Then e w e ng l a n d j o u r na l of m e dic i n e original article 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* 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
[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. 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 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 psychiatrist’s 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 Long-acting injectable risperidone was not superior to a psychiatrist’s 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.) 842 n engl j med 364;9 nejm.org march 3, 2011 The New England Journal of Medicine Downloaded from nejm.org on September 9, 2015. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. org on September 9. Randomization Randomization was conducted centrally and stratified according to site because of potential practice differences. long-acting injectable delivery may improve adherence and symptom control and reduce the rate of relapse and hospitalization. the first second-generation antipsychotic agent to be made available in a longacting injectable delivery system was risperidone (Risperdal Consta. we hypothesized that long-acting injectable risperidone would be superior in reducing the risk of hospitalization for up to 2 years as compared with a psychiatrist’s choice of an oral antipsychotic.15 and were at risk for psychiatric hospitalization as evidenced by current psychiatric hospitalization.1. current treatment with long-acting injectable antipsychotics. 2015. All authors designed the trial. California. with 209 of 369 patients (56. All rights reserved.org march 3.12-14 In this trial involving patients with unstable disease. Me thods Participants Patients were eligible to participate in the study if they were 18 years of age or older.7 and before-andafter studies have shown tolerability in switching from oral to long-acting injectable risperidone. The patients’ decisional capacity was assessed with the use of the MacArthur Competence Assessment Tool. interpreted the findings. the data analyses. agreed to publication of the manuscript. or a combination of these agents. Boston. Randomization was conducted with the use of randomly permuted blocks of variable size to ensure an approximate balance over time.2 By ensuring sustained levels of drug in the blood. After written informed consent had been obtained from the patient or guardian.9%) assigned in the second year.4%) assigned during the first 3 months of the third year. and data collection continued for 3 years.2-5 In the United States. The original entry criteria required hospitalization in the previous year but were extended to enhance recruitment (see the study protocol.6 A randomized trial showed the efficacy of long-acting injectable risperidone over placebo in patients with schizophrenia. serious medical conditions. and reviewed and approved the manuscript. Three randomized trials that also involved patients with stable disease showed no advantage of long-acting injectable risperidone therapy over oral treatment.16 Guardian consent was allowed. testing for allergic reactions was performed with an oral test dose of 1 mg of risperidone. Follow-up continued for up to 2 years. unstable living arrangements. Subjects received payment for their travel expenses and time: $25 for monthly and injectiononly visits and $45 for extended quarterly assessment visits. Randomization began in September 2006.6%) randomly assigned in the first year. and a history of assault or suicidal behavior requiring urgent intervention. oral clozapine. Exclusion criteria were the following: detoxification in the previous month. available with the full text of this article at NEJM.org). warfarin. had a diagnosis of schizophrenia or schizoaffective disorder as assessed with the use of the Structured Clinical Interview based on the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. hospitalization in the previous 2 years.8-11 These studies involved clinically stable patients and lacked randomized control groups. which had no role in the study. or increased use of mental health services to prevent relapse as adjudicated by the study chairpersons (the first two authors). Menlo Park. The study and consent forms were approved by the institutional review boards of the 19 collaborating centers.9 nejm. Copyright © 2011 Massachusetts Medical Society. No other uses without permission.Long-Acting Risperidone in schizophrenia T he most common and potentially remediable