Real-World Outcomes of Paliperidone Palmitate Compared to Daily Oral Antipsychotic Therapy in Schizophrenia: A Randomized, Open-Label, Review Board-Blinded 15-Month Study

This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Schizophrenia is a serious chronic mental illness characterized by hallucinations, delusions, and significant functional disabilities that affects approximately 1.1% of adults in the United States.1,2 Schizophrenia places a large economic burden on the health care system, resulting in estimated direct annual medical costs of $43 to $58 billion3 and a significant societal impact in terms of overall health care burden.4

For individuals with schizophrenia to fulfill their potential and lead more meaningful lives their real-world treatment needs must be better understood and addressed. At present, effective management of schizophrenia is complicated by a variety of factors, including contacts with the criminal justice system, multiple hospitalizations, comorbid substance abuse, challenges to treatment adherence, unemployment, and unstable living conditions.5-7 Most clinical trials select for individuals who are not broadly representative of patients from these real-world settings,8-10 limiting the generalizability of their results. Their broad applicability is further complicated by the frequent choice of scale-based rather than clinically defined end points.11,12 A consequence of such designs is that they fail to evaluate many of the complex issues associated with the daily management of schizophrenia.

Poor treatment adherence is common among individuals with schizophrenia, particularly in patients with prior involvement with the criminal justice system or comorbid substance abuse.6,13,14 Such problems with adherence is frequently a precursor to cycles of relapse and recidivism. Long-acting injectable (LAI) antipsychotic therapies can deliver therapeutic concentrations continuously over several weeks and eliminate the need for daily medication administration.15 Further, their mode of administration provides physicians with certain knowledge of adherence. As a result, use of LAI antipsychotic therapy may facilitate continuity of treatment and support better outcomes. Despite these apparent advantages, clinical trials comparing LAI and oral antipsychotics have produced inconsistent results.16-21 We hypothesize that the inconsistencies in these reports might be a consequence of the study designs chosen for these comparisons and, possibly, a failure to follow a broad spectrum of patients using measures that reflect an adequate breadth of real-world outcomes.22 We describe a study, Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE), that compares once-monthly paliperidone palmitate with daily oral antipsychotics in patients with schizophrenia who are at risk for relapse. The study was designed to reflect real-world management of schizophrenia, as defined by the patients included, and clinically meaningful outcome measures.

METHOD

Study Design

The PRIDE study is a randomized, prospective, open-label, event-monitoring board-blinded, parallel-group study that compared paliperidone palmitate and oral antipsychotics on treatment failure in subjects with schizophrenia. The study incorporated both explanatory (efficacy) and pragmatic (effectiveness) design elements, allowing documentation of efficacy and effectiveness outcomes. Conducted between May 5, 2010, and December 9, 2013, the study included a screening phase of up to 2 weeks, followed by a 15-month randomized, open-label treatment phase. It was registered on ClinicalTrials.gov (identifier: NCT01157351). More complete details of the study design have been previously published.23

Participants

Participants were enrolled from 50 sites across 25 US states and Puerto Rico. To enhance enrollment of subjects often excluded from trials, efforts were made to recruit subjects from nontraditional locations, such as homeless shelters, soup kitchens, and jail-release or diversion programs. The study’s major inclusion criteria enlisted adults aged 18 to 65 years with a current diagnosis of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria24 that was confirmed by the Mini-International Neuropsychiatric Interview [MINI], version 6.025). Subjects must have been taken into custody by the criminal justice system ≥ 2 times in the previous 2 years, with ≥ 1 of these events leading to incarceration; released from most recent custody within 90 days of the screening visit; and accepting of a once-monthly, LAI antipsychotic. To maximize study retention, subjects designated a reliable external contact (eg, family member, case manager). Major exclusion criteria included use of either clozapine within 3 months of screening or an injectable antipsychotic within 2 injection cycles of screening. Substance abuse was not exclusionary, but subjects who had abused intravenous drugs within 3 months of screening or had an opiate dependence disorder (DSM-IV) were excluded. The study was approved by each site’s institutional review board and was conducted in accordance with the Declaration of Helsinki. All subjects provided written informed consent.

Interventions

Before random treatment assignment, clinicians, together with each subject, reviewed the 7 oral antipsychotics available in this study (aripiprazole, haloperidol, olanzapine, paliperidone, perphenazine, quetiapine, and risperidone) to determine their acceptability based on prior experience. Up to 6 medications could be deselected by the participant or physician.

