Rates and predictors of remission in first-episode schizophrenia within 1 year of antipsychotic maintenance treatment. Results of a randomized controlled trial within the German Research Network on Schizophrenia
Introduction
After a first episode in schizophrenia, the further course and outcome are highly heterogeneous and variable (Menezes et al., 2006). Despite great efforts in schizophrenia research and enhancements in treatment strategies, some still call schizophrenia a “poor-outcome disorder” (Jobe and Harrow, 2005), in particular when considering the longer-term outcome and comparing schizophrenia to other psychiatric disorders. To improve treatment outcome, research has focused increasingly on more refined outcome concepts, as characterized by response, remission, and recovery (Leucht and Lasser, 2006). In particular, the consensus-based criteria for remission by the Remission in Schizophrenia Working Group (RSWG, Andreasen et al., 2005) have stimulated a great number of research. The criteria define remission as the absence of the (core) symptoms underlying the DSM-IV diagnostic criteria for schizophrenia for a defined time frame. In addition, the criteria have been operationalized on the basis of the assessment instruments most often used in schizophrenia research (see below).
Patients with a first-episode of schizophrenia have specific treatment needs. First-episode patients in general are more responsive to lower doses of antipsychotics but also more prone to side effects (e.g. APA, 2004). In addition, first episode patients have a more favorable treatment outcome than multiple-episode patients (e.g. Watt et al., 1983). Some researchers have highlighted the importance of the early illness and treatment phase and call it “critical” for the entire illness course (Birchwood et al., 1998) considering also the hypothesis of a negative impact of acute symptoms on pathogenesis (Lieberman et al., 2001). Accordingly, early full and sustained symptom remission is a fundamental goal in the treatment of first-episode patients.
Earlier studies found remission rates of up to 87% one year after the first illness episode (for a summary, see Bradford et al., 2003). More recent studies that used different criteria from Andreasen et al. (2005) found the following remission rates: 66% after one year in an epidemiological sample in North Europe (Simonsen et al., 2007, Simonsen et al., 2010); 82% after 2 years in a specialized first-episode care program in Canada (Malla et al., 2006); 60% after 3 years in a sub-sample of first-episode patients in a large observational study conducted across Europe (SOHO, Lambert et al., 2008); and 47% after 5 years in a standardized treatment program (Robinson et al., 2004). Besides the variability due to the different criteria applied, remission rate seems first to increase in the early treatment phase, and afterwards to decline most likely due to relapse or symptom recurrence (Robinson et al., 1999).
A similar picture evolves from first-episode studies that applied the Andreasen et al. (2005) criteria (see Table 1a, Table 1b). Despite the clarity of the RSWG criteria, there is still some variation in the way they are applied, mainly whether the 6-month time criterion is considered (so-called “enduring remission”) or not (so-called “symptomatic remission”). Another, reasonable distinction is whether an interval prevalence is applied (once within an observed time frame, here called “within” × months/years) or a point prevalence (here called “at” × months/years) is reported. As summarized in Table 1a, about 70% of patients reach symptomatic remission within 1 to 2 years after the first episode (Emsley et al., 2006, Emsley et al., 2007, Addington and Addington, 2008, de Haan et al., 2008, Emsley et al., 2008, Menezes et al., 2009, Cassidy et al., 2010), with somewhat lower rates of 30% to 40% (eventually) in epidemiological samples with broader inclusion criteria (Petersen et al., 2008, Alvarez-Jiménez et al., 2012). After the second post-acute year, the rate of patients in full symptom remission seems to decline to 30% to 50% (de Haan et al., 2008, Bodén et al., 2009, Henry et al., 2010), most likely because of relapse or symptom recurrence.
Rates for enduring remission (full symptom remission for at least 6 months; see Table 1b) are noticeably lower, ranging from 24% to 64% within the first and second post-acute years (Emsley et al., 2006, Emsley et al., 2007, Wunderink et al., 2007, Addington and Addington, 2008, Emsley et al., 2008, Boter et al., 2009, Cassidy et al., 2010, Crespo-Facorro et al., 2011, Üçok et al., 2011, Ventura et al., 2011), with an average rate of 41% (own estimate of weighted mean). Again, rates appear to decline afterwards to about 27% after 5 years (De Haan et al., 2008).
