Int J Psychiatry Clin Pract 2015; 19: 90–98. © 2015 Informa Healthcare ISSN 1365-1501 print/ISSN 1471-1788 online. DOI: 10.3109/13651501.2014.1002501
ORIGINAL ARTICLE
Towards a pragmatic and operational definition of relapse in schizophrenia: A Delphi consensus approach
informahealthcare.com/ijpcp
Luis San1, Manuel Serrano2, Fernando Cañas3, Samuel Leopoldo Romero4, Ángeles Sánchez-Cabezudo5 & Mariano Villar6 1
Department of Child and Adolescent Psychiatry, Hospital Sant Joan de Déu, CIBERSAM, Barcelona, Spain, 2Head of Psychiatry Department, Complejo Universitario Hospitalario de A Coruña, Spain, 3 Department of Psychiatry, Hospital “Dr. R. Lafora”, and Universidad Francisco de Vitoria School of Medicine, Madrid. Spain, 4Department of Psychiatry, U.G.C. Hospital Virgen Macarena, Seville, Spain, 5 Department of Psychiatry, Complejo hospitalario de Toledo, Spain, and 6Department of Psychiatry, Policlinica psiquiátrica. Hospital provincial de Castellón, Spain Abstract Objective. To develop pragmatic and operational definitions of relapse in schizophrenia. Methods. A two-round Delphi consensus approach was used. The final questionnaire based on seven pre-established definition relapse models developed by a panel of eight experts was presented to 33 general psychiatrists who attended an “ad hoc” meeting. Results. The most frequent components of the pragmatic definition were the psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), and impairment in functioning and social behavior (67%). In the operational definition, reappearance of symptoms was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was considered recommendable by 67%. Between 46% and 53% rated worsening of severity status and worsening of functioning as indispensable or recommendable. An increase of ⱖ 10 points in the positive subscale of Positive and Negative Symptom Scale was rated by 51% of the participants, a score of 6 points in the Clinical Global Impression scale (much worse) by 89%, and a reduction of ⱖ 20 points in the Global Assessment of Functioning scale by 62%. Conclusions. A better understanding of the definition of relapse in schizophrenia is necessary to improve effective prevention strategies. Key words: Schizophrenia, relapse, treatment outcome (Received 17 March 2014; accepted 16 December 2014)
Introduction Relapse, characterized by an acute psychotic exacerbation, is a highly prevalent component of the course of the disease in patients with schizophrenia. The nature of these episodes, however, has not been fully characterized and clinicians may not always be aware of important implications of recurrent relapses in the outcome of patients (Emsley et al. 2013). Relapses are associated with worsening of symptoms, cognitive deterioration, impaired functioning, and reduced quality of life (Lader 1995; Olivares et al. 2013). Moreover, relapse is one of the most costly aspects of schizophrenia, mainly due to the need of admission to the hospital for the patient’s care (Almond et al. 2004; Hong et al. 2009). Improving medication adherence and relapse prevention have been consistently emphasized as key therapeutic objectives in the management of schizophrenia (Agid et al. 2010; Dilla et al. 2013; Higashi et al. 2013; Leucht et al. 2003; Smeraldi et al. 2013). Our current understanding of the complex interactions of many personal and environmental factors, including Correspondence: Dr. Luis San, Department of Child and Adolescent Psychiatry, Hospital Sant Joan de Déu, CIBERSAM, Passeig Sant Joan de Déu 2, E-08950 Esplugues del Llobregat, Barcelona, Spain. Tel: ⫹ 34 93 32806349. Fax: ⫹ 34 93 6009454. E-mail: [email protected]
early warning signs to predict a relapse, are frequently insufficient to identify patients at risk and, therefore, to develop effective strategies to manage this problem (Alvarez Jimenez et al. 2012; Emsley et al. 2013; Gleeson et al. 2010; Robinson et al. 1999). This picture is further complicated by the lack of consensus about what constitutes a relapse and no established definite criteria by which to define a relapse. A recent systematic review of the literature identified numerous factors that have been used to define relapse (Olivares et al. 2013). Hospitalization (and exacerbation of symptoms leading hospitalization) was the factor most frequently used to define relapse. Other factors included assessment of symptom severity especially positive symptoms using different scales, such as the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI) (including CGI-Severity and CGIImprovement), Brief Psychiatric Rating Scale (BPRS), and Global Assessment of Functioning (GAF) scale, as well as changes in behavioral pattern, adherence problems, stress/ depression, substance use, poor patient insight, and history of hospitalization or relapse, among others. This excellent review (Olivares et al. 2013) has highlighted that there is still an ongoing debate of what elements truly comprise a relapse episode in schizophrenia.
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
The present study was conducted with the aim of developing pragmatic and operational definitions of relapse in schizophrenia that can be applied in clinical daily practice and in clinical research. A Delphi process was used to elicit and quantify the opinions of a group of expert psychiatrists working in Spain. The results obtained will further contribute to increase our knowledge of the symptomatic, phenomenological, and behavioral levels of the term “relapse,” as well as to develop strategies to reduce the risk of relapse in the real-world setting. Methods Design and organization of the study A two-round Delphi technique was used to reach agreement among members of the Spanish Society of Psychiatry with recognized experience in clinical psychiatry throughout Spain, about the pertinence of establishing a definition (pragmatic and operational) of relapse in schizophrenia and to identify the essential elements for such a definition. The Delphi method is a technique to arrive at a group of consensus regarding an issue under investigation that was originally developed at the Rand Corporation in the 1950s (Dalkey et al. 1969). It is a structured, systematic, and multistage process where a panel of experts are invited to take part in a series of rounds to identify, clarify, and finally reach a consensus for a subject matter in which precise information is lacking or inconsistent. The method relies on soliciting anonymous individual answers to questions by survey. Consensus is sought through the feedback of information and iteration. The study was conducted in four phases: (1) formation of the scientific committee composed of eight expert consultant psychiatrists with academic positions and large experience in research and clinical practice in the field of schizophrenia, selection of an external methodological expert for review of the literature, and distribution of the relevant articles subjected to debate; (2) “idea-generating” stage comprising definition of relapse into two concepts: pragmatic definition (with the main focus on clinical practice) and operational definition (with the main focus on research), and development of six essential items that any definition of relapse should contain and seven definitions of relapse models; (3) development of a list of items for the prediction of relapse; (4) with the feedback of each of the expert’s responses on components, definitions, and risk factors for relapse, a series of questions related to proposals of pragmatic and operational definitions were developed; (5) the final questions were electronically presented to 33 general psychiatrists who attended an “ad hoc” meeting, which was held in Lisbon on June 1, 2013, in the framework of the VIVE project, using the PowerVote voting system; and (6) collection of data, analysis of final results, and summary of findings. The VIVE project, supported by Janssen, involves the active participation of more than 300 Spanish psychiatrists and includes a series of continuing education, release of information, and research activities aimed at improving the care of individuals with schizophrenia, especially to achieve integration based on sustained treatment of people with psychotic disorder.
