 weeks, 86% of injec-tion doses were 25 mg, 11% were 37.5 mg, and 3% were 50 mg, with an average of 1.8 injections

per month. During the remainder of the trial, 17% of doses were 25 mg, 31% were 37.5 mg, and 50% were 50 mg, with an average of 1.5 injec-tions per month (the percentages do not sum to 100 because of rounding). During the first 6 weeks, 40% of patients receiving long-acting injectable risperidone received concomitant oral antipsy-chotics. During the remainder of the trial, 32% of injections were accompanied by prescriptions for oral antipsychotics during the same month.

The follow-up interview rates in the intention-to-treat analysis were as follows: 60% (223 pa-tients) at 1 year, 46% (170) at 18 months, and 29% (107) at 24 months, with no significant dif-ferences between groups at these time points (P = 0.42 to 0.99). The mean (SD) duration of participation was 474235 days for long-acting injectable risperidone versus 502226 days for oral antipsychotics (P = 0.22).

382 Underwent randomization

1045 Patients were assessed for eligibility

514 Were ineligible110 Patients or physicians declined participation39 Patients or physicians never called back

192 Were assigned to receiveoral treatment

190 Were assigned to receiveinjectable risperidone

185 Received oral treatment120 Completed study65 Were lost to follow-up or discon-

tinued intervention

188 Received injectable risperidone117 Completed study71 Were lost to follow-up or discon-

tinued intervention

3 Were excluded becausepatient did not have a

Social Security number ordid not have baseline data

1 Was excluded becauseof lack of baseline data

182 Were included in analysis 187 Were included in analysis

7 Declined participation 2 Declined participation

Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.





Outcomes

Long-acting injectable treatment was not superi-or to oral treatment in the duration of adherence to the randomized treatment (P = 0.19) (Fig. 1 in the Supplementary Appendix). Among partici-pants receiving oral treatment, however, 21 of 182 (12%) switched to long-acting injectable risperi-done an average of 153203 days after randomiza-tion. 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 par-ticipation 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 inject-able 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 superi-ority of long-acting injectable risperidone was observed on the blindly rated HeinrichsCarpenter Quality of Life Scale or its subscales, the Per-sonal and Social Performance scale or the self-reported Quality of Well-Being scale, the current CGI functioning measure, or the Addiction Sever-ity Index composite drug scores (Table 1). The composite alcohol index of the Addiction Sever-ity Index was higher in the oral-antipsychotic group (P = 0.04) and the Drug Attitude Inventory

favored long-acting injectable risperidone (P = 0.02). Although there was no superiority of long-acting injectable risperidone on the unblinded assess-ment of illness severity at each time point, the unblinded CGI improvement score, representing the rater-perceived change from baseline, favored long-acting injectable risperidone (P



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 Oral Antipsychotic Injectable Risperidone Mean Difference 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

HeinrichsCarpenter Quality of Life Scale

Total score 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

Personal and Social Performance Scale 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

Clinical Global Impressions

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



Discussion

This randomized, controlled trial showed that in high-risk patients with schizophrenia or schizo-affective disorder, long-acting injectable risperi-done was not superior to oral antipsychotics with respect to the primary outcome of time to hospi-talization, or multiple standard measures of symptoms, quality of life, side effects, or service use. Greater numbers of adverse events were re-ported by the injectable-risperidone group. These events primarily included injection-site phenom-

ena, headache, and extrapyramidal signs and symptoms, suggesting that patients receiving oral medication may flexibly adjust their medication use to avoid such adverse effects. The duration of treatment with long-acting injectable risperidone was not significantly longer than the duration of treatment with oral antipsychotics.

The findings were not modified by the addi-tion of covariates or the exclusion of crossover observations (for participants who switched from oral to long-acting injectable treatment). Differ-ences in the alcohol composite index of the Ad-

Table 2. Use of Health Services Provided by the Veterans Affairs System.*

Type of Use

Oral Antipsychotic

(N = 182)

Injectable Risperidone

(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



diction Severity Index and the Drug Attitude In-ventory 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 as-signed by these raters indicated significantly greater improvement in the group of patients who received long-acting injectable risperidone, sug-gesting an unblinded rater bias favoring long-acting 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 schizo-phrenia.12-14 Two studies have suggested that unintended intramuscular injections into fat tis-sue 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-to-treat analysis. Replication of the analyses of hos-pitalization risk and blinded outcomes excluding observations after these crossovers or discontinu-ation of long-acting injectable risperidone yield-ed no significant findings favoring long-acting injectable treatment.

Second, the dose of long-acting injectable ris-peridone may have been inadequate in some pa-

tients, and some injections were missed, but this reflects the real-world practice that was the focus of this effectiveness study.

Third, decisions regarding hospitalization were unblinded, and the direction of any bias is unknown. If physicians thought there was less need to hospitalize patients, knowing that they were receiving ample medication, the bias could favor long-acting injectable risperidone. On the other hand, if admitting physicians knew that patients receiving long-acting risperidone were symptomatic in spite of being adequately medi-cated, the bias could favor oral treatment.

Fourth, this sample involved older, primarily male veterans, and results may not be generaliz-able to other populations.

Finally, although our revised target sample was 450 subjects, we enrolled only 382 subjects, and data were available for only 369 because of early dropouts. Dropout patterns and sample sizes were similar to those of previous schizo-phrenia trials.36,37 Our study did not show the superiority of long-acting injectable risperidone, but the confidence intervals for the time to hos-pitalization were fairly wide (hazard ratio, 0.87; 95% CI, 0.63 to 1.20), and the study was not large enough to exclude modest differences between the groups.

Supported by the Veterans Affairs Cooperative Studies Pro-gram and an unrestricted grant from Ortho-McNeil Janssen Scientific Affairs.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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