Faculty Bibliography

OBJECTIVE: The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study compared the effects of once-monthly paliperidone palmitate with daily oral antipsychotics on treatment failure in adults with schizophrenia. METHOD: The PRIDE study is a 15-month, randomized, multicenter study (May 5, 2010, to December 9, 2013) of adult subjects with a DSM-IV diagnosis of schizophrenia and a history of incarceration. Subjects were randomly assigned to once-monthly paliperidone palmitate injections or daily oral antipsychotics (randomly assigned from 7 acceptable, prespecified oral antipsychotics) for 15 months. The primary end point was time to first treatment failure, defined as arrest/incarceration; psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. Time to first treatment failure was determined by a blinded event-monitoring board and analyzed with the Kaplan-Meier method. RESULTS: In this study, 450 patients were randomly assigned, and 444 were included in the intent-to-treat population. Paliperidone palmitate was associated with significant delay in time to first treatment failure versus oral antipsychotics (hazard ratio, 1.43; 95% CI, 1.09-1.88; log rank P = .011). Observed treatment failure rates over 15 months were 39.8% and 53.7%, respectively. Arrest/incarceration and psychiatric hospitalization were the most common reasons for treatment failure in the paliperidone palmitate and oral antipsychotic groups (21.2% vs 29.4% and 8.0% vs 11.9%, respectively). The 5 most common treatment-emergent adverse events for the paliperidone palmitate treatment group were injection site pain (18.6% of subjects), insomnia (16.8%), weight increased (11.9%), akathisia (11.1%), and anxiety (10.6%). CONCLUSIONS: In a trial designed to reflect real-world management of schizophrenia, once-monthly paliperidone palmitate demonstrated superiority compared to oral antipsychotics in delaying time to treatment failure. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01157351.

OBJECTIVE: Schizoaffective disorder is a complex illness for which optimal treatment is not well established. Results of the first controlled, relapse-prevention study of paliperidone palmitate once-monthly injectable (paliperidone monthly) in schizoaffective disorder are presented. METHOD: The study was conducted between September 20, 2010, and October 22, 2013. Patients with schizoaffective disorder (confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders) experiencing acute exacerbation of psychotic and depressive/manic symptoms were stabilized with paliperidone monthly as monotherapy or as adjunctive therapy to mood stabilizers or antidepressants and randomly assigned (1:1) to paliperidone monthly or placebo in a 15-month, double-blind, relapse-prevention phase. Randomization was stratified by administration as monotherapy or adjunctive therapy and by study center. The primary endpoint was time to relapse. RESULTS: 334 patients were evaluated. Paliperidone monthly significantly delayed time to relapse for psychotic, depressive, and manic symptoms compared with placebo (P < .001, log-rank test). Relapse risk was 2.49 times greater for placebo (hazard ratio = 2.49; 95% CI, 1.55 to 3.99; P < .001, Cox proportional hazards model). Overall relapse rates were 33.5% for placebo and 15.2% for paliperidone monthly. For monotherapy, relapse risk was 3.38 times greater with placebo (P = .002), and for adjunctive treatment it was 2.03 times greater with placebo (P = .021). Paliperidone monthly was superior to placebo in maintaining functioning as measured by the Personal and Social Performance scale (P = .014, mixed-model repeated-measures analysis). The most common adverse events (placebo, paliperidone monthly) were increased weight (4.7%, 8.5%), insomnia (7.1%, 4.9%), schizoaffective disorder (5.9%, 3.0%), headache (3.5%, 5.5%), and nasopharyngitis (3.5%, 5.5%). Incidence of any extrapyramidal-related adverse event was 7.1% for placebo and 8.5% for paliperidone monthly. CONCLUSIONS: Paliperidone monthly as monotherapy or adjunctive therapy significantly delayed psychotic, depressive, and/or manic relapses; reduced their risk; and better maintained functioning in patients with schizoaffective disorder. Results support the value of maintenance treatment with paliperidone monthly in schizoaffective disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01193153.

Background: The Positive and Negative Syndrome Scale (PANSS) assesses multiple domains of schizophrenia. Evaluation of each of these domains was conducted to assess differences in the characteristics of psychopathology and their relative predominance in sub-populations. Method: Subjects (N = 1,832) with DSM-IV schizophrenia were represented in three sub-populations: First Episodes, n = 305, Chronic Inpatients, n = 694, and Ambulatory Outpatients, n = 833. Nonparametric Item Response Analysis (IRT) was performed with Option Characteristic Curves (OCC), Item Characteristic Curves (ICC), slopes and item biserial correlation. Items were characterized as Very Good, Good, or Weak based on specified operational criteria for item selection. Results: First episode patients were represented by negative, disorganized hostility and anxiety. Some negative domain items (Poor Rapport, Passive/Apathetic Social Withdrawal) and most positive domain items were scored as Weak. For chronic inpatients, all items of the anxiety domain and some items of the positive domain (Suspiciousness/Persecution, Stereotyped Thinking, Somatic Concerns) were Weak; for all other domains, items were Very Good or Good. For ambulatory outpatients, most items in the anxiety and hostility domain were scored as Weak. The majority of PANSS items were either Very Good or Good at assessing the overall illness severity: chronic inpatients (73.33%, 22 items), first episodes (60.00%, 18 items), and only 46.67% (14 items) in the ambulatory group. Conclusion: Findings confirm differences in symptom presentation and predominance of particular domains in subpopulations of schizophrenia. Identifying symptom domains characteristic of subpopulations may be more useful in assessing efficacy endpoints than total or subscale scores