91
Round 1 All eight experts rated six previously defined components that should be present in any definition of relapse on a scale of 1 to 3 (where 1 ⫽ necessary [essential], 2 ⫽ additional, and 3 ⫽ unnecessary). Also, the expert panel rated seven pre-established models to define relapse on a scale of 1 to 3 (where 1 ⫽ good, 2 ⫽ acceptable, and 3 ⫽ poor). Components and models of definition of relapse are shown in Table I. A final list of questions addressed to reach a pragmatic definition of relapse on which there was strong agreement among the experts was developed. In relation to risk factors for relapse, a series of 66 items regarding sociodemographic factors, clinical data, premorbid adjustment, personality traits, cognitive function, biological markers, neuroimaging data, and clinical course were previously developed by one of the experts, and then rated by each of the experts on a scale of 1 to 3 (where 1 ⫽ poorly relevant, 2 ⫽ quite relevant, and 3 ⫽ very relevant). Items with a sum score of at least 16 were selected (Table II). The expert panel finally developed a list of nine questions related to the operational definition of relapse. Round 2 The finalized questionnaire containing questions identified in the two steps of round 1 was constructed and formatted for a Power Point presentation at the Lisbon meeting. Details and ratings for each question are shown in Table III. Of the different choices, usually three or four, only one category could be selected. A descriptive analysis was undertaken. Results Round 1 In relation to the components that should contain a definition of relapse, the following four criteria were scored 1 (necessary) by all experts: 1) previously stabilized condition or persistence of residual symptoms, 2) severity of psychopathology and/or appearance of significant clinical symptoms of mental health deterioration, 3) implication in functioning and social behavior, and 4) more intensive management of the case with changes in the consumption of resources or in the therapeutic regimen. Inclusion of the minimal duration of the episode was considered necessary by 40% of the experts and additional by the remaining 60%. In relation to the period of appearance, 25% rated this item as necessary, 60% as additional, and one expert as unnecessary. Table IV shows the results of the assessment of pragmatic relapse models by the expert panel. Models I and II were rated 1 (good) by all experts (one of the experts suggested to substitute the term “relapse” by a synonymous or homonymous concept). Models III and IV were rated 1 (good) by 62.5% and 75% of the experts, respectively. Models V, VI, and VII were mostly rated 2 (acceptable). Round 2 Participants in the second round of the process had different opinions regarding the existence of a definition of relapse but strongly agree (76%) that developing a better definition of
92
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table I. Round 1 (expert panel): components and definition of relapse models. Components that should contain a definition of relapse (rated as 1 ⫽ necessary, 2 ⫽ additional, and 3 ⫽ unnecessary) Previous stabilized condition or persistence of residual symptoms Severity of psychopathology and/or development of significant clinical symptoms of deterioration of mental status Implication in functioning and social behavior More intensive management of the case with changes in the consumption of resources or changes in the therapeutic regimen Minimal duration of the episode Period of appearance Definitions of models of relapse (rated as 1 ⫽ good, 2 ⫽ acceptable, and 3 ⫽ poor) Model 1: General complete definition “Relapse defines the situation that occurs in a patient previously diagnosed with psychotic disorder and in a stage of remission (without symptoms or only residual symptoms) who develops new symptoms, which fulfil criteria of a psychotic episode (delusions, hallucinations, conceptual disorganization, insertion of thoughts, posturing), with a significant impairment of functioning and social behaviour, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources (modification of treatment and/or change in the level of care) that occurred during the last 6 months” Model II: Simple complete definition “Relapse defines the situation that occurs in a patient in a stage of remission that develops new symptoms, which fulfil criteria of a psychotic episode, with a significant impairment in functioning and social behaviour, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources, occurring during the last 6 months” Model III: Extensive complete definition “Relapse expresses a change from a previously stabilized condition, with absence of symptoms, to reappearance of psychotic symptoms or significant clinical features of mental status deterioration (including suicidal attempts or exacerbation of depressive symptoms), with a clear impairment in functioning and social behaviour, lasting at least 1 week, in the last 6 months and that obliges to a change in the clinical management” Model IV: Simple definition “Relapse is defined as a reappearance or exacerbation of persistent symptoms in a symptom-free patient or with residual symptoms after a psychotic episode, which causes a change in functioning or social deterioration, lasting at least 7 days and determining a change in the health care management, in the last 6 months” Model V: Narrow definition “Relapse expresses a change from a previously stabilized situation, with absence of symptoms or persistence of negative residual symptoms to a clear deterioration, so that the patient needs to be hospitalized or medication should be substantially modified, lasting at least 1 week” Model VI: Concrete simplified definition “Relapse expresses a change from a previously stabilized condition to an increase in the florid psychotic symptoms, which causes a change in functioning or social deterioration, lasting at least 7 days” Model VII: General simplified definition “Relapse expresses a change from a previously stabilized status to the appearance of new symptoms or behavioural patterns interfering functioning, lasting at least one week and occurring in the last 6 months”
relapse was needed (Figure 1). The most frequent individual components rated as indispensable in a definition of relapse were the psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), impairment in functioning and social behavior (67%), presence of the term “exacerbation” (65%), and presence of the term “worsening” (61%). In contrast, poorly relevant components included residual symptoms (40%), presence of the term “reappearance” (35%), affective-suicidal risk symptoms (26%), and presence of the term “significant clinical deterioration” (21%) (Table V). Table VI shows the results of the assessment of pragmatic relapse models by the expert panel. Models I, II, and III were rated as “agree” for more than 2/3 parts of the expert panel (85%, 79%, and 74%, respectively). Model IV was accepted and rejected by half of the expert panel (48% and 52%, respectively). In relation to operational definition of relapse (Table VII), reappearance of symptoms in symptom-free patients after an initial episode was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was rated as recommendable by 67%. Between 46% and 53% rated worsening of severity status and worsening of functioning as indispensable or recommendable. Also, 54% considered indispensable to state a minimum
period of time for reappearance of schizophrenic symptoms. In relation to changes in the different scales (Figure 2), an increase of ⱖ 10 points in the positive subscale of PANSS was rated by 51% of the participants, a score of 6 points in the CGI (much worse) by 89% and a reduction of ⱖ 20 points in the GAF scale by 62%. Seventy-two percent of participants considered a minimum of 1 week for reappearance of schizophrenic symptoms (Figure 2). Discussion The term relapse is used extensively in psychiatric practice and as a main outcome criterion in schizophrenia studies, although it is rarely defined, which is in contrast to wellknown Andreasen symptomatic remission criteria (Andreasen et al. 2005). In fact, the concept of relapse expresses a sufficiently noticeable change from a previously stabilized condition and, therefore, has to be examined qualitatively and quantitatively. Overall, 76% of participants strongly agreed on the need to establish a better definition of relapse. In the literature, relapse has been defined in several ways, in particular, because of the need of hospitalization due to relevant clinical deterioration of the patient, increase in the severity of psychopathology, more intense management and most demanding of resources, and reduced social role function (Bustillo et al. 1995; Gleeson et al. 2010; Karow et al
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
Table II. Detailed of the 34 items selected as risk factors for the prediction of relapse. Variables Sociodemographic data (1 item) Social support Clinical data (20 items) Onset (acute or gradual) Age at onset Duration of untreated psychosis Duration of untreated disease Duration of prodromal symptoms Low insight Psychosocial stressors PANSS/BPRS scores Positive psychotic symptoms Thoughts disturbance Negative psychotic symptoms Catatonic symptoms Perplexity Behavioral disorders Suicidal ideation Substance abuse (alcohol) Substance abuse (cannabis) Adherence to medication CGI GAF/functioning Premorbid adjustment (2 items) PAS Violent behavior Cognitive function (1 item) Minor neurological signs Clinical course (10 items) Time to therapeutic response Symptomatic improvement Insight improvement Improvement of GAF/functioning Discontinuation of treatment Residual symptoms between episodes Extrapyramidal symptoms during the first 16 weeks of treatment Risky behavior Grade of social contact Regular follow-up
Final score (sum of ⱖ 16 for all experts) 17 16 18 17 17 16 20 17 20 19 20 16 17 17 19 16 22 22 23 20 21 16 16 16 17 16 19 18 22 18 17 17 18 21
2012; Koening et al. 2011; Lader 1995; Lafeuille et al. 2013; Lader 1998; Olivares et al. 2013; Thomas 2013). The present study was designed to reach a definition of relapse, both from a pragmatic and operational definition of relapse using a Delphi approach procedure. Previous studies have used a Delphi process to characterize relapse (Burns et al. 2000), to identify essential components of schizophrenia care (Fiander and Burns 1998), and to define the components of cognitive behavioral therapy for psychosis (Morrison and Barratt 2010). We used a two-round Delphi methods in which a panel of eight experts defined (a) the components that should be included in a definition of relapse, (b) evaluated seven models of definitions of relapse, and (c) selected risk factors for relapse. The purpose of this first round was to reach a consensus regarding core components to characterize an episode of relapse and an operational definition of relapse. In relation to core components to define a situation of relapse, the areas that were considered indispensable between
93
61% and 70% of the participants in round 2 referred to the following items: presence of a previously stabilized clinical status, psychopathological severity of the psychotic spectrum, more intense management, impaired functioning and social behavior, and use of the terms “worsening” or “exacerbation” to define better the concept of appearance of new symptoms. Also, in the study of Burns et al. (Burns et al. 2000), increase in positive symptoms was at the heart of relapse but not considered sufficient in itself. Association with secondary level changes referred to an “uncharacteristic” indicating a deviation from an individual’s usual functioning was required. In a systematic review and meta-analysis of 29 studies involving 3978 participants (Alvarez Jimenez et al. 2012), clinical variables and general demographic variables had little impact on relapse rates. Conversely, non-adherence with medications, persistence substance use disorder, and poorer premorbid adjustment significantly increased the risk of relapse in patients diagnosed of the first episode of psychosis. In a study of Fiander et al. (Fiander and Burns 1998) using a three-round questionnaire based on a Delphi method, essential components of schizophrenia care were identified, which included range of accommodation, medication compliance/ optimizing medication, outreach in the community, proper assessment (in-depth and multidisciplinary), psychosocial package (for patient and carer), long stay in-patient care, rapid response, fail-safe follow-up systems, range of rehabilitation opportunities, and range of occupational leisure and work opportunities. In our study, at the time of depuration of variables related to the risk of relapse, adherence to medication and regular follow-up were two items which the expert panel consistently rated as very relevant. It is of note that a very low percentage of psychiatrists (between 0% and 9%) who participated in round 2, considered “poorly relevant” reappearance of symptoms (including positive symptoms), and worsening of severity status of the disease and functioning measured by different scales in the framework of an operational definition of relapse. The reappearance of schizophrenic symptoms in a symptom-free patient after the initial episode, rated as indispensable by 71% of participants, is consistent with data reported in the literature (Emsley et al. 2013; Lader 1995). Also, the presence of positive symptoms measured by clinical scales, rated as recommendable or indispensable by 91% of psychiatrists, also agrees with data reported by others (Ayuso-Gutiérrez and del Río Vega 1997; Burns et al. 2000; Emsley et al. 2013; Lader 1995; Robinson et al. 1999; Zubin et al. 1992). Other results of our study including an increase of ⱖ 10 points in the positive subscale of PANSS reported by 51% of participants, a score 6 (much worse) in the assessment of change of the CGI scale by 89%, and a reduction of ⱖ 20 points in the GAF scale by 62% is also consisted with data found in the literature (Chabungbam et al. 2007; Csernansky et al 2002; Emsley et al 2012; Wunderink et al. 2007). However, in relation to definition of a minimum time for the reappearance of positive schizophrenic symptoms and worsening in disease severity and functioning, 72% of respondents indicated 1 week and 28% 2 weeks, whereas in studies reported by others, the minimum necessary time is defined as 2 weeks (Emsley et al 2013; Olivares et al 2013).