• Most randomized clinical trials do not enroll patients with complex comorbidities/histories; thus, these trials may not broadly reflect important treatment considerations for persons with schizophrenia.
• The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study was designed to reflect real-world treatment of schizophrenia, as defined by patient selection, treatment approaches, and clinically meaningful outcomes.
• The PRIDE study results demonstrate that, by using a design reflecting real-world considerations, once-monthly treatment with paliperidone palmitate was more effective in delaying treatment failure than treatment with daily oral antipsychotics.

Randomization

To reduce treatment selection bias, an equipoise-stratified randomization scheme26 was used for treatment assignment and implemented via an interactive voice response system. Subjects with the same oral antipsychotic selections were placed in the same randomization strata and assigned in a 1:1 ratio to treatment with flexibly dosed paliperidone palmitate (78-234 mg) or a flexibly dosed oral antipsychotic. For subjects assigned to the oral antipsychotics arm, the specific agent was randomly selected from the group of prespecified, acceptable oral antipsychotics. Any oral antipsychotic prescribed before randomization was tapered and discontinued over the first 8 days after randomization. Paliperidone palmitate injection was administered by staff at the clinical site. Patients randomized to oral antipsychotics received a prescription and a voucher to cover its cost. Prescriptions were filled at a local pharmacy.

Study Medications

Subjects assigned to the paliperidone palmitate group were initiated with 2 injections in the deltoid muscle that were given approximately 1 week apart: 234 mg on day 1 and 156 mg on day 8 (± 4 days). Flexible monthly maintenance doses of paliperidone palmitate within a range of 78-234 mg (50-150 mg equivalents; recommended target maintenance dose was 156 mg) were started on day 38. Doses of oral antipsychotic monotherapy were selected and adjusted within the dose range of the package insert (occasional dosing outside of package insert range was allowed). Non­antipsychotic psychotropic medications (ie, mood stabilizers, antidepressants, anxiolytics, or hypnotics) were allowed.

Clinical Assessments and Outcome Measure

Throughout the 15-month treatment period, study visits occurred on days 8 (± 4), 15 (± 3), and 38 (± 7), and monthly thereafter (every 30 [± 7] days). Subjects were assessed at each visit for treatment failure. Subjects were encouraged to continue in the study to their predefined, 15-month end-of-observation date, regardless of early discontinuation of their randomized treatment assignment or achievement of the primary end point. A subject was considered to be a completer for the efficacy analysis if he or she either experienced a treatment failure event or completed the 15-month study follow-up.

The primary study end point was time to first treatment failure, as determined by an independent event-monitoring board that was blinded to individual subject treatment assignment. Treatment failure was defined as 1 of the following: arrest/incarceration, psychiatric hospitalization, suicide, discontinuation of antipsychotic treatment due to inadequate efficacy, treatment supplementation with another antipsychotic due to inadequate efficacy, discontinuation of antipsychotic treatment due to safety or tolerability concerns, or an increase in the level of psychiatric services to prevent imminent psychiatric hospitalization.

Prespecified key secondary efficacy end points listed in order of priority were time to first psychiatric hospitalization or arrest/incarceration, change in Personal and Social Performance Scale (PSP) scores, time to first psychiatric hospitalization, and change in Clinical Global Impressions-Severity of Illness scale (CGI-S) score. Safety assessments included monitoring of adverse events (AEs), vital signs, physical examinations, and clinical laboratory tests.

Sample Size

Sample size estimation was based on testing treatment group differences measured by hazard ratio (HR), using a 2-sided exponential maximum likelihood test at a .05 significance level. Detecting an HR (treatment/control) of 0.516 with 80% power requires a total of at least 72 treatment failure events. Assuming 30% of randomized subjects would drop out of the study before experiencing a treatment failure event, a total of 442 subjects (221 per group) would need to be randomized to achieve the required number of treatment failure events.

Statistical Analysis

The intent-to-treat (ITT) population, defined as all randomly assigned subjects who received ≥ 1 dose of their study treatment, was used for efficacy and safety analysis. To determine the relative effects of assigned treatments, an explanatory approach was used to assess the primary, key secondary, and safety end points. Primary and secondary analyses included all data from randomization until the end of randomly assigned treatment (28 days after the last injection of paliperidone palmitate or 1 day after the last dose of oral antipsychotic).