BACKGROUND: Hospital-discharged patients with schizoaffective disorder have a high risk of re-hospitalization. However, limited data exist evaluating critical post-discharge periods during which the risk of re-hospitalization is significant. OBJECTIVE: Among hospital-discharged patients with schizoaffective disorder, we assessed pharmacotherapy adherence and healthcare utilization and costs during sequential 60-day clinical periods before schizoaffective disorder-related hospitalization and post-hospital discharge. METHODS: From the MarketScan(R) Medicaid database (2004-2008), we identified patients (>/=18 years) with a schizoaffective disorder-related inpatient admission. Study measures including medication adherence and healthcare utilization and costs were assessed during sequential preadmission and post-discharge periods. We conducted univariate and multivariable regression analyses to compare schizoaffective disorder-related and all-cause healthcare utilization and costs (in 2010 US dollars) between each adjacent 60-day post-discharge periods. No adjustment was made for multiplicity. RESULTS: We identified 1,193 hospital-discharged patients with a mean age of 41 years. The mean medication adherence rate was 46 % during the 60-day period prior to index inpatient admission, which improved to 80 % during the 60-day post-discharge period. Following hospital discharge, schizoaffective disorder-related healthcare costs were significantly greater during the initial 60-day period compared with the 61- to 120-day post-discharge period (mean US$2,370 vs US$1,765; p < 0.001), with rehospitalization (36 %) and pharmacy (40 %) accounting for over three-fourths of the initial 60-day period costs. Compared with the initial 60-day post-discharge period, both all-cause and schizoaffective disorder-related costs declined during the 61- to 120-day post-discharge period and remained stable for the remaining post-discharge periods (days 121-365). CONCLUSIONS: We observed considerably lower (46 %) adherence during 60 days prior to the inpatient admission; in comparison, adherence for the overall 6-month period was 8 % (54 %) higher. Our study findings suggest that both short-term (e.g., 60 days) and long-term (e.g., 6-12 months) medication adherence likely are important characteristics to examine among patients with schizoaffective disorder and help provide a more holistic view of patients' adherence patterns. Furthermore, we observed a high rate of rehospitalization and greater healthcare costs during the initial 60-day period post-discharge among patients with schizoaffective disorder. Further research is required to better understand and manage transitional care after discharge (e.g., monitor adherence), which may help reduce the likelihood of rehospitalization and the associated downstream costs.

It has been suggested that atypical antipsychotic drugs (A-APDs) other than clozapine may be effective to improve positive symptoms in some patients with treatment resistant schizophrenia (TRS), if both the dose is higher, and the duration of the trial longer, than those which have been ineffective in non-TRS (NTRS) patients. This hypothesis was tested with long acting injectable risperidone (Risperdal Consta(R), RLAI). One hundred sixty TRS patients selected for persistent moderate-severe delusions or hallucinations, or both, were randomized to RLAI, 50 or 100mg biweekly, in a six month, outpatient, double-blind, multicenter trial. We hypothesized that RLAI, 100mg, would be more effective than RLAI, 50mg. However, both doses produced clinically significant and equivalent improvement in PANSS Total, Positive, and Negative subscale scores, as well as key cognitive, global and functional measures, with increasing response during the course of the study, confirming the value of longer clinical trial duration for patients with TRS, but not superiority of the higher dose. The overall response rate was comparable to that previously reported for clozapine and high dose olanzapine, another A-APD, in TRS. Both doses of RLAI were equally well tolerated, producing minimal extrapyramidal side effects and few drop outs. Plasma levels of the active moiety, risperidone+9-hydroxyrisperidone, during treatment with RLAI 100mg, were comparable to those for 6-8 mg/day oral risperidone, which have not been effective in TRS. Further study of RLAI, >/= 50-100mg biweekly, should compare it with clozapine and oral risperidone in TRS, with duration of treatment >/= six months.

This study tested whether treatment with pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate receptor 2/3 agonist compared with placebo (PBO), when added to a fixed-dose second-generation antipsychotic (SGA) demonstrated significantly greater reduction of negative symptoms, as assessed by the 16-item Negative Symptom Assessment scale (NSA-16), in patients with schizophrenia. This parallel-group, 16-week study enrolled adults with schizophrenia who were receiving standard of care (SOC) therapy, which included >/=3months treatment with one of four SGAs: aripiprazole, olanzapine, risperidone, or quetiapine. Patients received either 20mg of twice daily LY2140023 monohydrate (LY2140023) or concurrent PBO SGA. The primary efficacy measure was change from baseline to final visit in NSA-16 total score. Secondary measures included additional measures of efficacy, cognition, and assessments of safety. Of 352 patients screened, 167 were randomly assigned to treatment, and 110 patients completed the study. Patients treated with LY2140023 and SOC failed to demonstrate a statistically significant improvement over patients treated with PBO and SOC on NSA-16 total score at endpoint or at any point during the study (all p>0.131). Changes in secondary efficacy measures were not significantly different between groups at endpoint. With the exception of vomiting which was greater in the LY2140023 group, there were no statistically significant differences in safety and tolerability measures. This study found no benefit of adjunctive LY2140023 versus PBO for negative symptoms in patients with schizophrenia receiving treatment with SOC. LY2140023 was generally well-tolerated in these patients.