Understanding the impact of persistent symptoms in schizophrenia: Cross-sectional findings from the Pattern study
Introduction
Schizophrenia is a severe mental disorder associated with high personal, family and societal burden (Van Os and Kapur, 2009). It is characterized by the presence of a variety of symptoms, which are commonly divided into three main symptom domains: 1) psychotic symptoms such as delusions, hallucinations (reality distortion) and disorganization (thought disorders and bizarre behavior); 2) negative symptoms, which include affective flattening, paucity of thought or speech, lack of motivation and emotional and social withdrawal; and 3) cognitive impairment (especially in memory, attention and executive function) (Liddle, 1987, Malla et al., 1993). The annual incidence of schizophrenia averages 15 per 100,000 and the lifetime prevalence is approximately 1% (Tandon et al., 2008). Schizophrenia is one of the most costly mental disorders in terms of human suffering and societal expenditure. This high burden to patients, their families and wider society is predominantly caused by the persistence of symptoms and occurrence of relapse throughout the course of illness.
A substantial proportion of patients with schizophrenia experience residual and unremitting positive symptoms despite antipsychotic treatment (Suzuki et al., 2012, Suzuki et al., 2011). Approximately 70% of patients treated with antipsychotics show improvement in positive symptoms in the short-term (up to 6 months). However, the response is not consistent or fully effective for all patients (Menezes et al., 2006, Novick et al., 2007, Novick et al., 2009, Van Os and Kapur, 2009). Indeed, it has been estimated that around two-thirds of patients continue to experience significant symptoms two years after treatment initiation, and approximately one-third will continue to experience these symptoms six years after diagnosis (Hegarty et al., 1994, Menezes et al., 2006, Novick et al., 2007, Novick et al., 2009). Insufficiently controlled positive symptoms can lead to poor patient outcomes, including relapse, rehospitalization, impaired functioning and a reduced quality of life (Norman et al., 1999, Norman et al., 2001, Novick et al., 2009, Csernansky and Schuchart, 2002, Doering et al., 1998, Postrado and Lehman, 1995, Menezes et al., 2006, Novick et al., 2007, Novick et al., 2009, Jordan et al., 2014).
A recent follow-up study of individuals experiencing a first psychotic episode has challenged this negative prognosis. The AESOP-10 study followed up a cohort of 557 people with a first psychotic episode. Of the 126 patients with schizophrenia who were reevaluated about half of them were classified as having a good end state (Morgan et al., 2014). Seventy percent of the cases who were followed up had experienced at least a period of sustained remission. However, these results are somehow in conflict with recent review that found that the proportion of those with schizophrenia who recover on both symptom and functional outcome is modest (approximately 14%). The discrepancies can be explained by disparities in the patient samples, whether first-episode or not, but also by the lack of consistent definitions of remission and recovery. Recovery should be conceptualized as a multifaceted process, in which symptoms, functioning and patient perception need to be taken into account (McGrath et al., 2014). Recovery obviously depends on remission. Nevertheless, there are a number of other intervening factors affecting recovery that are responsible for the marked variation in outcome observed (Menendez-Miranda et al., 2015, Jordan et al., 2014).
At any point in time, including during the first episode of illness, negative symptoms affect up to 60% of patients with schizophrenia (Bobes et al., 2010), with 30% having primary negative symptoms (Buchanan, 2007, Stahl and Buckley, 2007). Currently available antipsychotics may not have a direct effect on primary negative symptoms (Erhart et al., 2006); therefore, many patients experience persistent negative symptoms even after control of their positive symptoms (Stahl and Grady, 2004, Chue and Lalonde, 2014). The severity of negative symptoms is a predictor of poor patient functioning, also contributing, to a greater extent than positive symptoms, to worse patient outcomes (Fervaha et al. (2014a,b). Negative symptoms affect the ability of the patient to live independently, perform activities of daily living, engage in social activity, maintain personal relationships and participate in work or study (Rabinowitz et al., 2012, White et al., 2009, Novick et al., 2009). This impact is often evident even within one to two years following treatment of a first episode of illness (Cassidy et al., 2010, Jordan et al., 2014).
Resolution of persistent symptoms is necessary to achieve complete remission and serves to expand patient progress beyond just “stability” and towards improved social and occupational functioning. Furthermore, psychosocial therapies and rehabilitation are most effective when both positive and negative symptoms are effectively controlled (Andreasen et al., 2005). Many patients experience persistent morbidity over the course of their illness and the attainment of remission (defined as a ‘mild or less’ symptom level for the eight core Positive and Negative Syndrome Scale [PANSS] symptoms for at least six consecutive months) remains a significant challenge (Andreasen et al., 2005). A recent literature review of remission in schizophrenia reported that only 45–70% of first-episode and multi-episode patients fulfilled remission criteria at some point during treatment (Lambert et al., 2010).