Some studies have also identified predictors of remission in first episode patients. The following have evolved as favorable predictors of remission (in descending order according to the frequency of significant study results): a shorter duration of untreated psychosis (DUP; Emsley et al., 2006, Malla et al., 2006, Emsley et al., 2007, Simonsen et al., 2007, Wunderink et al., 2007, Addington and Addington, 2008, Petersen et al., 2008, Bodén et al., 2009, Simonsen et al., 2010, Alvarez-Jiménez et al., 2012) or an overall shorter illness duration (Robinson et al., 2004); better premorbid functioning (Robinson et al., 2004, Malla et al., 2006, Wunderink et al., 2007, Addington and Addington, 2008, Üçok et al., 2011, Alvarez-Jiménez et al., 2012) or a (potentially associated) higher age at illness onset (Malla et al., 2006, Wunderink et al., 2007, Simonsen et al., 2010); a more favorable initial response in acute treatment (Emsley et al., 2006, Emsley et al., 2007, Wunderink et al., 2007, Addington and Addington, 2008, de Haan et al., 2008, Emsley et al., 2008, Menezes et al., 2009, Üçok et al., 2011, Alvarez-Jiménez et al., 2012); better treatment adherence (Malla et al., 2006, Petersen et al., 2008, Boter et al., 2009, Üçok et al., 2011); certain symptom characteristics at baseline, specifically fewer overall baseline symptoms (Addington and Addington, 2008, de Haan et al., 2008, Petersen et al., 2008) and fewer negative symptoms (Simonsen et al., 2007, Wunderink et al., 2007, Simonsen et al., 2010, Üçok et al., 2011) and heterogeneous findings regarding more (Simonsen et al., 2010, Üçok et al., 2011) or fewer positive symptoms to be favorable (Wunderink et al., 2007); female gender (Emsley et al., 2006, Wunderink et al., 2007, Alvarez-Jiménez et al., 2012); no substance abuse (Boter et al., 2009, Menezes et al., 2009); neurological soft signs (Emsley et al., 2006); better cognitive functioning (Robinson et al., 2004); and treatment with second generation antipsychotics (SGAs; Boter et al., 2009).
The aim of this study was to contribute additional data to the topic of remission (defined according to the RSWG criteria) after a first episode in schizophrenia. Rates and predictors of symptomatic and enduring remission were calculated from the data obtained from the “first-episode study” (FES; Gaebel et al., 2007, Gaebel et al., 2011) within the German Research Network on Schizophrenia (GRNS; Wölwer et al., 2003). An additional aim was to identify symptoms that prevent remission.
Section snippets
Study setting and design
The “first-episode study” (FES) was part of the German Research Network on Schizophrenia (GRNS, Wölwer et al., 2003), a nationwide research network funded by the German Federal Ministry of Education and Research (BMBF). The study was conducted at 13 German psychiatric university hospitals according to the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. Adherence to GCP was assured by the involvement of the Düsseldorf Coordinating Centre for Clinical Trials (head:
Results
The characteristics of the 166 patients included in the analyses are given in Table 2. At entry into the 1-year maintenance study phase, the mean age of the patients was 31.8 years (SD = 10.0) and the mean time since illness onset was about one year. About 60% of the patients were male; 133 (80.1%) had continued from the acute study phase and 33 (19.9%) had joined by lateral entry at the beginning of the 1-year maintenance study phase. About two-thirds of the patients also participated in the
Discussion
This study evaluated the rates and predictors of remission, defined according to the Andreasen et al.'s (2005) criteria, on the basis of data from a multicenter RCT comparing risperidone and haloperidol in post-acute, 1-year maintenance treatment in first-episode schizophrenia (Gaebel et al., 2007). A total of n = 166 first-episode patients were eligible for the study, and 152 (91.5%) of them reached symptomatic remission (i.e. all respective symptoms were below the defined threshold at some
Conclusions
Within the first year of maintenance treatment after the acute phase of a first episode in schizophrenia, about 90% of patients who adhere to treatment reach a full symptomatic remission according to the criteria of Andreasen et al. (2005), irrespective of whether they are administered an FGA (haloperidol) or SGA (risperidone). However, this symptomatic remission is often temporary (in almost 70% of patients), i.e. the patients again develop symptoms above the threshold level. Only about 60% of
Role of funding source
This study was conducted within the German Research Network on Schizophrenia, funded by the German Federal Ministry for Education and Research BMBF (grants 01 GI 9932 and 01 GI 0232). Risperidone and haloperidol were provided by Janssen-Cilag, Germany. Study design and execution, data acquisition and analyses and preparation of the manuscript were completely independent from funding.