cause of treatment failure in patients with schizophrenia is lack of adherence to prescribed oral medications. and 20 patients (5. n engl j med 364. and the fidelity of this report to the study protocol. reported past intolerance to risperidone or intramuscular injections. All authors vouch for the completeness and accuracy of the data. The analyses were conducted at the Veterans Affairs (VA) Cooperative Studies Program Coordinating Center. Ortho-McNeil Janssen). Longacting injectable risperidone was provided free of charge by Ortho-McNeil Janssen Scientific Affairs. Longacting injectable risperidone may cause fewer extrapyramidal symptoms than the long-acting injectable first-generation antipsychotic agents. The injectable-risperidone group thus had more planned paid visits than the oral-antipsychotic group. For personal use only. 140 patients (37. The first author wrote the first draft of the manuscript. 843 . with improved symptoms and reduced hospital use. and the VA Health Economics Resource Center. 2011 The New England Journal of Medicine Downloaded from nejm. 22 PANSS ratings were obtained from standardized videoconferences conducted by trained raters from MedAvante who were unaware of the patients’ study-drug assignments. with higher scores indicating poorer functioning or less improvement). Dosage increments of 12. The use of long-acting injectable risperidone was documented according to study prescribing records.19 Quality of life was measured with the use of the Heinrichs–Carpenter Quality of Life Scale (ranging from 0 to 120.21 Retention on the assigned drug was measured according to the number of days until discontinuation of the assigned treatment or. with higher scores indicating greater satisfaction). 2015. Previous oral antipsychotics were to be continued for at least 3 weeks. For personal use only. quality of life.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..26 the latter providing a global assessment of social functioning. All patients were seen monthly by their psychiatrist and by the nurse. with higher scores indicating greater well-being). 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. and its positive.org on September 9. Efforts were made to ensure that patients continued to receive the medications selected by their doctor if they discontinued the study drug. with higher scores indicating greater distress). antianxiety agents. with higher scores reflecting better functioning).17 long-acting injectable risperidone was administered intramuscularly at an initial dose of 25 mg every 2 weeks. Satisfaction with medication was measured with the use of the Drug Attitude Inventory (on a scale of 1 to 20. All rights reserved. On the basis of consensus guidelines. Control-group participants continued to receive oral antipsychotic therapy as prescribed by their treating physician. 2011 The New England Journal of Medicine Downloaded from nejm. or if the interruption was longer than 6 weeks.27 which has been validated for use in schizophrenia. antidepressants.28 Measures Blinded videoconference assessments were completed every 3 months on measures of symptoms. Psychiatric assessments by video conference are reliable in patients with schizophrenia and are well received.24 Concomitant Psychosocial Treatment Quality of Life and Social Functioning To ensure that no patient was randomly assigned to less than standard best practice — an ethical imperative — a short checklist of potentially useful ancillary psychosocial services available at the participating centers was provided to all participants during follow-up visits. which ranges from 30 to 210. with higher scores indicating more symptoms). At a monthly unblinded meeting with the study nurse. negative. based on published recommendations. and general subscales. Treating psychiatrists were given a summary of optimal dosage ranges for oral antipsychotic and anticholinergic agents.5 mg were permitted every 4 weeks at the discretion of the treating psychiatrist. Health-related quality of life was assessed with the use of the Quality of Well-Being scale (ranging from 0 to 1. days to crossover to any new oral or long-acting injectable treatment. Steady-state drug levels are reached 6 to 8 weeks after initiation of treatment with long-acting injectable risperidone. and oral antipsychotics and mood stabilizers) and anticholinergic medications were allowed. Copyright © 2011 Massachusetts Medical Society. the Clinical Global Impressions (CGI) scale20 