94
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table III. Questions and ratings developed by the expert panel presented to participants in round 2 related to pragmatic and operational definitions of relapse. Pragmatic definition In the field of schizophrenia, do you consider that there is a valid, reliable, and clinically useful definition of relapse? Do you consider it necessary to work to develop a better definition of relapse in the field of schizophrenia?
Ratings Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
What components do you consider should be present in any definition of relapse? Existence of a previously stabilized clinical situation Persistence of residual symptoms Psychopathological severity of the psychotic spectrum. Specific exacerbation of clear psychotic clinical features, such asdelirium, hallucinations, conceptual disorganization, strange behavior, insertion of thoughts, and alterations in the course and content of thoughts How would you rate the term “worsening” to define the concept of “appearance of new symptoms”? How would you rate the term the term “exacerbation” to define better the concept of “appearance of new symptoms”? How would you rate the term “reappearance” to define better the concept of “appearance of new symptoms”? How would you rate the term “significant clinical deterioration” to define better the concept of “appearance of new symptoms”? Affective-suicidal risk symptomatology (includes suicidal attempts or exacerbation of depressive symptoms) More intense management of the case (changes in resources consumption: hospitalization, day hospital; more active action: increase in the follow-up frequency, increase of care or caregivers; changes of therapeutic regimen) Impairment in functioning and social behavior (reduction of social functioning, behavioral disturbance, or social crisis)
Ratings Poorly relevant
Recommendable
Indispensable
Poorly relevant Poorly relevant
Recommendable Recommendable
Indispensable Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Operational definition Reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode Reappearance includes positive schizophrenic symptoms measured by clinical scales (PANSS, BPRS, etc.) Increase in positive symptoms of PANSS (positive subscale) Worsening of severity status of the disease measured by scales such CGI Worsening of the severity status of the disease measured by the physician with the CGI scale, score change Worsening of functioning measured by scales, such as GAF, SOFAS, or PSP Worsening of functioning measured with the GAF scale A minimum period of time should be considered for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning Minimum time necessary for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning
Ratings Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
ⱖ 5 points
ⱖ 10 points
ⱖ 15 points
ⱖ 20 points
Indispensable
Recommendable
Poorly relevant
5 (minimally worse)
6 (much worse)
7 (very much worse)
Poorly relevant
Recommendable
Indispensable
Reduction ⱖ 10 points
Reduction ⱖ 20 points
Reduction ⱖ 30 points
Poorly relevant
Recommendable
Indispensable
1 week
2 weeks
3 weeks
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
95
Table IV. Assessment of definitions for the different models of pragmatic relapse by the eight experts. Ratings Models
1 ⫽ good
2 ⫽ acceptable
3 ⫽ poor
Model I: general complete definition Model II: simple complete definition Model III: extensive complete definition Model IV: simple definition Model V: narrow definition Model VI: concrete simplified definition Model VII: general simplified definition
8 (100)
0
0
8 (100)
0
0
5 (62.5)
3 (37.5)
0
6 (75) 3 (37.5) 1 (12.5)
0 2 (25) 5 (62.5)
2 (25) 3 (37.5) 2 (25)
0
4 (50)
4 (50)
Percentages in parenthesis. Definitions of models in Table I.
Consensus was reached on a pragmatic definition of relapse, which refers to the situation that occurs in a patient in a stage of remission that develops new symptoms, which fulfill criteria of a psychotic episode, with a significant impairment in functioning and social behavior, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources, occurring during the last 6 months. In relation to operational definition of relapse, the majority of participants agreed on the reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode, presence of positive symptoms measured as an increase of ⱖ 10 points in the PANSS scale, worsening of psychopathological severity of the spectrum of psychotic symptoms (score 6 in the CGI scale),
Figure 1. Responses of participants in round 2 to the questions of whether there was a valid, reliable, and clinically useful definition of relapse, and the need to develop a better definition of relapse.
worse functioning measured as an increase of ⱖ 20 points in the GAF scale, and a necessary minimum period of time for the reappearance of schizophrenic symptoms. There are several limitations to this study. The ad hoc selection of the expert panel and general psychiatrists who participated in round 1 and 2, respectively, may have excluded many clinical experts with sufficient experience in the field of schizophrenia. It should also be noted that this study identified what experts think are intrinsic elements of components of a definition of relapse, but are clearly not concerned with what constitutes the essential components in terms of efficacy of medication or adherence to antipsychotic
Table V. Components that should be present in any definition of relapse. Opinion of the participants in round 2. Category of response Component of the definition Existence of a previously stabilized clinical situation Persistence of residual symptoms Psychopathological severity of the psychotic spectrum. Specific exacerbation of clear psychotic clinical features, such as delirium, hallucinations, conceptual disorganization, strange behavior, insertion of thoughts and alterations in the course and content of thoughts Rating of the term “worsening” to define the concept of “appearance of new symptoms”? Rating of the term the term “exacerbation” to define better the concept of “appearance of new symptoms”? Rating of the term “reappearance” to define better the concept of “appearance of new symptoms”? Rating of the term “significant clinical deterioration” to define better the concept of “appearance of new symptoms”? Affective-suicidal risk symptomatology (includes suicidal attempts or exacerbation of depressive symptoms) More intense management of the case (changes in resources consumption: hospitalization, day hospital; more active action: increase in the follow-up frequency, increase of care or caregivers; changes of therapeutic regimen) Impairment in functioning and social behavior (reduction of social functioning, behavioral disturbance, or social crisis) Data expressed as percentage.
Indispensable
Recommendable
Poorly relevant
67 14 70
30 46 27
3 40 3
61 65
24 29
15 6
44
21
35
52
27
21
35
38
26
68
32
0
67
27
6
96
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table VI. Assessment of definitions for the different models of pragmatic relapse by the expert panel (Round II). Models of pragmatic relapse Model I: general complete definition Model II: simple complete definition Model III: extensive complete definition Model IV: simple definition
Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
31 21 17 17
54 58 57 31
11 21 14 40
3 0 11 11
Data expressed as percentage. Definitions of models in Table I
Table VII. Operational definition of relapse: opinion of participants in round 2. Category of response
Reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode Reappearance includes positive schizophrenic symptoms measured by clinical scales (PANSS, BPRS, etc.) Worsening of severity status of the disease measured by scales such CGI Worsening of functioning measured by scales, such as GAF, SOFAS, and PSP A minimum period of time should be considered for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning
Indispensable
Recommendable
Poorly relevant
71
26
3
24
67
9
53 49 54
47 46 40
0 6 6
Data expressed as percentages.
treatment. It is also likely that the profile of agreed aspects of the pragmatic and operational definitions of relapse for patients with schizophrenia may differ between countries, so the exclusively Spanish-based sample is also a limitation. The decision regarding the selection of items and the formulation of questions was a subjective one taken by the eight members of the expert panel, which probably reflect the areas with highest personal experience or the clinical setting in which more studies have been done. The Delphi process was used in finding a consensus for pragmatic and operational definitions of relapse
in patients with schizophrenia. The applicability of the present results to clinical practice should be evaluated individually and reviewed periodically in the light of new emerging evidence. However, a better understanding of specific conceptual and practical components for establishing a valid, reliable, and useful definition of relapse will contribute to the development of more effective prevention strategies for patients with schizophrenia in daily practice. Although experts’ opinions collected in a consensus like those reported here have a low grade of evidence, due
Figure 2. Ratings of participants in round 2 regarding scores of different scales and time period required for reappearance of symptoms.