Demographic and baseline characteristics and AEs were summarized using descriptive statistics. Event-free probabilities of treatment failure and components of treatment failure were estimated by the Kaplan-Meier method. Treatment differences were compared using a log rank test. The HR and 95% confidence interval (CI) were estimated using a Cox proportional hazards model, with treatment as a fixed factor. Statistical significance was based on a 2-sided α of .05. A mixed-model repeated-measures analysis of covariance, using an unstructured covariance matrix with terms for treatment, time, treatment-by-time interaction, and baseline score, compared PSP total scores and CGI-S scores. To preserve the overall type I error rate at the 2-sided .05 significance level, the primary and key secondary hypotheses were tested using a fixed sequence gatekeeper approach. The hierarchy of the procedure was to test the primary hypothesis first at the .05 significance level, then to test the key secondary hypothesis at the .05 significance level. At each step, if the null hypothesis failed to be rejected (P ≥ .05), formal testing would be terminated and current and all subsequent null hypotheses would not be rejected. Testing of subsequent hypotheses continued, but the results were considered exploratory. All analyses were performed using SAS version 9.2 (SAS Institute Inc; Cary, North Carolina).

RESULTS

Patient Disposition and Baseline Characteristics

In this study, 693 subjects were screened, and 450 were randomly assigned (230 to paliperidone palmitate and 220 to oral antipsychotics; Figure 1); 444 subjects were included in the ITT population (paliperidone palmitate, n = 226; oral antipsychotics, n = 218). Overall, 305 subjects (68.7%) either had an event-monitoring board-identified treatment failure event or completed the 15-month study; 60 subjects (13.5%) were lost to follow-up, and 42 (9.5%) withdrew consent (Figure 1).

Baseline demographics and clinical characteristics did not differ significantly between arms (Table 1). Most subjects were male (86.3%) and black/African American (62.1%). The mean (SD) age was 38.1 (10.5) years, and the mean (SD) time since release from last incarceration was 42.2 (51.7) days. The majority of arrests prior to enrollment in the study were for nonviolent or drug offenses; 54.2%, 37.8%, and 29.1% of subjects were previously arrested due to felonies, misdemeanors, or infractions, respectively. It should be noted that definitions for arrest-type classifications vary by jurisdiction. A total of 59.5% of subjects had comorbid substance abuse. Additionally, 16.1% of the oral antipsychotic group had been taking their randomly selected medication within 7 days of randomization. For the paliperidone palmitate group, 22.6% had been taking either paliperidone or risperidone within 7 days of randomization. Overall, 74.3% in the paliperidone palmitate treatment arm and 80.3% in the oral antipsychotic treatment arm used ≥ 1 concomitant psychotropic medication (including antipsychotics) during the study (see eTable 1 at Psychiatrist.com). Frequently used concomitant nonantipsychotic psychotropic medications for paliperidone palmitate versus oral antipsychotic groups included antidepressants (37.2% vs 41.3%), benzodiazepines (19.9% vs 22.5%), mood stabilizers/antiepileptics (17.3% vs 17.0%), and nonbenzodiazepine hypnotics/anxiolytics (14.6% vs 10.6%) (eTable 1).

Primary Outcome: First Treatment Failure

Ninety subjects (39.8%) in the paliperidone palmitate group and 117 subjects (53.7%) in the oral antipsychotic group had a treatment failure event. Paliperidone palmitate was superior to oral antipsychotics in delaying time to first treatment failure (HR, 1.43; 95% CI, 1.09-1.88; P = .011) (Figure 2). Median times to first treatment failure were 416 and 226 days in the paliperidone palmitate and oral antipsychotic groups, respectively. The most common reasons for first treatment failure were arrest/incarceration (21.2% vs 29.4%) and psychiatric hospitalization (8.0% vs 11.9%) (Figure 2). No suicides were reported.

Secondary Outcomes

Time to first psychiatric hospitalization or arrest/incarceration. Seventy-six subjects (33.6%) in the paliperidone palmitate group and 98 subjects (45.0%) in the oral antipsychotic group had a psychiatric hospitalization or arrest/incarceration as a first treatment failure event. Paliperidone palmitate was superior to oral antipsychotics in delaying time to first psychiatric hospitalization or arrest/incarceration (HR, 1.43; 95% CI, 1.06-1.93; P = .019) (Figure 3). Median time to first psychiatric hospitalization or arrest/incarceration was not reached in the paliperidone palmitate group (> 450 days) and was 274 days in the oral antipsychotic group.

Personal and Social Performance Scale. No significant between-group differences were observed in mean change in PSP total scores (least squares mean [standard error (SE)] difference = 0.39 [0.98]; P = .689). Subsequent analyses of other secondary efficacy variables were considered exploratory.