was used to assess the patient’s global mental health status and the change from 844 of n engl j med 364. No other uses without permission. Concomitant psychotropic medications (i. Symptoms of schizophrenia were measured according to the total score on the Positive and Negative Syndrome Scale (PANSS. and functioning. among participants assigned to the oral medication.org march 3.23 Subjective psychological distress was measured with the use of the depression and anxiety subscales of the Brief Symptom Index (on a scale of 0 to 4.e.18 baseline (on a scale of 1 to 7. .9 nejm. with higher scores indicating better quality of life)25 and the Personal and Social Performance scale (ranging from 1 to 100. and the use of oral medication was documented according to patient interviews. Both were administered by videoconference assessors who were unaware of the study-drug assignments. up to the maximum approved dose of 50 mg.17 and efforts to reduce the use of oral antipsychotics subsequently were encouraged in the injectable-risperidone group. the alternative hypothesis was that for long-acting injectable risperidone versus oral agents. had been hospitalized within the previous 2 years n engl j med 364. the interaction of treatment with time. Psychiatric inpatient admissions were identified through the VA’s Patient Treatment File. Further descriptive analysis of outcome and side-effect measures used mixed models of all outcome data up to 18 months because of extensive sample attrition after that time. Confirmatory Cox proportional-hazards analyses controlled for potential confounding factors. site. With a null hypothesis that the hazard ratio would equal 1.60.org march 3. compared the hazard ratios associated with the time to the first psychiatric hospitalization. Five sites discontinued the study because of insufficient recruitment. 2011 The New England Journal of Medicine Downloaded from nejm. 1. Confirmatory mixed models were run with the PANSS score. 1). 2015. the hazard ratio was greater than or equal to 1. yielding a final analytic sample of 369 patients (Fig. The primary outcome measure was the time from randomization to psychiatric hospitalization (in both VA and non-VA hospitals) or.33. a rate ratio of 1.2.65 or less than or equal to 0. R e sult s Study Participants Altogether.. Copyright © 2011 Massachusetts Medical Society. Non-VA admissions were identified according to discharge summaries validated as psychiatric by a physician who was unaware of the patients’ study-drug assignments. were available for all VA health services.e. terminating with hospitalization or discontinuation of the assigned study medication. with the use of the logrank test. These factors included prior use of risperidone.30-32 Sexual dysfunction was measured with items from the Novel Antipsychotic Medication Experience Scale (ranging from 0 to 4. in the case of patients who were hospitalized at randomization..e.5% (i. the significance of differences was tested with the Wilcoxon rank-sum test. history of substance abuse. The model had fixed effects for treatment group and time (a categorical variable).org on September 9.29 Side Effects Neurologic side effects were measured with the use of three scales. 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 secondary outcome. First. This hypothesis 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 intramuscular-medication group (i.9 nejm.64 [41 ÷ 25] corresponding to a difference of 16 percentage points [41% – 25%] in the annual rate of a first psychiatric hospitalization). All rights reserved. each with a two-sided test and a type I error of 2. With a null hypothesis of no difference. Hospitalization and Use of Other Medical Services Administrative data on service use. rather than the difference between follow-up scores and baseline scores at one specific time point.25% in each tail). the alternative hypothesis was that the difference was greater than or equal to 5 units or less than or equal to –5 units. Alcohol and drug use in the previous 30 days was assessed with the use of the alcohol and drug composite indexes from the Addiction Severity Index (on a scale of 0 to 1. No other uses without permission. For personal use only. 845 . a time-to-event analysis. Participants were hospitalized at the time of randomization (40%). and hospitalization at the time of enrollment. 