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
to the absence of other type of assessment we consider this study a first step in a long process to reach the level of evidence required. Relapse represents burden and costs for patients, their environment, and society in general and seems to increase illness progression at the biological level; in other words, relapse prevention is one of the major treatment objectives and we try to just introduce a systematic study of this phenomenon. There are many unanswered questions regarding the nature of relapse making further studies of this component of the illness imperative. In summary, the present study was designed to reach a definition of relapse using a Delphi approach procedure with two rounds due to the absence of an operational definition. The core characteristics of relapse identified as indispensable criteria by participants were as follows: the reappearance of schizophrenia symptoms in patients who have been symptom-free after an initial episode (71% of participants), need to consider a minimum period of time for reappearance of schizophrenia symptoms (54%), worsening of severity clinical status (53%), worsening of functioning (49%), and reappearance of positive symptoms (24%). Operational definitions and assessment of relapse in schizophrenia are very heterogeneous, which limit comparison of study results. Probably the steps needed to reach a consensus in this field require a specific study designed with this objective including a large sample of experts in this field. Key points •
•
•
•
•
A pragmatic and operational definition of relapse in schizophrenia that can be applied to clinical research and in clinical daily practice was developed using a two-round Delphi consensus approach. Psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), impairment in functioning and social behavior (67%), presence of the term “exacerbation” (65%), and presence of the term “worsening” (61%) were considered indispensable individual components of a pragmatic definition. In relation to operational definition, reappearance of symptoms in symptom-free patients after an initial episode was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was rated as recommendable by 67%. In relation to changes in the different scales, an increase of ⱖ 10 points in the positive subscale of PANSS was rated by 51% of the participants, a score of 6 points in the CGI (much worse) by 89%, and a reduction of ⱖ 20 points in the GAF scale by 62%. Seventy-two percent of participants considered a minimum of 1 week for reappearance of schizophrenic symptoms. Participants strongly agree (76%) that developing a better definition of relapse was needed.
97
Acknowledgments The authors acknowledge Content’Ed Net Communications, S.L., for editorial assistance and Marta Pulido, MD, for editing the manuscript. Statement of interests Janssen-Cilag. provided unrestricted support to the meeting and development of this consensus paper. Dr. San has served as a consultant or speaker for Alexza, AstraZeneca, Bristol-Myers-Squibb, Ferrer, Janssen-Cilag, Lilly, Lundbeck, Organon, Otsuka, Pfizer, Servier, and Wyeth and has received grant support from AstraZeneca, Ferrer, FIS, Janssen-Cilag, Lilly, Health Ministry, Otsuka, and Pfizer. Dr. Cañas has served as a consultant or speaker for Janssen, Lundbeck, Otsuka, Pfizer, and Servier. Dr. Romero has served as speaker for Janssen-Cilag, Pfizer, and Lundbeck. Dr. Villar has served as speaker for Janssen-Cilag and has received hospitality and honoraria from various pharmaceutical firms. Dr Sanchez-Cabezudo has served as speaker for Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Lilly, and Bristol-Meyers. The other authors declared no conflict of interests. References Agid O, Foussias G, Remington G. 2010. Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention. Expert Opin Pharmacother 11:2301–2317. Almond S, Knapp M, Francois C, Toumi M, Brugha T. 2004. Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br J Psychiatry 184:346–351. Alvarez Jimenez M, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, et al. 2012. Risk factors for relapse following treatment for first-episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res 139:116–128. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 162:441–449. Ayuso-Gutiérrez JL, del Río Vega JM. 1997. Factors influencing relapse in long-term course of schizophrenia. Schizophr Res 28:199–206. Burns T, Fiander M, Audini B. 2000. A Delphi approach to characterising ‘relapse’ and used in UK clinical practice. Int J Soc Psychiatry 46:220–230. Bustillo J, Buchanan RW, Carpenter WT Jr. 1995. Prodromal symptoms vs. early warning signs and clinical action in schizophrenia. Scizhophr Bull 21:553–559. Chabungbam G, Avasthi A, Sharan P. 2007. Sociodemographic and clinical factors associated with relapse in schizophrenia. Psychiatry Clin Neurosci 61:587–593. Csernansky J, Mahmoud R, Brenner R, Risperidone-USA-79 Study Group. 2002. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 346:16–22. Dalkey N, Brown B, Cochran S. 1969. The Delphi method, III: use of self ratings to improve group estimates. Santa Monica, CA: Rand Corp. Publication RM-6115-PR. Dilla T, Ciudad A, Alvarez M. 2013. Systematic review of the economic aspects of nonadherence to antipsychotic medication in patients with schizophrenia. Patient Prefer Adherence 7:275–284. Emsley R, Chiliza B, Asmal L, Harvey BH. 2013. The nature of relapse in schizophrenia. BMC Psychiatry 13:50. Emsley R, Oosthuizen PP, Koen L, Niehaus DJH, Martinez G. 2012. Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-yer openlabel clinical study. J Clin Psychiatry 73:e541–e547.
98
L. San et al.
Fiander M, Burns T. 1998. Essential components of schizophrenic care: a Delphi approach. Acta Psychiatr Scand 98: 400–405. Gleeson JF, Alvarez-Jimenez M, Cotton SM, Parker AG, Hetrick S. 2010. A systematic review of relapse measurement in randomized controlled trials of relapse prevention in first-episode psychosis. Schizophr Res 119:79–88. Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. 2013. Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther Adv Psychopharmacol 3:200–18. Hong J, Windmeijer F, Novick D, Haro JM, Brown J. 2009.The cost of relapse in patients with schizophrenia in the European SOHO (Schizophrenia Outpatient Health Outcomes) study. Prog Neuropsychopharmacol Biol Psychiatry 33:835–841. Karow A, Moritz S, Lambert M, Schöttle D, Naber D. 2012. Remitted but still impaired? Symptomatic versus functional remission with schizophrenia. Eur Psychiatry 27:401–405. Koening M, Casyillo MC, Urdapilleta I, le Borgne P, Bouleau JH. 2011. Relapse in schizophrenia: an exploratory study of the joint conceptions of patients: parents and caregivers. [Article in French]. Encephale 37:207–216. Lader M. 1995. What is relapse in schizophrenia? Int Clin Psychopharmacol 9:5–9. Lader M. 1998. Pharmacological prevention of relapse. Kaohsiung J Med Sci 14:448–457. Lafeuille MH, Gravel J, Lefebvre P, Fastenau J, Muser E, Doshi D, Duh MS. 2013. Patterns of relapse and associated cost burden in
Int J Psychiatry Clin Pract 2015;19:90–98
schizophrenia patients receiving atypical antipsychotics. J Med Econ 16:1290–1299. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. 2003. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 160:1209–1222. Morrison AP, Barratt S. 2010. What are the components of CBT for psychosis? A Delphi study. Schizophr Bull 36:136–142. Olivares JM, Sermon J, Hemels M, Schreiner A. 2013. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry 12:32. Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al. 1999. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 56:241–247. Smeraldi E, Cavallaro R, Folnegović-Šmalc V, Bidzan L, Emin Ceylan M, Schreiner A. 2013. Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Ther Adv Psychopharmacol 3:191–199. Thomas P. 2013. Relapse: causes and consequences. [Article in French]. Encephale 39:S79–S82. Wunderink L, Nienhuis FJ, Sytema S, Slooff C, Knegtering R, Wiersma D. 2007. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 68:654–661. Zubin J, Steinhauer SR, Condray R. 1992. Vulnerability to relapse in schizophrenia. Br J Psychiatry 161:13–18.