CGI-S. No significant between-group differences were observed in mean change in CGI-S scores (least squares mean [SE] difference = -0.06 [0.05]; nominal P = .296).

First psychiatric hospitalization and first arrest/incarceration. No significant difference in time to first psychiatric hospitalization was seen between the paliperidone palmitate and oral antipsychotic groups (HR, 1.19; 95% CI, 0.67-2.11; nominal P = .552). In contrast, paliperidone palmitate was superior to oral antipsychotics in delaying time to first arrest/incarceration (HR, 1.49; 95% CI, 1.08-2.06; nominal P = .016).

Adherence. When injection records were used to assess adherence, 95.2% in the paliperidone palmitate group had a medication possession ratio (MPR) > 80%. When clinician-based “prescription” records were used to assess oral medication adherence, 78.6% had an MPR > 80%. When pharmacy-based “refill” prescription records were used to assess oral medication adherence, 24.3% in the oral group had an MPR > 80%.

Exposure to study medication. Mean (SD) exposure to paliperidone palmitate was 266.2 (174.5) days, and mean exposure to oral antipsychotics was 271.5 (178.5) days. Doses are summarized in eTable 2. Additionally, the mean and median number of injections received by paliperidone palmitate patients was generally comparable to the mean and median number of prescriptions received by patients in the oral antipsychotic group (eTable 2).

Safety. Treatment-emergent AEs (TEAEs) were reported in 85.8% and 79.8% of subjects in the paliperidone palmitate and oral antipsychotic treatment arms, respectively. Most common were injection site pain (18.6% of subjects), insomnia (16.8%), weight increase (11.9%), akathisia (11.1%), and anxiety (10.6%) in the paliperidone palmitate group and insomnia (11.5%), headache (8.3%), dry mouth (8.3%), anxiety (7.3%), and sedation (7.3%) in the oral antipsychotic group (Table 2). Incidence of serious TEAEs was 17.3% and 21.6% in the paliperidone palmitate and oral antipsychotic groups, respectively. Treatment-emergent AEs leading to study drug discontinuation occurred in 11.9% of paliperidone palmitate and 7.8% of oral antipsychotic subjects (eTable 3). Rates of extrapyramidal symptom-related TEAEs for paliperidone palmitate versus oral antipsychotics were akathisia (11.1% vs 6.9%), dyskinesia (2.7% vs 1.4%), dystonia (2.2% vs 2.8%), and Parkinsonism (1.8% vs 1.8%). Incidence of prolactin-related TEAEs was 23.5% and 4.1% in the paliperidone palmitate and oral antipsychotic groups, respectively. Incidences of prolactin-related AEs by gender are presented in eTable 4. In all, 32.4% of subjects in the paliperidone palmitate group and 14.4% in the oral antipsychotic group had a ≥ 7% increase in weight. One death occurred in the paliperidone palmitate group and was considered by the investigator as unlikely related to the study drug. There were no unexpected safety concerns related to vital signs, physical examination findings, or clinical laboratory test results.

DISCUSSION

The PRIDE study demonstrated the superiority of once-monthly paliperidone palmitate over daily oral antipsychotics in delaying time to treatment failure in an innovative randomized study that reflects real-world management of schizophrenia. The study’s premise that clinical trials with more pragmatic designs are more likely to demonstrate advantages of LAIs over oral antipsychotics was supported.19-21 To increase the pragmatic focus of the study, persons at high risk for treatment nonadherence (ie, those with recent involvement with the criminal justice system, comorbid substance abuse, or unstable living conditions) were enrolled. In addition, considerable flexibility in treatment/management decisions by physicians and patients was allowed. Finally, objective and clinically relevant outcome measures were chosen as primary end points. The robust results favoring paliperidone palmitate over oral formulations of commonly used antipsychotics in delaying time to treatment failure suggest that these design differences may be relevant for demonstrating these treatment differences.

In the United States, the criminal justice system has become a frequent setting for management of patients with severe mental illness. It has overtaken psychiatric hospitals as a site for their institutionalization.27 The results of the PRIDE study suggest that outcomes for this vulnerable population can be improved by medication choice. Indeed, outcomes of particular public health and economic importance (ie, arrest, incarceration, and hospitalization) were the most commonly observed primary end points in this study. We speculate that treatment with paliperidone palmitate leads to more consistent treatment exposure, resulting in fewer symptoms that lead to treatment failure.