1045 patients were screened at 19 VA medical centers between 2006 and 2009.34 The follow-up period for this outcome was up to 2 years. with higher scores indicating worse side effects) (Ames D: personal communication). with higher scores indicating more severe problems). including hospitalizations. 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.Long-Acting Risperidone in schizophrenia Substance Use At screening. The baseline PANSS score was added to the model to assess its effect on changes from baseline. the time from the date of discharge from the initial stay to subsequent hospitalization. Because of the skewed distribution of service use. and individual patients were treated as random effects. physicians and patients were asked whether substance abuse was a problem. 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. A first-order autocorrelation structure was used. At screening. and 3% were 50 mg. 46% (170) at 18 months. with no significant differences between groups at these time points (P = 0.5 mg. Treatment and Follow-Up Assessments For patients assigned to and receiving long-acting injectable risperidone. Randomization. There were no significant differences between groups at baseline in this sample of older male veterans (Table 1 in the Supplementary Appendix. and 50% were 50 mg. . n engl j med 364. 17% of doses were 25 mg. 40% of patients receiving long-acting injectable risperidone received concomitant oral antipsychotics.9 nejm. and Follow-up of the Study Patients.org). 2011 The New England Journal of Medicine Downloaded from nejm. and 29% (107) at 24 months. 86% of injection doses were 25 mg.42 to 0. The mean (±SD) duration of participation was 474±235 days for long-acting injectable risperidone versus 502±226 days for oral antipsychotics (P = 0. All rights reserved. 25% were reported by the participants and 36% were reported by their physicians. (55%).22).8 injections 846 per month.The n e w e ng l a n d j o u r na l of m e dic i n e 1045 Patients were assessed for eligibility 514 Were ineligible 110 Patients or physicians declined participation 39 Patients or physicians never called back 382 Underwent randomization 192 Were assigned to receive oral treatment 190 Were assigned to receive injectable risperidone 7 Declined participation 2 Declined participation 185 Received oral treatment 120 Completed study 65 Were lost to follow-up or discontinued intervention 188 Received injectable risperidone 117 Completed study 71 Were lost to follow-up or discontinued intervention 3 Were excluded because patient did not have a Social Security number or did not have baseline data 1 Was excluded because of lack of baseline data 182 Were included in analysis 187 Were included in analysis Figure 1. at 6 weeks. or had recent increased service use indicating a risk of hospitalization (5%).5 mg. No other uses without permission. For personal use only.99). 2015. Enrollment. 31% were 37.org march 3. During the first 6 weeks. with an average of 1. The follow-up interview rates in the intentionto-treat analysis were as follows: 60% (223 patients) at 1 year.org on September 9. Copyright © 2011 Massachusetts Medical Society. During the remainder of the trial. with an average of 1. available at NEJM. Active problems with alcohol or drug use were reported for 37% of the patients. problems with medication adherence were reported for 64% of the patients. problems were reported by physicians. 32% of injections were accompanied by prescriptions for oral antipsychotics during the same month.5 injections per month (the percentages do not sum to 100 because of rounding). 43% of the patients reported problems by themselves and in 60% of the cases. 11% were 37. During the remainder of the trial. respectively. For personal use only.39 by the log-rank test.19) (Fig. A total of 237 of 369 patients (64%) continued to receive the study drug throughout their participation in the study. 0. 1 in the Supplementary Appendix).8 months. 21 of 182 (12%) switched to long-acting injectable risperidone an average of 153±203 days after randomization. and Fig. 0.02). With a mean follow-up of 11. 95% CI. at Risk Oral antipsychotic 182 Injectable 187 risperidone 136 136 116 110 96 92 84 82 71 65 58 53 Figure 2.3 and 10. hazard ratio. or the Addiction Severity Index composite drug scores (Table 1). 1.001). and another from accidental drowning.0 0 3 6 9 12 15 18 21 24 49 45 28 37 Months after Randomization No. An analysis that excluded the 21 subjects who switched from an oral antipsychotic to long-acting injectable risperidone provided similar results (hazard ratio. 