Drug-exposure data indicated that the [mean (SD)] RLAI drug doses appeared to be similar between patients who did and did not relapse: 35.2 (12.4) versus 38.0 mg (12.5), respectively. As expected, the [mean (SD)] duration of RLAI treatment was significantly shorter among patients who relapsed versus those who did not relapse [138.3 (97.6) vs. 263.1 (119.9) days; P<0.0001]; the median durations were 111.0 and 340.5 days, respectively.
Univariate predictors of relapse
Univariate regression analyses showed that duration of illness (>10 vs. ≤5 years; P=0.0255), previous AP dosing (>4 vs. ≤4 mg/day, risperidone equivalents; P=0.0243), treatment in Canada versus the USA (P=0.0016), and negative symptoms (PANSS negative factor; P=0.0384) were significantly associated with greater risk of relapse at P value less than 0.05 level (Table 3). In addition, previous number of psychiatric hospitalizations (≥1 vs. 0; P=0.0642) and current age (P=0.0511) were also identified to be associated with relapse at P value less than 0.10 level. Although 20% of patients in the study population had a diagnosis of schizoaffective disorder, the analysis found that there was no unique, additional association between risk of relapse and diagnosis type (i.e. schizophrenia vs. schizoaffective disorder).
Stepwise multiple regression analyses
Correlational analyses were run among related variables of interest; duration of illness, number of previous hospitalizations, current age, and age at onset were shown to be highly correlated. Numerous regression models were run to determine whether one of these variables emerged as more important than the others. The relative importance of predictors was examined using differences on −2 log likelihoods from the Cox regression models. In addition, the regression coefficients from univariate regression models were considered in deciding the importance of predictors. No single variable emerged as being most important. Duration of illness was selected not only for numerical reasons for inclusion in the stepwise models but also because it was considered to be the most clinically relevant factor. On the basis of entry and stay criteria of less than or equal to 0.10, the stepwise multiple Cox proportional hazards model showed that duration of illness of >10 versus ≤5 years (P=0.0181) and being in Canada versus the USA (P=0.0008) were significantly associated with an increased risk of relapse (Table 4). The duration of illness in years as a continuous predictor was also included in a separate stepwise multiple Cox proportional hazards model and showed that each 1-year increase in duration of illness was associated with a 6.0% increase in the risk of relapse (P=0.0003) in the population sample studied.
The smoothed hazard functions for relapse were graphed by duration of illness (Fig. 1a and b). The risk of relapse was lowest in patients with a duration of illness of less than or equal to 5 years and highest for those with a duration of illness of more than 10 years (Fig. 1a and b).
Psychiatric hospitalization was the most common outcome accounting for relapse in all three duration of illness categorical groups (≤5 years, 3.9%; 6–10 years, 11.8%; >10 years, 8.9%) (Table 2). The most common outcomes accounting for relapse by country of origin were administration of rescue medication in Canada (17.5%), psychiatric hospitalization in the USA (9.2%), and more than 25% change in the PANSS total score in Argentina/Chile (9.3%).
Adverse events for relapse versus nonrelapse groups
The majority of the patients in the relapse (100%) and nonrelapse (86.7%) groups experienced at least one treatment-emergent adverse event (AE). The most common AEs (≥10%) for the relapse group were psychotic disorder not otherwise specified (NOS; 47.5%), insomnia (42.4%), schizophrenia NOS (39.0%), anxiety (18.6%), headache (15.3%), auditory hallucination (11.9%), suicidal ideation (10.2%), agitation (10.2%), and upper respiratory infection NOS (10.2%). The most common (≥10%) AEs for the nonrelapse group were insomnia (24.2%), headache (19.3%), anxiety (15.9%), psychotic disorder NOS (14.4%), and nasopharyngitis (10.2%). The percentage of patients with extrapyramidal symptom-related AEs was 20.3% for the relapse group and 20.5% for the nonrelapse group. The most common extrapyramidal symptom-related AEs for the relapse and nonrelapse groups were akathisia (5.1 vs. 7.6%) and tremor (8.5 vs. 4.9%).
The aim of this exploratory post-hoc analysis was to identify factors associated with an increased risk of relapse in patients with schizophrenia or schizoaffective disorder who were receiving RLAI. The main results of this analysis indicate that in the population sample studied, a longer duration of illness (especially >10 years) was associated with an increased risk of relapse compared with a shorter duration of disease, despite continuous LAT.
Previous studies have identified additional factors that may be associated with remission or relapse in patients with schizophrenia. An analysis of data from a multicenter cohort study suggests that lower quality of life, as assessed by the 36-item Short Form Health Survey, may be an independent predictor of increased risk for relapse in patients with schizophrenia (Boyer et al., 2013). Other predictors of remission in patients with schizophrenia have also been identified. These include lower PANSS global, negative, or general psychopathology subscores; a shorter duration of untreated psychosis; and early treatment response (Schennach-Wolff et al., 2009, 2011). A study measuring symptomatic and functional remission in patients with schizophrenia treated with RLAI indicates that baseline symptom severity, country of origin, higher mode doses of RLAI, male sex, and the additional use of psychoactive medications may predict relapse (Lambert et al., 2010). A systematic literature review also identified numerous potential treatment-related, disease-related, and patient-related drivers of relapse, such as adherence problems, substance abuse, and hospitalization/relapse history (Olivares et al., 2013). Finally, a long-term prognostic study found a positive correlation between the duration of untreated psychosis and the number of relapses over 12 years of follow-up in patients with schizophrenia (Cechnicki et al., 2011).