Copyright of International Journal of Psychiatry in Clinical Practice is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ORIGINAL ARTICLE
Towards a pragmatic and operational definition of relapse in schizophrenia: A Delphi consensus approach
informahealthcare.com/ijpcp
Luis San1, Manuel Serrano2, Fernando Cañas3, Samuel Leopoldo Romero4, Ángeles Sánchez-Cabezudo5 & Mariano Villar6 1
Department of Child and Adolescent Psychiatry, Hospital Sant Joan de Déu, CIBERSAM, Barcelona, Spain, 2Head of Psychiatry Department, Complejo Universitario Hospitalario de A Coruña, Spain, 3 Department of Psychiatry, Hospital “Dr. R. Lafora”, and Universidad Francisco de Vitoria School of Medicine, Madrid. Spain, 4Department of Psychiatry, U.G.C. Hospital Virgen Macarena, Seville, Spain, 5 Department of Psychiatry, Complejo hospitalario de Toledo, Spain, and 6Department of Psychiatry, Policlinica psiquiátrica. Hospital provincial de Castellón, Spain Abstract Objective. To develop pragmatic and operational definitions of relapse in schizophrenia. Methods. A two-round Delphi consensus approach was used. The final questionnaire based on seven pre-established definition relapse models developed by a panel of eight experts was presented to 33 general psychiatrists who attended an “ad hoc” meeting. Results. The most frequent components of the pragmatic definition were the psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), and impairment in functioning and social behavior (67%). In the operational definition, reappearance of symptoms was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was considered recommendable by 67%. Between 46% and 53% rated worsening of severity status and worsening of functioning as indispensable or recommendable. An increase of ⱖ 10 points in the positive subscale of Positive and Negative Symptom Scale was rated by 51% of the participants, a score of 6 points in the Clinical Global Impression scale (much worse) by 89%, and a reduction of ⱖ 20 points in the Global Assessment of Functioning scale by 62%. Conclusions. A better understanding of the definition of relapse in schizophrenia is necessary to improve effective prevention strategies. Key words: Schizophrenia, relapse, treatment outcome (Received 17 March 2014; accepted 16 December 2014)
Introduction Relapse, characterized by an acute psychotic exacerbation, is a highly prevalent component of the course of the disease in patients with schizophrenia. The nature of these episodes, however, has not been fully characterized and clinicians may not always be aware of important implications of recurrent relapses in the outcome of patients (Emsley et al. 2013). Relapses are associated with worsening of symptoms, cognitive deterioration, impaired functioning, and reduced quality of life (Lader 1995; Olivares et al. 2013). Moreover, relapse is one of the most costly aspects of schizophrenia, mainly due to the need of admission to the hospital for the patient’s care (Almond et al. 2004; Hong et al. 2009). Improving medication adherence and relapse prevention have been consistently emphasized as key therapeutic objectives in the management of schizophrenia (Agid et al. 2010; Dilla et al. 2013; Higashi et al. 2013; Leucht et al. 2003; Smeraldi et al. 2013). Our current understanding of the complex interactions of many personal and environmental factors, including Correspondence: Dr. Luis San, Department of Child and Adolescent Psychiatry, Hospital Sant Joan de Déu, CIBERSAM, Passeig Sant Joan de Déu 2, E-08950 Esplugues del Llobregat, Barcelona, Spain. Tel: ⫹ 34 93 32806349. Fax: ⫹ 34 93 6009454. E-mail: [email protected]
early warning signs to predict a relapse, are frequently insufficient to identify patients at risk and, therefore, to develop effective strategies to manage this problem (Alvarez Jimenez et al. 2012; Emsley et al. 2013; Gleeson et al. 2010; Robinson et al. 1999). This picture is further complicated by the lack of consensus about what constitutes a relapse and no established definite criteria by which to define a relapse. A recent systematic review of the literature identified numerous factors that have been used to define relapse (Olivares et al. 2013). Hospitalization (and exacerbation of symptoms leading hospitalization) was the factor most frequently used to define relapse. Other factors included assessment of symptom severity especially positive symptoms using different scales, such as the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI) (including CGI-Severity and CGIImprovement), Brief Psychiatric Rating Scale (BPRS), and Global Assessment of Functioning (GAF) scale, as well as changes in behavioral pattern, adherence problems, stress/ depression, substance use, poor patient insight, and history of hospitalization or relapse, among others. This excellent review (Olivares et al. 2013) has highlighted that there is still an ongoing debate of what elements truly comprise a relapse episode in schizophrenia.
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
The present study was conducted with the aim of developing pragmatic and operational definitions of relapse in schizophrenia that can be applied in clinical daily practice and in clinical research. A Delphi process was used to elicit and quantify the opinions of a group of expert psychiatrists working in Spain. The results obtained will further contribute to increase our knowledge of the symptomatic, phenomenological, and behavioral levels of the term “relapse,” as well as to develop strategies to reduce the risk of relapse in the real-world setting. Methods Design and organization of the study A two-round Delphi technique was used to reach agreement among members of the Spanish Society of Psychiatry with recognized experience in clinical psychiatry throughout Spain, about the pertinence of establishing a definition (pragmatic and operational) of relapse in schizophrenia and to identify the essential elements for such a definition. The Delphi method is a technique to arrive at a group of consensus regarding an issue under investigation that was originally developed at the Rand Corporation in the 1950s (Dalkey et al. 1969). It is a structured, systematic, and multistage process where a panel of experts are invited to take part in a series of rounds to identify, clarify, and finally reach a consensus for a subject matter in which precise information is lacking or inconsistent. The method relies on soliciting anonymous individual answers to questions by survey. Consensus is sought through the feedback of information and iteration. The study was conducted in four phases: (1) formation of the scientific committee composed of eight expert consultant psychiatrists with academic positions and large experience in research and clinical practice in the field of schizophrenia, selection of an external methodological expert for review of the literature, and distribution of the relevant articles subjected to debate; (2) “idea-generating” stage comprising definition of relapse into two concepts: pragmatic definition (with the main focus on clinical practice) and operational definition (with the main focus on research), and development of six essential items that any definition of relapse should contain and seven definitions of relapse models; (3) development of a list of items for the prediction of relapse; (4) with the feedback of each of the expert’s responses on components, definitions, and risk factors for relapse, a series of questions related to proposals of pragmatic and operational definitions were developed; (5) the final questions were electronically presented to 33 general psychiatrists who attended an “ad hoc” meeting, which was held in Lisbon on June 1, 2013, in the framework of the VIVE project, using the PowerVote voting system; and (6) collection of data, analysis of final results, and summary of findings. The VIVE project, supported by Janssen, involves the active participation of more than 300 Spanish psychiatrists and includes a series of continuing education, release of information, and research activities aimed at improving the care of individuals with schizophrenia, especially to achieve integration based on sustained treatment of people with psychotic disorder.