2011 The New England Journal of Medicine Downloaded from nejm. 2 in the Supplementary Appendix). the unblinded CGI improvement score. including the number of hospital days. Copyright © 2011 Massachusetts Medical Society. 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 1.00. Use of Services A larger proportion of patients receiving longacting injectable risperidone were hospitalized at the time of randomization and they were hospitalized for more days during the period before randomization (Table 2).20) (Fig.04) and the Drug Attitude Inventory P=0.001).org on September 9.72). After randomization.2 0.0 Freedom from Hospitalization Long-acting injectable treatment was not superior to oral treatment in the duration of adherence to the randomized treatment (P = 0.04) and “nervous system disorders” (headache and extrapyramidal signs and symptoms) (P<0. data on patients who withdrew from the study were censored at the time of withdrawal from the study. the current CGI functioning measure. Reasons for medication discontinuation were not significantly different between groups (Table 2 in the Supplementary Appendix). 95% CI. In the oral-antipsychotic group. 95% confidence interval [CI]. 0.59 to 1.6 Oral antipsychotic 0. representing the rater-perceived change from baseline. 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 = 0.87. Analysis of adverse events (Table 3 in the Supplementary Appendix) showed that patients who received long-acting injectable risperidone had more “general disorders and administration site conditions” (injection-related pain or induration) (P = 0.org march 3.40).63 to 1.13). Although there was no superiority of long-acting injectable risperidone on the unblinded assessment of illness severity at each time point. the Personal and Social Performance scale or the selfreported Quality of Well-Being scale. favored long-acting injectable risperidone (P = 0. In the injectable-risperidone group. there were no significant differences between groups with respect to VA service use (Table 2) or non-VA service use (Table 4 in the Supplementary Appendix). In this analysis. one patient died in his sleep from an unknown cause and another committed suicide.4 0. 81 of 182 (45%) patients receiving oral medication and 72 of 187 (39%) receiving long-acting injectable risperidone were hospitalized. one patient died from chronic obstructive pulmonary disease. 2015. Among participants receiving oral treatment. favored long-acting injectable risperidone (P<0. No other uses without permission. 847 . 2). as did an analysis that was adjusted for covariates (hazard ratio. 0. n engl j med 364.71 to 1.8 Injectable risperidone 0. Long-acting injectable risperidone was not superior to oral treatment with respect to the time to hospitalization (P = 0. however. There were four deaths. No significant superiority of long-acting injectable risperidone was observed on the blindly rated Heinrichs–Carpenter Quality of Life Scale or its subscales.9 nejm.Long-Acting Risperidone in schizophrenia Outcomes 1. All rights reserved. There were no significant differences with respect to the initiation of concomitant psycho tropic medications (Fig. The composite alcohol index of the Addiction Severity Index was higher in the oral-antipsychotic group (P = 0. Time to Hospitalization after Randomization.39 by the log-rank test 0. 0.82. 3 in the Supplementary Appendix). 69±0.05 0.18±0.38 −0.51 0.10 0.06 0. and time–treatment interaction).86±0. No other uses without permission.06 <0.66±0.08±0. with higher scores indicating poorer functioning or less improvement.06 2.26±0.04 0.09 0. § Scores on the Personal and Social Performance Scale range from 1 to 100.38 18.66±0. ‡ Scores on the Heinrichs–Carpenter Quality of Life Scale range from 0 to 120. 848 n engl j med 364.11 0.06±0. with higher scores indicating greater distress.67 Positive symptoms 18.09 0. 2015.001 0.91 −0.10 1.27±0.10 0. ║ ¶¶ Scores on the Simpson–Angus Scale range from 0 to 4.48 0.06 0.45 −0. ║ ‖ Scores on the Clinical Global Impressions scale range from 1 to 7. †† Scores on the Brief Symptom Index range from 0 to 4.06±0.45±0.13 7. with higher scores indicating better quality of life.07±0. ‖‖ Scores on the Barnes Akathisia Scale range from 0 to 5.37 0. 