Such predictors may aid in the identification of persons who are at risk of relapse and may suggest populations to target for interventions that might decrease this risk. These predictors may also support treatment selection because a post-hoc analysis of AP drug trials in schizophrenia indicates that chronicity of illness may have an impact on between-drug treatment differences (Leucht et al., 2007).
Emerging models investigating the stages of schizophrenia suggest that the neurobiology of the disease may change with each successive relapse. These models for disease progression might explain why duration of illness and the number of previous relapses would predict response to AP treatment as observed in this study. It is speculated that psychotic episodes may produce neurotoxic effects (through neuroinflammation and oxidative stress) that lead to changes in the brain’s neurochemical infrastructure and/or connectivity (i.e. loss of white matter integrity). Thus, a long cumulative duration of psychosis because of inadequate or lack of treatment or multiple episodes of psychosis may result in the gradual loss of responsiveness to dopamine blockade and make patients more vulnerable to environmental stressors that lead to relapse. Such changes might be the basis for increased treatment resistance and further clinical and functional deterioration (Shenton et al., 2010; Bartzokis et al., 2011; Reis et al., 2014). This model is supported by a recent study that has identified an association between relapse and changes in both cognition and intracortical myelin and by a randomized study showing the robust value of uninterrupted treatment of treating patients with first-episode schizophrenia with long-acting APs compared with oral APs (Bartzokis et al., 2011; Subotnik et al., 2015).
Another consideration is that a longer duration of illness may be indicative of greater progression of the disease process. This hypothesis is supported by the identification of certain items identified in the univariate model, including greater severity of negative symptoms and higher doses of previous APs in individuals with a longer duration of illness.
In this analysis, receipt of LAT in Canada was identified as a significant predictor of relapse. Although this may reflect country-based differences in treatment practice, caution must be exercised when interpreting this result because it may represent chance findings arising from the limited sampling of Canadian patients and sites (n=40 at two sites) and differences in how relapses were identified at these sites. Although not evaluated as predictors for relapse, the marked differences in two of the most common AEs in the relapse group versus the nonrelapse group suggest that insomnia (42.4 vs. 24.2%) and agitation (10.2 vs. 3.8%) may be associated with relapse and their onset may predict impending relapse.
This work has several limitations that affect interpretation of the results. The variables tested in this analysis and its overall findings are based on data from a single, controlled, clinical trial database with an explanatory design that included multiple inclusion and exclusion criteria. Therefore, the results may not be generalizable to broader patient groups, such as those with active substance abuse (a known contributor to relapse) who were excluded from the studies. Further, the participants were not selected randomly and were treated in the context of a highly supervised clinical trial that may not reflect results in a naturalistic setting. Both design considerations increase uncertainty about the generalizability of the results.
The relatively small number of relapses and the 1-year duration of the study limit a robust examination of all variables that might be related to the explanation of relapse risk. Furthermore, these relapses were defined by several component outcomes, ranging from hospitalization to changes in PANSS scores. These components, although standard for most explanatory-type studies, such as study NCT00297388, almost certainly differ from the definitions of relapse used in most clinical settings. As a consequence, the identified predictors of relapse found in this study may differ from those that predict relapse in a naturalistic study.
The main findings of this research suggest that patients with a longer duration of illness (i.e. particularly >10 years) have a higher risk of relapse despite ensured adherence to LAT than those with more recent disease onset. These exploratory results suggest that increasing chronicity may increase the likelihood of future relapses despite certain knowledge of treatment at effective doses. Although these exploratory results are purely hypothesis generating, they do raise a number of important questions. Does repeated relapse result in treatment resistance to dopamine antagonists? Does relapse prevention throughout the course of illness decrease the risk of future relapse and possibly modify the course of schizophrenia? Is the early psychotic episode a distinct treatment-responsive stage of the illness that moves to a different stage after subsequent episodes? Additional prospective studies are required to answer these questions and to show that the results identified here are generalizable to the broad population of patients with schizophrenia when they are treated in a real-world environment.
The authors thank Maxwell Chang and Matthew Grzywacz, PhD, of ApotheCom (Yardley, Pennsylvania, USA) for their writing and editorial assistance, which was funded by Janssen Scientific Affairs, LLC. The analysis was also supported by Janssen Scientific Affairs.
Author contributions: Larry Alphs, Henry A. Nasrallah, Cynthia A. Bossie, and Dong-Jing Fu contributed to the design and interpretation of the post-hoc analysis and to manuscript preparation; Ibrahim Turkoz contributed to the statistical analysis of the data, the design and interpretation of the post-hoc analysis, and manuscript preparation; Srihari Gopal and David Hough contributed to the design of the study, the design and interpretation of the post-hoc analysis, and manuscript preparation. All authors approved the final version of the manuscript before submission.
Conflicts of interest
Larry Alphs, Cynthia Bossie, and Dong-Jing Fu are employees of Janssen Scientific Affairs, LLC, and Johnson & Johnson stockholders. Henry Nasrallah has received honoraria from Acadia, Alkermes, Allergan, Grünenthal, Boehringer-Ingelheim, Genentech, Janssen, Merck, Lundbeck, Novartis, Otsuka, Roche, Shire, Teva, and Sunovion, and has received research grants provided through his university from Forest Laboratories, Janssen, Merck, Novartis, Otsuka, and Sunovion. Srihari Gopal, David Hough, and Ibrahim Turkoz are employees of Janssen Research & Development, LLC, and Johnson & Johnson stockholders.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
antipsychotic agents; recurrence; schizophrenia