91
Round 1 All eight experts rated six previously defined components that should be present in any definition of relapse on a scale of 1 to 3 (where 1 ⫽ necessary [essential], 2 ⫽ additional, and 3 ⫽ unnecessary). Also, the expert panel rated seven pre-established models to define relapse on a scale of 1 to 3 (where 1 ⫽ good, 2 ⫽ acceptable, and 3 ⫽ poor). Components and models of definition of relapse are shown in Table I. A final list of questions addressed to reach a pragmatic definition of relapse on which there was strong agreement among the experts was developed. In relation to risk factors for relapse, a series of 66 items regarding sociodemographic factors, clinical data, premorbid adjustment, personality traits, cognitive function, biological markers, neuroimaging data, and clinical course were previously developed by one of the experts, and then rated by each of the experts on a scale of 1 to 3 (where 1 ⫽ poorly relevant, 2 ⫽ quite relevant, and 3 ⫽ very relevant). Items with a sum score of at least 16 were selected (Table II). The expert panel finally developed a list of nine questions related to the operational definition of relapse. Round 2 The finalized questionnaire containing questions identified in the two steps of round 1 was constructed and formatted for a Power Point presentation at the Lisbon meeting. Details and ratings for each question are shown in Table III. Of the different choices, usually three or four, only one category could be selected. A descriptive analysis was undertaken. Results Round 1 In relation to the components that should contain a definition of relapse, the following four criteria were scored 1 (necessary) by all experts: 1) previously stabilized condition or persistence of residual symptoms, 2) severity of psychopathology and/or appearance of significant clinical symptoms of mental health deterioration, 3) implication in functioning and social behavior, and 4) more intensive management of the case with changes in the consumption of resources or in the therapeutic regimen. Inclusion of the minimal duration of the episode was considered necessary by 40% of the experts and additional by the remaining 60%. In relation to the period of appearance, 25% rated this item as necessary, 60% as additional, and one expert as unnecessary. Table IV shows the results of the assessment of pragmatic relapse models by the expert panel. Models I and II were rated 1 (good) by all experts (one of the experts suggested to substitute the term “relapse” by a synonymous or homonymous concept). Models III and IV were rated 1 (good) by 62.5% and 75% of the experts, respectively. Models V, VI, and VII were mostly rated 2 (acceptable). Round 2 Participants in the second round of the process had different opinions regarding the existence of a definition of relapse but strongly agree (76%) that developing a better definition of
92
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table I. Round 1 (expert panel): components and definition of relapse models. Components that should contain a definition of relapse (rated as 1 ⫽ necessary, 2 ⫽ additional, and 3 ⫽ unnecessary) Previous stabilized condition or persistence of residual symptoms Severity of psychopathology and/or development of significant clinical symptoms of deterioration of mental status Implication in functioning and social behavior More intensive management of the case with changes in the consumption of resources or changes in the therapeutic regimen Minimal duration of the episode Period of appearance Definitions of models of relapse (rated as 1 ⫽ good, 2 ⫽ acceptable, and 3 ⫽ poor) Model 1: General complete definition “Relapse defines the situation that occurs in a patient previously diagnosed with psychotic disorder and in a stage of remission (without symptoms or only residual symptoms) who develops new symptoms, which fulfil criteria of a psychotic episode (delusions, hallucinations, conceptual disorganization, insertion of thoughts, posturing), with a significant impairment of functioning and social behaviour, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources (modification of treatment and/or change in the level of care) that occurred during the last 6 months” Model II: Simple complete definition “Relapse defines the situation that occurs in a patient in a stage of remission that develops new symptoms, which fulfil criteria of a psychotic episode, with a significant impairment in functioning and social behaviour, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources, occurring during the last 6 months” Model III: Extensive complete definition “Relapse expresses a change from a previously stabilized condition, with absence of symptoms, to reappearance of psychotic symptoms or significant clinical features of mental status deterioration (including suicidal attempts or exacerbation of depressive symptoms), with a clear impairment in functioning and social behaviour, lasting at least 1 week, in the last 6 months and that obliges to a change in the clinical management” Model IV: Simple definition “Relapse is defined as a reappearance or exacerbation of persistent symptoms in a symptom-free patient or with residual symptoms after a psychotic episode, which causes a change in functioning or social deterioration, lasting at least 7 days and determining a change in the health care management, in the last 6 months” Model V: Narrow definition “Relapse expresses a change from a previously stabilized situation, with absence of symptoms or persistence of negative residual symptoms to a clear deterioration, so that the patient needs to be hospitalized or medication should be substantially modified, lasting at least 1 week” Model VI: Concrete simplified definition “Relapse expresses a change from a previously stabilized condition to an increase in the florid psychotic symptoms, which causes a change in functioning or social deterioration, lasting at least 7 days” Model VII: General simplified definition “Relapse expresses a change from a previously stabilized status to the appearance of new symptoms or behavioural patterns interfering functioning, lasting at least one week and occurring in the last 6 months”
relapse was needed (Figure 1). The most frequent individual components rated as indispensable in a definition of relapse were the psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), impairment in functioning and social behavior (67%), presence of the term “exacerbation” (65%), and presence of the term “worsening” (61%). In contrast, poorly relevant components included residual symptoms (40%), presence of the term “reappearance” (35%), affective-suicidal risk symptoms (26%), and presence of the term “significant clinical deterioration” (21%) (Table V). Table VI shows the results of the assessment of pragmatic relapse models by the expert panel. Models I, II, and III were rated as “agree” for more than 2/3 parts of the expert panel (85%, 79%, and 74%, respectively). Model IV was accepted and rejected by half of the expert panel (48% and 52%, respectively). In relation to operational definition of relapse (Table VII), reappearance of symptoms in symptom-free patients after an initial episode was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was rated as recommendable by 67%. Between 46% and 53% rated worsening of severity status and worsening of functioning as indispensable or recommendable. Also, 54% considered indispensable to state a minimum
period of time for reappearance of schizophrenic symptoms. In relation to changes in the different scales (Figure 2), an increase of ⱖ 10 points in the positive subscale of PANSS was rated by 51% of the participants, a score of 6 points in the CGI (much worse) by 89% and a reduction of ⱖ 20 points in the GAF scale by 62%. Seventy-two percent of participants considered a minimum of 1 week for reappearance of schizophrenic symptoms (Figure 2). Discussion The term relapse is used extensively in psychiatric practice and as a main outcome criterion in schizophrenia studies, although it is rarely defined, which is in contrast to wellknown Andreasen symptomatic remission criteria (Andreasen et al. 2005). In fact, the concept of relapse expresses a sufficiently noticeable change from a previously stabilized condition and, therefore, has to be examined qualitatively and quantitatively. Overall, 76% of participants strongly agreed on the need to establish a better definition of relapse. In the literature, relapse has been defined in several ways, in particular, because of the need of hospitalization due to relevant clinical deterioration of the patient, increase in the severity of psychopathology, more intense management and most demanding of resources, and reduced social role function (Bustillo et al. 1995; Gleeson et al. 2010; Karow et al
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
Table II. Detailed of the 34 items selected as risk factors for the prediction of relapse. Variables Sociodemographic data (1 item) Social support Clinical data (20 items) Onset (acute or gradual) Age at onset Duration of untreated psychosis Duration of untreated disease Duration of prodromal symptoms Low insight Psychosocial stressors PANSS/BPRS scores Positive psychotic symptoms Thoughts disturbance Negative psychotic symptoms Catatonic symptoms Perplexity Behavioral disorders Suicidal ideation Substance abuse (alcohol) Substance abuse (cannabis) Adherence to medication CGI GAF/functioning Premorbid adjustment (2 items) PAS Violent behavior Cognitive function (1 item) Minor neurological signs Clinical course (10 items) Time to therapeutic response Symptomatic improvement Insight improvement Improvement of GAF/functioning Discontinuation of treatment Residual symptoms between episodes Extrapyramidal symptoms during the first 16 weeks of treatment Risky behavior Grade of social contact Regular follow-up
Final score (sum of ⱖ 16 for all experts) 17 16 18 17 17 16 20 17 20 19 20 16 17 17 19 16 22 22 23 20 21 16 16 16 17 16 19 18 22 18 17 17 18 21
2012; Koening et al. 2011; Lader 1995; Lafeuille et al. 2013; Lader 1998; Olivares et al. 2013; Thomas 2013). The present study was designed to reach a definition of relapse, both from a pragmatic and operational definition of relapse using a Delphi approach procedure. Previous studies have used a Delphi process to characterize relapse (Burns et al. 2000), to identify essential components of schizophrenia care (Fiander and Burns 1998), and to define the components of cognitive behavioral therapy for psychosis (Morrison and Barratt 2010). We used a two-round Delphi methods in which a panel of eight experts defined (a) the components that should be included in a definition of relapse, (b) evaluated seven models of definitions of relapse, and (c) selected risk factors for relapse. The purpose of this first round was to reach a consensus regarding core components to characterize an episode of relapse and an operational definition of relapse. In relation to core components to define a situation of relapse, the areas that were considered indispensable between
93
61% and 70% of the participants in round 2 referred to the following items: presence of a previously stabilized clinical status, psychopathological severity of the psychotic spectrum, more intense management, impaired functioning and social behavior, and use of the terms “worsening” or “exacerbation” to define better the concept of appearance of new symptoms. Also, in the study of Burns et al. (Burns et al. 2000), increase in positive symptoms was at the heart of relapse but not considered sufficient in itself. Association with secondary level changes referred to an “uncharacteristic” indicating a deviation from an individual’s usual functioning was required. In a systematic review and meta-analysis of 29 studies involving 3978 participants (Alvarez Jimenez et al. 2012), clinical variables and general demographic variables had little impact on relapse rates. Conversely, non-adherence with medications, persistence substance use disorder, and poorer premorbid adjustment significantly increased the risk of relapse in patients diagnosed of the first episode of psychosis. In a study of Fiander et al. (Fiander and Burns 1998) using a three-round questionnaire based on a Delphi method, essential components of schizophrenia care were identified, which included range of accommodation, medication compliance/ optimizing medication, outreach in the community, proper assessment (in-depth and multidisciplinary), psychosocial package (for patient and carer), long stay in-patient care, rapid response, fail-safe follow-up systems, range of rehabilitation opportunities, and range of occupational leisure and work opportunities. In our study, at the time of depuration of variables related to the risk of relapse, adherence to medication and regular follow-up were two items which the expert panel consistently rated as very relevant. It is of note that a very low percentage of psychiatrists (between 0% and 9%) who participated in round 2, considered “poorly relevant” reappearance of symptoms (including positive symptoms), and worsening of severity status of the disease and functioning measured by different scales in the framework of an operational definition of relapse. The reappearance of schizophrenic symptoms in a symptom-free patient after the initial episode, rated as indispensable by 71% of participants, is consistent with data reported in the literature (Emsley et al. 2013; Lader 1995). Also, the presence of positive symptoms measured by clinical scales, rated as recommendable or indispensable by 91% of psychiatrists, also agrees with data reported by others (Ayuso-Gutiérrez and del Río Vega 1997; Burns et al. 2000; Emsley et al. 2013; Lader 1995; Robinson et al. 1999; Zubin et al. 1992). Other results of our study including an increase of ⱖ 10 points in the positive subscale of PANSS reported by 51% of participants, a score 6 (much worse) in the assessment of change of the CGI scale by 89%, and a reduction of ⱖ 20 points in the GAF scale by 62% is also consisted with data found in the literature (Chabungbam et al. 2007; Csernansky et al 2002; Emsley et al 2012; Wunderink et al. 2007). However, in relation to definition of a minimum time for the reappearance of positive schizophrenic symptoms and worsening in disease severity and functioning, 72% of respondents indicated 1 week and 28% 2 weeks, whereas in studies reported by others, the minimum necessary time is defined as 2 weeks (Emsley et al 2013; Olivares et al 2013).