Patient symptoms and functioning as measured by the CGI-S and PSP failed to demonstrate differences between paliperidone palmitate and oral treatments in this study. Although these findings may be correct, this failure may also be a consequence of ascertainment bias. That is, assessment with the CGI-S and PSP was not possible when subjects were institutionalized, points at which symptoms and functioning would likely be most deviant from baseline. On the other hand, when subjects were available for assessment, they were most likely to have improved, as evidenced by their ability to keep their clinic visit.

The risk of reinstitutionalization in individuals with mental illness and contact with the criminal justice system is high.28-30 Data from studies conducted in subjects with significant exposure to the criminal justice system reported rehospitalization rates up to 48% and reincarceration rate up to 68%.28-30 In the PRIDE study, reinstitutionalization (ie, arrest/incarceration and hospitalization) rates were 33.6% for the paliperidone palmitate arm versus 45% for the oral antipsychotic arm. The lower reinstitutionalization rate observed in the PRIDE study suggests that paliperidone palmitate may reduce the risk of reinstitutionalization in this high-risk population.

In this study, neither patients nor clinicians were blinded to treatment assignment, but all primary end points were independently identified by a blinded event-monitoring board that had no knowledge of treatment assignment. Furthermore, the majority of the end points defined as treatment failures, such as incarceration and psychiatric hospitalization, were highly objective and were chosen for this study because they may indicate deterioration in the subject’s clinical state. Although some outcomes such as discontinuation due to efficacy or safety may have been influenced by the knowledge of treatment assignment, they represented only approximately 10% of the treatment failures identified by the blinded event-monitoring board.

Paliperidone palmitate treatment was associated with numerically greater AEs, such as prolactin elevations, sexual side effects, and weight gain. This study was not powered or designed to detect differences from 7 individual oral antipsychotics. Given the varied safety profiles among these agents, the pooled data may have obscured tolerability issues relative to any individual oral agent.

The study was designed to reproduce 2 clinical management practices commonly experienced by patients with chronic schizophrenia: clinical visits where patients receive an LAI antipsychotic and visits where patients receive a prescription for an oral antipsychotic, which they fill in an outside pharmacy. In actual practice, treatment with oral antipsychotic medications requires multiple points of adherence. These include whether a clinic visit is made, whether a prescription is received, whether the prescription is filled, and, finally, whether the medication is taken as prescribed. For injectable medications, these requirements are limited to whether the patient attends a clinic visit and receives an injection. In this study, there was indirect assessment of adherence to medications. Study visits, prescriptions written, and injections were carefully documented. In addition, vouchers provided to pay for subjects’ prescriptions when filled were also meant to serve as a record of this fulfillment. However, under the real-world conditions that existed for this study, other mechanisms for payment were potentially available. This led to a possible underestimation of medication possession. For these reasons, more reliable estimates of adherence were available for injectable than oral medications. In summary, the number of study visits was similar for subjects receiving oral medications and paliperidone palmitate, and the overall duration of exposure was comparable between the 2 groups; however, it was uncertain how many prescriptions were filled for the oral group and whether these patients took their medications as prescribed.

The study design retained some biases that may affect generalization of results. Subjects who were not willing to receive LAI therapy would not have enrolled. This may have contributed to a nonrandom selection process. Other notable differences in gender and race from the US population of persons with schizophrenia are also apparent.

CONCLUSIONS

The PRIDE study results demonstrated that once-monthly treatment with paliperidone palmitate was more effective in delaying treatment failure versus daily oral antipsychotics (median difference of 190 days) in a trial designed to reflect the real-world management of schizophrenia subjects at risk for treatment failure. These findings support the value of real-world study designs when attempting to identify treatment differences that may relate to formulation differences.

Drug names: aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and others), haloperidol (Haldol and others), olanzapine (Zyprexa and others), paliperidone (Invega), paliperidone palmitate (Invega Sustenna), quetiapine (Seroquel and others), risperidone (Risperdal and others).

Author affiliations: Janssen Scientific Affairs, LLC (Drs Alphs and Starr, Ms Benson, and Mr Rodriguez); Janssen Research and Development, LLC (Dr Mao and Ms Cheshire-Kinney), Titusville, New Jersey; and Department of Psychiatry, New York University, New York (Dr Lindenmayer).

Author contributions: All authors were responsible for analysis and interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and approval of the final version of the manuscript. In addition, Dr Alphs, Mss Benson and Cheshire-Kinney, and Mr Rodriguez were responsible for study concept and design. Dr Starr was responsible for overall study conduct, while Dr Mao was responsible for study concept and design and acquisition of data.