2011 The New England Journal of Medicine Downloaded from nejm.012±0.05 −0. with higher scores indicating more severe akathisia.01±0.11 −0.12±0.39 Clinical Global Impressions‖ ║ Severity of illness 4.org march 3.44±0.03±0.24±0.27±0. .22±0. † Scores on the Positive and Negative Syndrome Scale (PANSS) range from 30 to 210.62 0.01±0.35 0. All rights reserved. ‡‡ Scores on the Quality of Well-Being scale range from 0 to 1.04 Addiction Severity Index** Alcohol use 0.08 0.78 −0.* Variable Oral Antipsychotic Injectable Risperidone Mean Difference P Value PANSS† Total score 74.78 53.17±0.10 −0.13 8.81 Intrapsychic foundations 3.72±0.006±0. For all outcomes.06 −0.08 −0.02 NAMES*** Sexual interest Sexual activities Drug Attitude Inventory††† * Plus–minus values are means ±SE.09 0.07±0. with higher scores reflecting better functioning.10±0. Copyright © 2011 Massachusetts Medical Society.18 Personal and Social Performance Scale§ 53.13 0.64±0.018±0.62 −0.11 0.03±0.69±0.07 0.27 0.22±0.90 0.59±1.03 −0.05 −0.08 3.36 Instrumental functioning 2.35 19. treatment.The n e w e ng l a n d j o u r na l of m e dic i n e Table 1.30±0.64 0.62±0.67±0. with higher scores indicating more severe extrapyramidal symptoms.03 0.01± 0.14±0.01 0.83±0.03 0.31±0.06 0.03 0.04 −0.11 Simpson–Angus Scale¶¶ 0.17±0. with higher scores indicating better well-being.78±0.004 0.55 Quality of Well-Being scale‡‡ 0.13 Negative symptoms 18.50 30.92 74.08 −0.65±0.03 0.22±0. *** Scores on the Novel Antipsychotic Medication Experience Scale (NAMES) range from 0 to 4.01±0.02 0. For personal use only.46±0. with site as a random effect and with autocorrelated repeated measures over time.19±0. with higher scores indicating worse side effects.96±0. with higher scores indicating more severe tardive dyskinesia.65 General symptoms 37.89±0.13 4. ** Scores on the Addiction Severity Index range from 0 to 1. with higher scores indicating greater satisfaction.80 1.10±0.21±0.34 Change in condition 3.55±0.64±0.003 0.9 nejm.23±0. the treatment comparison was a linear contrast based on a mixed-effects model with three fixed effects (time.09±0. with higher scores indicating more symptoms.05±0.93±0.72 0.01±0.02 0.28 Interpersonal relations 2.67±0.13±0.08 2.org on September 9.10± 0.13 Brief Symptom Index†† Drug use 0.52±0.84±0. with higher scores indicating more severe problems.05 2.69±0.35±0.46 36. ¶ Body-mass index is the weight in kilograms divided by the square of the height in meters.06 −0.13 0.003 0.03±0.06 3.36 Heinrichs–Carpenter Quality of Life Scale‡ Total score 2.06±0. §§ Scores on the Abnormal Involuntary Movement Scale range from 0 to 4.84 Body-mass index¶ 30.61 1.60 Barnes Akathisia Scale‖‖ 0. Follow-up Assessment Outcomes Based on Mixed Models with the Use of All Available Data over All Time Points up to 18 Months.63 Abnormal Involuntary Movement Scale§§ 0. ††† Scores on the Drug Attitude Inventory range from 1 to 20.13 0. The findings were not modified by the addition of covariates or the exclusion of crossover observations (for participants who switched from oral to long-acting injectable treatment).1±40.org on September 9. Greater numbers of adverse events were reported by the injectable-risperidone group.1 10.Long-Acting Risperidone in schizophrenia Discussion This randomized.0 0. quality of life.4±33.1 64.* Type of Use Oral Antipsychotic (N = 182) Injectable Risperidone (N = 187) P Value 1.05 1. of subsequent stays among patients with any stays Residential treatment. For personal use only. All rights reserved.1 1.6 19.22 0.9 16.5 2.0 122. Differences in the alcohol composite index of the Ad- Table 2.) 22. n engl j med 364.9 0.2 0.8 0.6±41.1±15.60 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 35.31 26.0±56.95 15.0 0. 2011 The New England Journal of Medicine Downloaded from nejm.7±14.9 36.9±65.20 17.6 0.6 2.0 0.33 15.0 0.5 24.4 18.3 23.9 19.0±4.91 20.3±43.9 0.2±4.77 Days Outpatient care Outpatient visits after randomization (no.9 nejm. 2015.1±24.5 0. or service use. side effects. 849 . at either VA or non-VA hospitals).7 <0.6±2.2±1. and extrapyramidal signs and symptoms.25 Telephone psychiatry 3. Use of Health Services Provided by the Veterans Affairs System.4 8.7 0.3 0.3 0. The duration of treatment with long-acting injectable risperidone was not significantly longer than the duration of treatment with oral antipsychotics.4±4.36 Vocational rehabilitation 5. or multiple standard measures of symptoms..2±59.5 0.80 62.7 0. headache. controlled trial showed that in high-risk patients with schizophrenia or schizo affective disorder.04 2.4 3.6±2.001 * 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.0±4.4 15.) Other psychiatry Medical and surgical Other ancillary care Total outpatient