A number of epidemiological cohort studies have been followed but none has specifically evaluated the natural course of persistent positive and negative symptoms of schizophrenia or compared them between countries (Buchanan, 2007, Chakos et al., 2006; Haro et al., 2003a; Haro et al., 2003b). The Pattern study was designed to evaluate the burden and course of schizophrenia, patient-reported outcomes, healthcare resource utilization and associated costs for patients with persistent symptoms of schizophrenia, not conditioned by any particular therapy or intervention, under standard routine clinical practice. In addition, family members and other informal carers were assessed for their burden and associated costs with caring for these patients. This study is unique in the field of schizophrenia owing to its analysis of the individual contributions of positive and negative persistent symptoms on patient functioning across countries. Whereas previous studies have evaluated the course of illness in patients with schizophrenia by assessing overall symptom burden, the Pattern study examines individual symptom subgroups. The study consists of two phases: a cross-sectional assessment, which forms the baseline observation; and a longitudinal assessment, in order to collect data on all patients who were not in recovery at baseline. The aim of this study is to describe the characteristics of the patients with schizophrenia receiving outpatient treatment in different countries and to examine the relationship between the persistence of different types of symptoms and patient functioning.
Section snippets
Study design
Pattern is an international, multicenter, non-interventional, prospective, cohort study of schizophrenia patients attending psychiatric outpatient clinics. The study was conducted by psychiatrists treating patients with schizophrenia in outpatient facilities. Recruitment within the sites was based on a sequential selection from patients with a diagnosis of schizophrenia. From a list of current clinic patients generated for each site, those patients without a recent acute relapse, within the
Patient characteristics
A total of 1433 patients were recruited into the Pattern study, from 140 study sites in eight countries (Argentina, Brazil, Canada, France, Germany, Italy, Spain and the United Kingdom). Overall, 1379 patients were included in the CS-PAS; 54 (3.8%) patients were excluded, the majority because they did not have a diagnosis of schizophrenia (primarily schizoaffective disorders). Socio-demographic information was similar across the eight countries (Table 2). Overall, patients were predominantly
Discussion
The cross-national characteristics of the Pattern study allowed comparison of various patient characteristics and outcome variables between countries, similar to recent investigations into psychopathological characteristics of patients with schizophrenia from Brazil, China and the US (Stefanovics et al., 2014). The data of more than 1300 patients and their family members or informal carers represent a valuable epidemiological contribution towards the study of schizophrenia. Clinically stable
Conclusion
This cross-sectional study of 1379 patients, and their carers represents a valuable real-world contribution to the study of schizophrenia, particularly given that naturalistic data from 140 centers across eight countries were collected. Based on this cross-sectional assessment, there was a high prevalence of patients with positive and/or negative persistent symptoms of schizophrenia and associated functional impairment. These results further substantiate the deleterious impact of persistent
Funding
This research was sponsored by F. Hoffmann-La Roche Ltd.
Author contributions
Josep Maria Haro contributed to development of all drafts of the manuscript and approved the final version.
Carlo Altamura contributed to the first draft of the manuscript and literature analyses and approved the final version.
Ricardo Corral recruited and evaluated patients, and contributed to and approved the final manuscript.
Helio Elkis reviewed and contributed to all versions of the manuscript and approved the final version.
Jonathan Evans recruited patients, discussed the analysis plan and
Conflicts of interest
Carlo Altamura has served as a consultant or advisory board member for F. Hoffmann-La Roche, Ltd., Lundbeck, Merck, Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, Sanofi, Eli Lilly, Pfizer and Otsuka. Helio Elkis has received research grants from the São Paulo Research Foundation (FAPESP), Janssen-Cilag and Roche, participated on advisory boards for Janssen-Cilag and Roche, and received honoraria and travel support from Janssen-Cilag and Roche. Ashok Malla has received honoraria or
Acknowledgments
The authors received medical editing support from inVentiv Medical Communications, which was funded by F. Hoffmann-La Roche Ltd. The authors would like to acknowledge Bridge Medical for their support in the development of the Pattern study protocol and to thank OXON Epidemiology for their support with the health economic aspect of the study. The authors would also like to thank all investigators, their site staff, and patients and their caregivers in the collection of these data.
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