Potential conflicts of interest: Drs Alphs and Starr, Ms Benson, and Mr Rodriguez are employees of Janssen Scientific Affairs, LLC, and Johnson & Johnson stockholders. Dr Mao and Ms Cheshire-Kinney are employees of Janssen Research and Development, LLC, and Johnson & Johnson stockholders. Dr Lindenmayer has received grant/research support from Janssen, Alkermes, Pfizer, Neurocrine, EnVivo, and Roche, and is a consultant for Janssen.

Funding/support: This study, including writing and editorial assistance, was funded by Janssen Scientific Affairs, LLC.

Role of the sponsor: The study sponsor was responsible for the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.

Previous presentations: This work has been presented in part at the following conferences: ▪ American Psychiatric Association 167th Annual Meeting; May 3-7, 2014; New York, New York ▪ Society of Biological Psychiatry 69th Annual Scientific Meeting; May 8-10, 2014; New York, New York ▪ ASCP Annual Meeting; June 16-19, 2014; Hollywood, Florida ▪ XVI World Congress of Psychiatry; September 14-18, 2014; Madrid, Spain ▪ APNA 28th Annual Conference; October 22-25, 2014; Indianapolis, Indiana ▪ 27th ECNP Congress of Applied and Translational Neuroscience; October 18-21, 2014; Berlin, Germany ▪ NCCHC 2014 National Conference on Correctional Health Care; October 18-22, 2014; Las Vegas, Nevada.

Acknowledgments: The authors thank Carol Price, BS, from Janssen Scientific Affairs, LLC (administration of the event-monitoring board); William Olson, PhD, from Janssen Scientific Affairs, LLC (contribution to the study design and statistical methods); Jim O’ Neill, BS, from Janssen Scientific Affairs, LLC (contributions to the conduct of the study); Lucy Mahalchick, BA, from Janssen Scientific Affairs, LCC (contribution to the conduct of the study and analysis of the data); Qin Li, MS, from Regeneron Pharmaceuticals, Inc (contributions to the statistical programming and analysis); Cynthia A. Bossie, PhD, from Janssen Scientific Affairs, LLC (contributions to manuscript development); and Joe Hulihan, MD, from Janssen Global Services, LLC (for contributions to study design). The acknowledged individuals have no additional conflicts of interest to report.

The authors also thank the event-monitoring board members: Leslie Citrome, MD, MPH (New York Medical College Valhalla, New York); John Lauriello, MD (through contract with University of Missouri, Columbia); Richard Kavoussi, MD (Neurite Consulting LLC, Raleigh, North Carolina); and Douglas Feltner, MD (Vice President, Pharmaceutical Development, Neuroscience, AbbVie Inc, Ann Arbor, Michigan).