visits Visits to administer long-acting injectable risperidone (no.1±71.26 1.4±53.60 Hospitalizations subsequent to the original stay Patients with new hospitalization after randomization (%)* Days in subsequent stays No.1±63.5±137.2 45.4±130. These events primarily included injection-site phenom- ena.8 52. suggesting that patients receiving oral medication may flexibly adjust their medication use to avoid such adverse effects.7±7.6±6.8±15.4±86.3 0.3 0.02 42.49 Individual psychiatry 58.5 136.e. nonhospital Patients with any residential treatment admission (%) 23.0±2. long-acting injectable risperidone was not superior to oral antipsychotics with respect to the primary outcome of time to hospitalization.4±15.8±28.org march 3. No other uses without permission.0 0.67 Group psychiatry 30.4 0. Copyright © 2011 Massachusetts Medical Society.21 2.4 19.5±56. Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized. this sample involved older. Blake L. Longacting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. 0. the dose of long-acting injectable risperidone may have been inadequate in some paReferences 1. Nemeroff C. Olfson M. Neuropsychopharmacology: the fifth generation of progress. 12% of control patients received long-acting injectable risperidone treatment an average of 5 months into the trial. 12. Arch Gen Psychiatry 1979.64:12507. Keith SJ. if admitting physicians knew that patients receiving long-acting risperidone were symptomatic in spite of being adequately medicated. On the other hand. All rights reserved. 850 of m e dic i n e tients. Schizophr Bull 1995. Bai YM. Matalon L. Am J Psychiatry 2003. Philadelphia: Lippincott Williams & Wilkins. Supported by the Veterans Affairs Cooperative Studies Program and an unrestricted grant from Ortho-McNeil Janssen Scientific Affairs. Lieberman JA. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. n engl j med 364. If physicians thought there was less need to hospitalize patients. Ferro P.org on September 9. Int Clin Psychopharmacol 2005. prospective. Goff DC. Chen JY. Coyle JT.37 Our study did not show the superiority of long-acting injectable risperidone.org march 3. For personal use only.12-14 Two studies have suggested that unintended intramuscular injections into fat tissue may decrease pharmacologic effectiveness. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. Karcher K. Kane JM. Therapeutics of schizophrenia. Dropout patterns and sample sizes were similar to those of previous schizophrenia trials.63 to 1. but this reflects the real-world practice that was the focus of this effectiveness study.20).179:290-9. 2002:775-807. J Clin Psychiatry 2004. the CGI improvement scores assigned by these raters indicated significantly greater improvement in the group of patients who received long-acting injectable risperidone.54:508-16. Augustyns I. Fleischhacker WW. Parellada E. Ulrich R. Davis JM. Copyright © 2011 Massachusetts Medical Society. 2. Second. 52:S29-S36. Eerdekens M. and the study was not large enough to exclude modest differences between the groups. but the confidence intervals for the time to hospitalization were fairly wide (hazard ratio. Ting Chen T. and data were available for only 369 because of early dropouts. Safety and efficacy of long-acting risperidone in schizophrenia: a 12-week. Miyamoto S. David AS. Duncan GE. Br J Psychiatry Suppl 2009. multicenter. Fluphena zine and social therapy in the aftercare of schizophrenic patients: relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Eerdekens M.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. Kane J.36. Br J Psychiatry 2001. Beard S. 3. Second-generation antipsychotic long-acting injections: systematic review. but this was not assessed in our study. 9.9 nejm. Eerdekens M. This may have biased the results in favor of oral treatment in the intention-totreat analysis. eds. Herron E. et al. Adams CE. primarily male veterans. et al. the bias could favor long-acting injectable risperidone. Matalon L. decisions regarding hospitalization were unblinded. J Clin Psychiatry 2003. 2011 The New England Journal of Medicine Downloaded from nejm. 5. 7. Eur Neuropsychopharmacol 2005. Sacchetti E. Cost of relapse in schizophrenia. Third. Disclosure forms provided by the authors are available with the full text of this article at NEJM. although our revised target sample was 450 subjects. First. the bias could favor oral treatment. Lindenmayer J-P.20:121-30. et al. Medori R. Finally. Karcher K. Lindenmayer JP. 10.36 Our study had several limitations. No other uses without permission.160: 1125-32. Fenton MK. 