Contributors
Wolfgang Gaebel, Wolfgang Wölwer, Ansgar Klimke and Matthias Eickhoff were responsible for the study design and organization of the study. Mathias Riesbeck and Wolfgang Köpcke conducted the data analyses. Wolfgang Gaebel and Mathias Riesbeck provided the first draft of the manuscript. All authors contributed equally to the final revision of the manuscript.
Conflict-of-interest statement
Dr. Gaebel reports having received symposia support from Janssen-Cilag GmbH, Neuss, Lilly Deutschland GmbH, Bad Homburg and Servier, Munich and being a Faculty member of the Lundbeck International Neuroscience Foundation (LINF), Denmark. Dr. Klimke reports having received Speakers honoraria from Astra-Seneca and Janssen-Cilag. Dr. Maier has served as a consultant for Roche (International, Germany), Otsuka (Germany), and Lilly (Germany). Dr. Heuser acted as a consultant to GE Healthcare, Astra
Acknowledgments
The authors are much obliged to the members of the German Study Group on First-Episode Schizophrenia as well as to the members of the scientific advisory board of the German Research Network on Schizophrenia for all their contributions. We also would like to thank Janssen-Cilag for providing the study drugs and Jacquie Klesing, ELS, for editing assistance with the manuscript.
The German Study Group on First-Episode Schizophrenia consists of: W. Gaebel (P.I.), W. Wölwer, M. von Wilmsdorff, R.
References (58)
- et al.
Symptom remission in first episode patients
Schizophr. Res.
(2008) - et al.
A depression rating scale for schizophrenics
Schizophr. Res.
(1990) - et al.
Association between symptomatic remission and functional outcome in first-episode schizophrenia
Schizophr. Res.
(2009) - et al.
Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission: an open randomized clinical trial (EUFEST)
Schizophr. Res.
(2009) - et al.
Relapse prevention and remission attainment in first-episode non-affective psychosis. A randomized, controlled 1-year follow-up comparison of haloperidol, risperidone and olanzapine
J. Psychiatr. Res.
(2011) - et al.
Remission in early psychosis: rates, predictors, and clinical and functional outcome correlates
Schizophr. Res.
(2007) - et al.
Extent of attaining and maintaining symptom remission by antipsychotic medication in the treatment of chronic schizophrenia: evidence from the CATIE study
Schizophr. Res.
(2011) - et al.
The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches
Biol. Psychiatry
(2001) - et al.
The Calgary Depression Rating Scale for Schizophrenia: development and interrater reliability of a German version (CDSS-G)
J. Psychiatr. Res.
(1999) - et al.
Remission after first-episode schizophrenia: results of a long-term follow-up
Psychiatry Res.
(2011)
Remission and recovery during the first outpatient year of the early course of schizophrenia
Schizophr. Res.
Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years
Psychol. Med.
Social and Occupational Functioning Assessment Scale (SOFAS)
Practice guideline for the treatment of patients with schizophrenia
Negative symptoms in schizophrenia
Arch. Gen. Psychiatry
Remission in schizophrenia: proposed criteria and rationale for consensus
Am. J. Psychiatry
Early intervention in psychosis. The critical period hypothesis
Br. J. Psychiatry
Pharmacological management of first-episode schizophrenia and related nonaffective psychoses
Drugs
Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years
Schizophr. Bull.
Improvement of subjective well-being and enduring symptomatic remission, a 5-year follow-up of first episode schizophrenia
Pharmacopsychiatry
Remission in first-episode psychosis: predictor variables and symptom improvement patterns
J. Clin. Psychiatry
Remission in patients with first-episode schizophrenia receiving assured antipsychotic medication: a study with risperidone long-acting injection
Int. Clin. Psychopharmacol.
The Hillside Akathisia Scale (HAS): a new rating instrument for neuroleptic-induced akathisia
Psychopharmacol. Bull.