The authors also thank the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study investigators: Neal Adams, MD, MPH (Oakland, California); Mohammed Alam, MD (Oak Brook, Illinois); Riaz Baber, MD (Naperville, Illinois); Michael Balkunas, MD (New Britain, Connecticut); Mohammed Bari, MD (National City, California); Carl Bell, MD (Chicago, Illinois); Jeffrey Bennett, MD (Springfield, Illinois); Jason Bermak, MD (San Francisco, California); Prakash Bhatia, MD (Escondido, California); Robert Brauer, MD (Willoughby, Ohio); Ronald Brenner, MD (Cedarhurst, New York); Wen Cai, MD (Tucson, Arizona); Alvaro Camacho, MD (Imperial, California); Jesse M. Carr, MD (Glendale, California); Rakesh Chandra, MD (Paduca, Kentucky); Marc Andrew Colon, MD (Shreveport, Louisiana); Kathleen Degen, MD (New London, Connecticut); Dale D’ Mello, MD (East Lansing, Michigan); Steven L. Dubovsky, MD (Buffalo, New York); Jean Fils, MD; Brian Keefe, MD (Tampa, Florida); Karen Frei, MD; Johnny A., Edrozo, MD (San Bernardino, California); Paul Gross, MD (Allentown, Pennsylvania); Robert Horne, MD (Las Vegas, Nevada); Javed Iqbal, MD (Paramus, New Jersey); Valentin Isacescu, MD (Oceanside, California); Shahid Jamil, MD (Novi, Michigan); Gregory Kaczenski, MD (Little Rock, Arkansas); Pravin Kansagra, MD (Anaheim, California); Mary A. Knesevich, MD, PA (Irving, Texas); David G. Krefetz, DO (Willingboro, New Jersey); Joseph Kwentus, MD (Flowood, Mississippi); Mark N. Lerman, MD (Hoffman Estate, Illinois); Jean-Pierre Lindenmayer, MD (New York, New York); Brett Y. Lu, MD (Honolulu, Hawaii); Robert J. Malcolm, MD (Charleston, South Carolina); Raymond A. Manning, MD (Pico Rivera, California); Emilio Mantero-Atienza, MD, PhD (Miami, Florida); Denis Mee-Lee, MD (Honolulu, Hawaii); Manuel Melendez, MD; Mario S, Cuervo, MD (Miami, Florida); Lawrence Edward Mobley, III, MD (Pensacola, Florida); Paul W. Murphy, MD (Wichita, Kansas); Syed Jamal Mustafa, MD (Bothell, Washington); Mark A. Novitsky, MD (Philadelphia, Pennsylvania); Nilesh J. Patel, MD (Wharton, Texas); Pierre Pean, MD (Tamarac, Florida); Marvin Lane Peyton, MD (Oklahoma City, Oklahoma); Mohamed Ramadan, MD (Bullhead City, Arizona); Sriram Ramaswamy, MD; Daniel Wilson, MD (Omaha, Nebraska); Robert A. Riesenberg, MD (Atlanta, Georgia); Martha Sajatovic, MD (Cleveland, Ohio); Stephen R. Saklad, PharmD, BCCP (San Antonio, Texas); Adonis Sfera, MD (Anaheim, California); Rajinder Shiwach, MD; Ernest Brownlee, Jr, MD (Arlington, Texas); Roger Sommi, PharmD, BCCP, FCCP (Kansas City, Missouri); Dwight S. St. Clair, DO (Wichita, Kansas); Mary L. Stedman, MD (Tampa, Florida); Rajagopal Keerthy Sunder, MD; Lily S. Chung, MD; Sadashiv Rajadhyaksha, MD; Samuel E. Dey, Jr, MD (Riverside, California); Jose R. Torres, MD (Rio Piedras, Puerto Rico); Mark H. Townsend, MD (New Orleans, Lousiana); John Tran, MD (Spokane, Washington); Tram K. Tran-Johnson, PharmD, PsyD (San Diego, California); Thomas J. Valente, MD (Leesburg, Florida); Ingrid Vasiliu-Feltes, MD; Richard Steinbook, MD (Miami, Florida); Stephen J. Volk, MD (Long Beach, California); Robert Weisman, DO (Rochester, New York); Mark J. Woyshville, MD (Middleburg Heights, Ohio); and Jose T. Zaglul, MD (Bradenton, Florida).

The authors also thank Maxwell Chang, BSc Hons, and Matthew Grzywacz, PhD (employees of ApotheCom, LLC, Yardley, Pennsylvania), for providing writing and editorial assistance.

Supplementary material: Available at PSYCHIATRIST.COM.

REFERENCES

1. Regier DA, Narrow WE, Rae DS, et al. The de facto US mental and addictive disorders service system: epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50(2):85-94. PubMed doi:10.1001/archpsyc.1993.01820140007001

2. National Institute of Mental Health. Schizophrenia. http://www.nimh.nih.gov/health/schizophrenia/index.shtml. Accessed February 5, 2015.

3. Kennedy JL, Altar CA, Taylor DL, et al. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol. 2014;29(2):63-76. PubMed doi:10.1097/YIC.0b013e32836508e6

4. Knapp M, Mangalore R, Simon J. The global costs of schizophrenia. Schizophr Bull. 2004;30(2):279-293. PubMed doi:10.1093/oxfordjournals.schbul.a007078

5. Hoge SK. Providing transition and outpatient services to the mentally ill released from correctional institutions. In: Greifinger RB, ed. Public Health Behind Bars: From Prisons to Communities. Dobbs Ferry, NY: Springer; 2007:461-477. doi:10.1007/978-0-387-71695-4_26

6. Ascher-Svanum H, Nyhuis AW, Faries DE, et al. Involvement in the US criminal justice system and cost implications for persons treated for schizophrenia. BMC Psychiatry. 2010;10(1):11. PubMed doi:10.1186/1471-244X-10-11

7. Folsom D, Jeste DV. Schizophrenia in homeless persons: a systematic review of the literature. Acta Psychiatr Scand. 2002;105(6):404-413. PubMed doi:10.1034/j.1600-0447.2002.02209.x