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. Llorca PM.65:1084-9. 11. Although the current CGI scores assigned by raters who were aware of the patients’ study-drug assignments did not differ between groups. suggesting an unblinded rater bias favoring longacting injectable risperidone. 95% CI. Weiden PJ. 2015. An economic review of compliance with medication in the treatment of schizophrenia. Mussare F. and results may not be generalizable to other populations. 13. 0. Psychiatr Serv 2003. open-label study in stable patients switched from typical and atypical oral antipsychotics.36: 1283-94. we enrolled only 382 subjects. 8. Quraishi S. Charney D. Schooler NR. Thieda P. Richter A. Depot antipsychotic drugs: place in therapy.47:74173. Fleischhacker WW. Lesem M. Systematic meta-review of depot antipsychotics for people with schizophrenia.15:111-7. Drugs 1994. Möller HJ. Taken together. knowing that they were receiving ample medication.org.21: 419-29. Chue P.35. 6. 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. Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies. Eerdekens E. Hogarty GE. . In: Davis KL. and some injections were missed. Fourth. and the direction of any bias is unknown.87. 4. Eerdekens M. Watanabe MD. Martin SD. Berry SA. Pioli R. Brambilla L. Med Care 2003. Psychol Med 1983. MacArthur Competence Assessment Tool — Treatment. Long-acting injectable risperidone v.55: 997-1005. Fiszbein A. Williams DK. et al. open-label study. Keith SJ. Kaplan RM. 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The Image Challenge app randomly selects from 300 challenging clinical photos published in NEJM. 32. 27. Arch Gen Psychiatry 1991. Csernansky JG. Psychiatr Serv 2004. Quality of life and pharmacoeconomics in clinical trials. Optimized for viewing on the iPhone and iPod Touch. 29.Long-Acting Risperidone in schizophrenia single-blind pharmacokinetic study.48:333-9. Comparing the sensitivity of generic effectiveness measures with symptom improvement in persons with schizophrenia. 2nd ed. get immediate feedback. 20. 35. 37. 18. The general health policy model: an integrated approach. Tanum L. Marder SR. Sullivan G. All rights reserved. The Image Challenge app is available at the iTunes App Store. Brenner R. 1995. 24. Psychiatr Serv 1998.14:105-22. Derogatis LR.346:16-22. Grisso T.9 nejm. Keks NA. 34. 2015. Medication noncompliance in schizophrenia: codification and update. Luborsky L. Shepler L. Opler LA. 23. New York: Biometrics Research Institute. A self-report scale predictive of drug com- pliance in schizophrenics: reliability and discriminative validity.68:1218-25. 13:177-83.151:825-35. Practical application of pharmacotherapy with long-acting risperidone for patients with schizophrenia. Rockville. Morosini PL. New York State Psychiatric Institute. Hanlon ET. Guy W. Risperidone in the treatment of schizophrenia.41:208-17. Appelbaum PS. Acta Psychiatr Scand Suppl 1970.org on September 9. In: ECDEU assessment manual for psychopharmacology. olanzapine tablets for schizophrenia or schizoaffective disorder: randomised. et al. anywhere. 14. J Clin Psychiatry 2007. 31.212:11-9. 28. Awad AG. and see how others answered. 26. 1976:534-7. A rating scale for drug induced akathisia. ed.org march 3. 1996. 21. Woody GE.30:193-217. J Nerv Ment Dis 1980. the Image Challenge app lets you test your diagnostic skills anytime. Ugolini S. Mostert MA. scoring and procedure manual. Simpson GM. Kaplan R. 30. Peters J. O’Brien CP. 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Ingham M. 49:1086-8. Schizophr Bull 1984. et al. N Engl J Med 2002. MD: National Institute of Mental Health. Carpenter WT Jr. Glazer WM. Barnes TR. Philadelphia: Lippincott-Raven. Does participation in psychosocial treatment augment the benefit of clozapine? Arch Gen Psychiatry 1998. Angus JW. Rosenheck R. 25. Buchanan RW. MD: National Institute of Mental Health. choose your answer. Abnormal Involuntary Movement Scale (AIMS). Guy W. 19. Nesvåg R. First MB. Anderson JP. Reliability and acceptability of psychiatric diagnosis via telecommunication and audiovisual technology.101:323-9. Lehman AF. Development. Clinical Global Impressions (CGI). No other uses without permission. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.] Copyright © 2011 Massachusetts Medical Society. 22. A rating scale for extrapyramidal side effects. 17.