The Global Assessment of Functioning Scale (GAF)
Diagnostic and Statistical Manual of Mental Disorders
Maintenance treatment with risperidone or low-dose haloperidol in first-episode schizophrenia. One-year results of a randomized controlled trial within the German Research Network on Schizophrenia
J. Clin. Psychiatry
Relapse prevention in first-episode schizophrenia: maintenance vs. intermittent drug treatment with prodrome-based early intervention. Results of a randomized controlled trial within the German Research Network on Schizophrenia
J. Clin. Psychiatry
Revising Axis V for DSM-IV. A review of measures of social functioning
Am. J. Psychiatry
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2020, Schizophrenia ResearchCitation Excerpt :Almost in all studies, apart from diagnosis of schizophrenia, diagnoses like schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, and psychotic mania were included in the first-episode psychosis group (Boonstra et al., 2011; Bowtell et al., 2018; Gaebel et al., 2016; Pelayo-Teran et al., 2017; Tiihonen et al., 2018; Wunderink et al., 2013). Definition of relapse varies across the studies as well (Gaebel et al., 2014; Hui et al., 2018; Ucok et al., 2011). Study sample is too small in some studies (Boonstra et al., 2011), some studies have a short-term follow-up of 2 years or less (Gilbert et al., 1995; Wunderink et al., 2007) and duration of antipsychotic medication use before discontinuation as short as 6 month in some others (Bowtell et al., 2018).
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2016, Schizophrenia ResearchCitation Excerpt :Therefore, the final sample size for predictor analysis was 19 patients. The following characteristics were included in the analyses as potential predictors for deterioration within 1 year after drug discontinuation (see also Table 1): Age; gender; different characteristics of the first year of the long-term phase (the foregoing MT treatment phase): assigned study drug (risperidone or haloperidol); assigned psychological treatment (none, short [psychoeducation], long [CBT]); PANSS positive, negative and general score at entry into first year/after acute treatment; completer of the first year drug trial; drug dose (haloperidol equivalents) at end of first year; total cumulative dose (haloperidol equivalents) in the first year; compliance rating scale (CRS, end of first year; Kemp and David, 1996); drug attitude inventory (DAI, end of first year; Hogan et al., 1983); subjective well-being under neuroleptics (SWN, end of first year; Naber, 1995); occurrence of “deterioration” (according to Csernansky et al., 2002) within first year; reaching symptom remission (according to Andreasen et al., 2005; for at least 1 week); maximum time (weeks) of symptom remission; and “enduring” symptom remission (according to Andreasen et al., 2005, for at least 6 months (Gaebel et al., 2014)); different characteristics at entry into the second year of the long-term phase: CGI severity score; CGI change score; PANSS positive, negative and general score; Scale for the Assessment of Negative Symptoms (SANS, Andreasen, 1982); Hamilton Rating Scale for Depression (HAM-D, Hamilton, 1960); Calgary Depression Rating Scale for Schizophrenia (CDSS, Addington et al., 1990; Müller et al., 1999); sum score for unspecific prodromes; sum score for specific prodromes; Extrapyramidal Side Effects scale (EPS, Simpson and Angus, 1970); Hillside Akathisia Scale (HAS, Fleischhacker et al., 1989); Abnormal Involuntary Movement Scale (AIMS, Guy, 1976a, Guy, 1976b); Udvalg for Kliniske Undersogelser Side Effect Rating Scale (Scandinavian Society of Psychopharmacology Committee of Clinical Investigations (UKU), 1987) subscores “neurological,” “psychological,” “autonomous,” and “other” and assigned drug for early intervention (antipsychotic or the benzodiazepine lorazepam). All the potential predictors mentioned above were first compared by univariate analyses in patients with and without deterioration after drug discontinuation in the second treatment year (see Table 1) by using a chi-square test (mostly Fisher's exact test because of low cell frequencies) for frequencies/proportions and a Mann–Whitney test for continuous data (because of low sample size, lack of normal distribution, and homogeneity of variances in many variables).
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2015, International Encyclopedia of the Social & Behavioral Sciences: Second EditionPsychosocial functioning in relation to symptomatic remission: A longitudinal study of first episode schizophrenia
2015, European PsychiatryCitation Excerpt :In 2005, The Remission in Schizophrenia Working Group (RSWG) proposed a set of criteria for symptomatic remission [2]. Subsequently, numerous studies have been published, most of them summarised by Al Aqeel and Margolese [1], Gaebel et al. [22], Lang et al. [40], and Zimmermann et al. [52]. These indicate that the number of patients meeting the remission criteria range from 17 to 78% in first-episode (FE) schizophrenia and from 16 to 62% in multi-episode patients.