8. Robinson D, Woerner MG, Pollack S, et al. Subject selection biases in clinical trials: data from a multicenter schizophrenia treatment study. J Clin Psychopharmacol. 1996;16(2):170-176. PubMed doi:10.1097/00004714-199604000-00009

9. Hofer A, Hummer M, Huber R, et al. Selection bias in clinical trials with antipsychotics. J Clin Psychopharmacol. 2000;20(6):699-702. PubMed doi:10.1097/00004714-200012000-00019

10. Fleischhacker WW, Hummer M. Do phase III trials have clinical value? J Clin Psychopharmacol. 1999;19(5):391-392. PubMed doi:10.1097/00004714-199910000-00001

11. Fleischhacker WW, Kemmler G. The clinical relevance of percentage improvements on the PANSS score. Neuropsychopharmacology. 2007;32(11):2435-2436. PubMed doi:10.1038/sj.npp.1301391

12. Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophr Bull. 2003;29(1):15-31. PubMed doi:10.1093/oxfordjournals.schbul.a006986

13. Wilk J, Marcus SC, West J, et al. Substance abuse and the management of medication nonadherence in schizophrenia. J Nerv Ment Dis. 2006;194(6):454-457. PubMed doi:10.1097/01.nmd.0000221289.54911.63

14. Hunt GE, Bergen J, Bashir M. Medication compliance and comorbid substance abuse in schizophrenia: impact on community survival 4 years after a relapse. Schizophr Res. 2002;54(3):253-264. PubMed doi:10.1016/S0920-9964(01)00261-4

15. Gopal S, Hough DW, Xu H, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. Int Clin Psychopharmacol. 2010;25(5):247-256. PubMed doi:10.1097/YIC.0b013e32833948fa

16. Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol. 2005;15(1):111-117. PubMed doi:10.1016/j.euroneuro.2004.07.003

17. Bai YM, Chen TT, Wu B, et al. A comparative efficacy and safety study of long-acting risperidone injection and risperidone oral tablets among hospitalized patients: 12-week randomized, single-blind study. Pharmacopsychiatry. 2006;39(4):135-141. PubMed doi:10.1055/s-2006-946703

18. Macfadden W, Ma YW, Thomas Haskins J, et al. A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry (Edgmont). 2010;7(11):23-31. PubMed

19. Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 2014;40(1):192-213. PubMed doi:10.1093/schbul/sbs150

20. Kishimoto T, Nitta M, Borenstein M, et al. Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry. 2013;74(10):957-965. PubMed doi:10.4088/JCP.13r08440

21. Kane JM, Kishimoto T, Correll CU. Assessing the comparative effectiveness of long-acting injectable vs oral antipsychotic medications in the prevention of relapse provides a case study in comparative effectiveness research in psychiatry. J Clin Epidemiol. 2013;66(suppl):S37-S41. PubMed doi:10.1016/j.jclinepi.2013.01.012

22. Fleischhacker WW, Goodwin GM. Effectiveness as an outcome measure for treatment trials in psychiatry. World Psychiatry. 2009;8(1):23-27. PubMed

23. Alphs L, Mao L, Rodriguez SC, et al. Design and rationale of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study: a novel comparative trial of once-monthly paliperidone palmitate versus daily oral antipsychotic treatment for delaying time to treatment failure in persons with schizophrenia. J Clin Psychiatry. 2014;75(12):1388-1393. PubMed doi:10.4088/JCP.13m08965

24. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Association; 1994.

25. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33, quiz 34-57. PubMed

26. Lavori PW, Rush AJ, Wisniewski SR, et al. Strengthening clinical effectiveness trials: equipoise-stratified randomization. Biol Psychiatry. 2001;50(10):792-801. PubMed doi:10.1016/S0006-3223(01)01223-9

27. Kuehn BM. Criminal justice becomes front line for mental health care. JAMA. 2014;311(19):1953-1954. PubMed doi:10.1001/jama.2014.4578

28. Kunz M, Yates KF, Czobor P, et al. Course of patients with histories of aggression and crime after discharge from a cognitive-behavioral program. Psychiatr Serv. 2004;55(6):654-659. PubMed doi:10.1176/appi.ps.55.6.654

29. Harris V, Koepsell TD. Criminal recidivism in mentally ill offenders: a pilot study. Bull Am Acad Psychiatry Law. 1996;24(2):177-186. PubMed

30. Feder L. A comparison of the community adjustment of the mentally ill offenders with those from the general prison population. Law Hum Behav. 1991;15(5):477-493. doi:10.1007/BF01650290