94
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table III. Questions and ratings developed by the expert panel presented to participants in round 2 related to pragmatic and operational definitions of relapse. Pragmatic definition In the field of schizophrenia, do you consider that there is a valid, reliable, and clinically useful definition of relapse? Do you consider it necessary to work to develop a better definition of relapse in the field of schizophrenia?
Ratings Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
What components do you consider should be present in any definition of relapse? Existence of a previously stabilized clinical situation Persistence of residual symptoms Psychopathological severity of the psychotic spectrum. Specific exacerbation of clear psychotic clinical features, such asdelirium, hallucinations, conceptual disorganization, strange behavior, insertion of thoughts, and alterations in the course and content of thoughts How would you rate the term “worsening” to define the concept of “appearance of new symptoms”? How would you rate the term the term “exacerbation” to define better the concept of “appearance of new symptoms”? How would you rate the term “reappearance” to define better the concept of “appearance of new symptoms”? How would you rate the term “significant clinical deterioration” to define better the concept of “appearance of new symptoms”? Affective-suicidal risk symptomatology (includes suicidal attempts or exacerbation of depressive symptoms) More intense management of the case (changes in resources consumption: hospitalization, day hospital; more active action: increase in the follow-up frequency, increase of care or caregivers; changes of therapeutic regimen) Impairment in functioning and social behavior (reduction of social functioning, behavioral disturbance, or social crisis)
Ratings Poorly relevant
Recommendable
Indispensable
Poorly relevant Poorly relevant
Recommendable Recommendable
Indispensable Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
Operational definition Reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode Reappearance includes positive schizophrenic symptoms measured by clinical scales (PANSS, BPRS, etc.) Increase in positive symptoms of PANSS (positive subscale) Worsening of severity status of the disease measured by scales such CGI Worsening of the severity status of the disease measured by the physician with the CGI scale, score change Worsening of functioning measured by scales, such as GAF, SOFAS, or PSP Worsening of functioning measured with the GAF scale A minimum period of time should be considered for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning Minimum time necessary for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning
Ratings Poorly relevant
Recommendable
Indispensable
Poorly relevant
Recommendable
Indispensable
ⱖ 5 points
ⱖ 10 points
ⱖ 15 points
ⱖ 20 points
Indispensable
Recommendable
Poorly relevant
5 (minimally worse)
6 (much worse)
7 (very much worse)
Poorly relevant
Recommendable
Indispensable
Reduction ⱖ 10 points
Reduction ⱖ 20 points
Reduction ⱖ 30 points
Poorly relevant
Recommendable
Indispensable
1 week
2 weeks
3 weeks
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
95
Table IV. Assessment of definitions for the different models of pragmatic relapse by the eight experts. Ratings Models
1 ⫽ good
2 ⫽ acceptable
3 ⫽ poor
Model I: general complete definition Model II: simple complete definition Model III: extensive complete definition Model IV: simple definition Model V: narrow definition Model VI: concrete simplified definition Model VII: general simplified definition
8 (100)
0
0
8 (100)
0
0
5 (62.5)
3 (37.5)
0
6 (75) 3 (37.5) 1 (12.5)
0 2 (25) 5 (62.5)
2 (25) 3 (37.5) 2 (25)
0
4 (50)
4 (50)
Percentages in parenthesis. Definitions of models in Table I.
Consensus was reached on a pragmatic definition of relapse, which refers to the situation that occurs in a patient in a stage of remission that develops new symptoms, which fulfill criteria of a psychotic episode, with a significant impairment in functioning and social behavior, lasting at least 1 week and forcing a change in the clinical care with higher consumption of health care resources, occurring during the last 6 months. In relation to operational definition of relapse, the majority of participants agreed on the reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode, presence of positive symptoms measured as an increase of ⱖ 10 points in the PANSS scale, worsening of psychopathological severity of the spectrum of psychotic symptoms (score 6 in the CGI scale),
Figure 1. Responses of participants in round 2 to the questions of whether there was a valid, reliable, and clinically useful definition of relapse, and the need to develop a better definition of relapse.
worse functioning measured as an increase of ⱖ 20 points in the GAF scale, and a necessary minimum period of time for the reappearance of schizophrenic symptoms. There are several limitations to this study. The ad hoc selection of the expert panel and general psychiatrists who participated in round 1 and 2, respectively, may have excluded many clinical experts with sufficient experience in the field of schizophrenia. It should also be noted that this study identified what experts think are intrinsic elements of components of a definition of relapse, but are clearly not concerned with what constitutes the essential components in terms of efficacy of medication or adherence to antipsychotic
Table V. Components that should be present in any definition of relapse. Opinion of the participants in round 2. Category of response Component of the definition Existence of a previously stabilized clinical situation Persistence of residual symptoms Psychopathological severity of the psychotic spectrum. Specific exacerbation of clear psychotic clinical features, such as delirium, hallucinations, conceptual disorganization, strange behavior, insertion of thoughts and alterations in the course and content of thoughts Rating of the term “worsening” to define the concept of “appearance of new symptoms”? Rating of the term the term “exacerbation” to define better the concept of “appearance of new symptoms”? Rating of the term “reappearance” to define better the concept of “appearance of new symptoms”? Rating of the term “significant clinical deterioration” to define better the concept of “appearance of new symptoms”? Affective-suicidal risk symptomatology (includes suicidal attempts or exacerbation of depressive symptoms) More intense management of the case (changes in resources consumption: hospitalization, day hospital; more active action: increase in the follow-up frequency, increase of care or caregivers; changes of therapeutic regimen) Impairment in functioning and social behavior (reduction of social functioning, behavioral disturbance, or social crisis) Data expressed as percentage.
Indispensable
Recommendable
Poorly relevant
67 14 70
30 46 27
3 40 3
61 65
24 29
15 6
44
21
35
52
27
21
35
38
26
68
32
0
67
27
6
96
L. San et al.
Int J Psychiatry Clin Pract 2015;19:90–98
Table VI. Assessment of definitions for the different models of pragmatic relapse by the expert panel (Round II). Models of pragmatic relapse Model I: general complete definition Model II: simple complete definition Model III: extensive complete definition Model IV: simple definition
Strongly agree
Moderately agree
Moderately disagree
Strongly disagree
31 21 17 17
54 58 57 31
11 21 14 40
3 0 11 11
Data expressed as percentage. Definitions of models in Table I
Table VII. Operational definition of relapse: opinion of participants in round 2. Category of response
Reappearance of schizophrenic symptoms in patients who have been symptom-free after an initial episode Reappearance includes positive schizophrenic symptoms measured by clinical scales (PANSS, BPRS, etc.) Worsening of severity status of the disease measured by scales such CGI Worsening of functioning measured by scales, such as GAF, SOFAS, and PSP A minimum period of time should be considered for reappearance of schizophrenic symptoms, with positive symptoms, and worsening of severity and functioning
Indispensable
Recommendable
Poorly relevant
71
26
3
24
67
9
53 49 54
47 46 40
0 6 6
Data expressed as percentages.
treatment. It is also likely that the profile of agreed aspects of the pragmatic and operational definitions of relapse for patients with schizophrenia may differ between countries, so the exclusively Spanish-based sample is also a limitation. The decision regarding the selection of items and the formulation of questions was a subjective one taken by the eight members of the expert panel, which probably reflect the areas with highest personal experience or the clinical setting in which more studies have been done. The Delphi process was used in finding a consensus for pragmatic and operational definitions of relapse
in patients with schizophrenia. The applicability of the present results to clinical practice should be evaluated individually and reviewed periodically in the light of new emerging evidence. However, a better understanding of specific conceptual and practical components for establishing a valid, reliable, and useful definition of relapse will contribute to the development of more effective prevention strategies for patients with schizophrenia in daily practice. Although experts’ opinions collected in a consensus like those reported here have a low grade of evidence, due
Figure 2. Ratings of participants in round 2 regarding scores of different scales and time period required for reappearance of symptoms.
Definition of relapse in schizophrenia
DOI: 10.3109/13651501.2014.1002501
to the absence of other type of assessment we consider this study a first step in a long process to reach the level of evidence required. Relapse represents burden and costs for patients, their environment, and society in general and seems to increase illness progression at the biological level; in other words, relapse prevention is one of the major treatment objectives and we try to just introduce a systematic study of this phenomenon. There are many unanswered questions regarding the nature of relapse making further studies of this component of the illness imperative. In summary, the present study was designed to reach a definition of relapse using a Delphi approach procedure with two rounds due to the absence of an operational definition. The core characteristics of relapse identified as indispensable criteria by participants were as follows: the reappearance of schizophrenia symptoms in patients who have been symptom-free after an initial episode (71% of participants), need to consider a minimum period of time for reappearance of schizophrenia symptoms (54%), worsening of severity clinical status (53%), worsening of functioning (49%), and reappearance of positive symptoms (24%). Operational definitions and assessment of relapse in schizophrenia are very heterogeneous, which limit comparison of study results. Probably the steps needed to reach a consensus in this field require a specific study designed with this objective including a large sample of experts in this field. Key points •
•
•
•
•
A pragmatic and operational definition of relapse in schizophrenia that can be applied to clinical research and in clinical daily practice was developed using a two-round Delphi consensus approach. Psychopathological severity of the psychotic spectrum (70%), more intense management of the case (68%), a previously stabilized episode (67%), impairment in functioning and social behavior (67%), presence of the term “exacerbation” (65%), and presence of the term “worsening” (61%) were considered indispensable individual components of a pragmatic definition. In relation to operational definition, reappearance of symptoms in symptom-free patients after an initial episode was considered indispensable by 71% of the participants, and reappearance of positive symptoms measured by clinical scales was rated as recommendable by 67%. In relation to changes in the different scales, an increase of ⱖ 10 points in the positive subscale of PANSS was rated by 51% of the participants, a score of 6 points in the CGI (much worse) by 89%, and a reduction of ⱖ 20 points in the GAF scale by 62%. Seventy-two percent of participants considered a minimum of 1 week for reappearance of schizophrenic symptoms. Participants strongly agree (76%) that developing a better definition of relapse was needed.
97
Acknowledgments The authors acknowledge Content’Ed Net Communications, S.L., for editorial assistance and Marta Pulido, MD, for editing the manuscript. Statement of interests Janssen-Cilag. provided unrestricted support to the meeting and development of this consensus paper. Dr. San has served as a consultant or speaker for Alexza, AstraZeneca, Bristol-Myers-Squibb, Ferrer, Janssen-Cilag, Lilly, Lundbeck, Organon, Otsuka, Pfizer, Servier, and Wyeth and has received grant support from AstraZeneca, Ferrer, FIS, Janssen-Cilag, Lilly, Health Ministry, Otsuka, and Pfizer. Dr. Cañas has served as a consultant or speaker for Janssen, Lundbeck, Otsuka, Pfizer, and Servier. Dr. Romero has served as speaker for Janssen-Cilag, Pfizer, and Lundbeck. Dr. Villar has served as speaker for Janssen-Cilag and has received hospitality and honoraria from various pharmaceutical firms. Dr Sanchez-Cabezudo has served as speaker for Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Lilly, and Bristol-Meyers. The other authors declared no conflict of interests. References Agid O, Foussias G, Remington G. 2010. Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention. Expert Opin Pharmacother 11:2301–2317. Almond S, Knapp M, Francois C, Toumi M, Brugha T. 2004. Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br J Psychiatry 184:346–351. Alvarez Jimenez M, Priede A, Hetrick SE, Bendall S, Killackey E, Parker AG, et al. 2012. Risk factors for relapse following treatment for first-episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophr Res 139:116–128. Andreasen NC, Carpenter WT Jr, Kane JM, Lasser RA, Marder SR, Weinberger DR. 2005. Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry 162:441–449. Ayuso-Gutiérrez JL, del Río Vega JM. 1997. Factors influencing relapse in long-term course of schizophrenia. Schizophr Res 28:199–206. Burns T, Fiander M, Audini B. 2000. A Delphi approach to characterising ‘relapse’ and used in UK clinical practice. Int J Soc Psychiatry 46:220–230. Bustillo J, Buchanan RW, Carpenter WT Jr. 1995. Prodromal symptoms vs. early warning signs and clinical action in schizophrenia. Scizhophr Bull 21:553–559. Chabungbam G, Avasthi A, Sharan P. 2007. Sociodemographic and clinical factors associated with relapse in schizophrenia. Psychiatry Clin Neurosci 61:587–593. Csernansky J, Mahmoud R, Brenner R, Risperidone-USA-79 Study Group. 2002. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 346:16–22. Dalkey N, Brown B, Cochran S. 1969. The Delphi method, III: use of self ratings to improve group estimates. Santa Monica, CA: Rand Corp. Publication RM-6115-PR. Dilla T, Ciudad A, Alvarez M. 2013. Systematic review of the economic aspects of nonadherence to antipsychotic medication in patients with schizophrenia. Patient Prefer Adherence 7:275–284. Emsley R, Chiliza B, Asmal L, Harvey BH. 2013. The nature of relapse in schizophrenia. BMC Psychiatry 13:50. Emsley R, Oosthuizen PP, Koen L, Niehaus DJH, Martinez G. 2012. Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-yer openlabel clinical study. J Clin Psychiatry 73:e541–e547.
98
L. San et al.
Fiander M, Burns T. 1998. Essential components of schizophrenic care: a Delphi approach. Acta Psychiatr Scand 98: 400–405. Gleeson JF, Alvarez-Jimenez M, Cotton SM, Parker AG, Hetrick S. 2010. A systematic review of relapse measurement in randomized controlled trials of relapse prevention in first-episode psychosis. Schizophr Res 119:79–88. Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. 2013. Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther Adv Psychopharmacol 3:200–18. Hong J, Windmeijer F, Novick D, Haro JM, Brown J. 2009.The cost of relapse in patients with schizophrenia in the European SOHO (Schizophrenia Outpatient Health Outcomes) study. Prog Neuropsychopharmacol Biol Psychiatry 33:835–841. Karow A, Moritz S, Lambert M, Schöttle D, Naber D. 2012. Remitted but still impaired? Symptomatic versus functional remission with schizophrenia. Eur Psychiatry 27:401–405. Koening M, Casyillo MC, Urdapilleta I, le Borgne P, Bouleau JH. 2011. Relapse in schizophrenia: an exploratory study of the joint conceptions of patients: parents and caregivers. [Article in French]. Encephale 37:207–216. Lader M. 1995. What is relapse in schizophrenia? Int Clin Psychopharmacol 9:5–9. Lader M. 1998. Pharmacological prevention of relapse. Kaohsiung J Med Sci 14:448–457. Lafeuille MH, Gravel J, Lefebvre P, Fastenau J, Muser E, Doshi D, Duh MS. 2013. Patterns of relapse and associated cost burden in
Int J Psychiatry Clin Pract 2015;19:90–98
schizophrenia patients receiving atypical antipsychotics. J Med Econ 16:1290–1299. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. 2003. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 160:1209–1222. Morrison AP, Barratt S. 2010. What are the components of CBT for psychosis? A Delphi study. Schizophr Bull 36:136–142. Olivares JM, Sermon J, Hemels M, Schreiner A. 2013. Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review. Ann Gen Psychiatry 12:32. Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, et al. 1999. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 56:241–247. Smeraldi E, Cavallaro R, Folnegović-Šmalc V, Bidzan L, Emin Ceylan M, Schreiner A. 2013. Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Ther Adv Psychopharmacol 3:191–199. Thomas P. 2013. Relapse: causes and consequences. [Article in French]. Encephale 39:S79–S82. Wunderink L, Nienhuis FJ, Sytema S, Slooff C, Knegtering R, Wiersma D. 2007. Guided discontinuation versus maintenance treatment in remitted first-episode psychosis: relapse rates and functional outcome. J Clin Psychiatry 68:654–661. Zubin J, Steinhauer SR, Condray R. 1992. Vulnerability to relapse in schizophrenia. Br J Psychiatry 161:13–18.
Copyright of International Journal of Psychiatry in Clinical Practice is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
