Risk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies

doi:10.1016/j.schres.2012.05.007

Schizophrenia Research

Volume 139, Issues 1–3, August 2012, Pages 116-128

https://doi.org/10.1016/j.schres.2012.05.007 Get rights and content

Abstract

Background

Preventing relapse is an essential element of early intervention in psychosis, but relevant risk factors and precise relapse rates remain to be clarified. The aim of this study was to systematically compile and analyse risk factors for and rates of relapse in the early course of psychosis.

Methods

Systematic review and meta-analysis of English and non-English language, peer-reviewed, longitudinal studies, with a minimum 12-month follow-up and at least 80% of participants diagnosed with a first episode of psychosis (FEP) that reported risk factors for relapse.

Results

Of 153 potentially relevant articles, 29 were included in the study. Pooled prevalence of relapse of positive symptoms was 28% (range = 12–47%), 43% (35–54%), 54% (40–63%) at 1, 1.5–2, and 3 years follow-up, in that order. A total of 109 predictors were analysed, with 24 being assessed in at least 3 studies. Of those, 20 predictors could be extracted for meta-analysis. Medication non-adherence, persistent substance use disorder, carers' critical comments (but not overall expressed emotion) and poorer premorbid adjustment, increased the risk for relapse 4-fold, 3-fold, 2.3-fold and 2.2-fold, respectively.

Conclusions

Clinical variables and general demographic variables have little impact on relapse rates. Conversely, non-adherence with medication, persistent substance use disorder, carers' criticism and poorer premorbid adjustment significantly increase the risk for relapse in FEP. Future studies need to address the methodological limitations of the extant research (e.g. definition of relapse), focus on the identification of protective factors and evaluate theoretically derived models of relapse.

Introduction

The majority of first episode psychosis (FEP) patients reach clinical remission on positive psychotic symptoms in response to antipsychotic medication (Emsley et al., 2007, Cassidy et al., 2010). However, the early course of psychosis is characterised by recurrent relapses, and up to 80% of FEP patients will experience a psychotic relapse within 5 years of remission from the initial episode (Wiersma et al., 1998, Robinson et al., 1999). Each new episode significantly increases the risk of chronicity (Wiersma et al., 1998), the burden for carers, and the economic cost of treating psychosis (Almond et al., 2004). For young people relapse means further disconnection with school, work, friends and their community, adversely affecting their long-term psychosocial development (Penn et al., 2005).

While there is broad consensus that preventing relapse is critical in the early phase of psychosis (Alvarez-Jimenez et al., 2011b), results conflict regarding the aetiology and risk factors of relapse. A rigorous examination of the available evidence is overdue and essential both to identify patients at high risk of relapse, and to inform novel approaches to preventive interventions.

The aims of this study were to undertake a systematic review and meta-analysis of risk factors for relapse in FEP and examine cumulative relapse risk in early psychosis.

Section snippets

Data sources

Searches to retrieve English and non-English language studies were carried out in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, EMBASE, PsycINFO, CINAHL, UMI Proquest Digital Dissertations, Information Science Citation Index Expanded (SCI‐EXPANDED), Information Social Sciences Citation Index (SSCI), and Information Arts and Humanities Citation Index (A&HCI), all from inception to December 2010. Conference abstracts from ISI Science and

Results

eFig. 1 illustrates the study retrieval and selection strategy. The electronic search yielded 2608 citations, 133 were retrieved for eligibility assessment, and a further 20 were identified via manual reference checking, making a total of 153 assessed publications. Of these, 117 were excluded on the basis of method or sampling characteristics, leaving a total of 29 included in the study (Fig. 1). Full reference list is available upon request.

Characteristics of the included studies are presented

Comment

To our knowledge, this is the first systematic review and meta-analysis examining rates and predictors of relapse in FEP patients. This study showed high rates of relapse in the early course of psychosis. Pooled cumulative risk for relapse was found to be 28–54% at 1–3 years follow-up for relapse of positive psychotic symptoms, and 26–83% at 1–7.5 years follow-up for hospital readmissions. In addition, the results of this study showed that, while a wide range of risk factors were considered

Summary

In conclusion, based on the current available evidence, the results of this study demonstrated that medication non-adherence, persistent drug use, carers' criticism, and poorer premorbid adjustment increased the risk of relapse 4-fold, 3-fold, 2.3-fold and 2.2-fold, respectively, in FEP patients. Conversely, baseline clinical variables and general demographic variables showed little impact on relapse rates. These findings have direct clinical implications for preventing relapse during the early

Role of funding source

This study was supported by generous funding from the Colonial Foundation to Orygen Youth Health Research Centre. Furthermore, support was provided by Marques de Valdecilla Public Foundation-Research Institute, Santander, Spain (Dr Priede). The sponsors did not participate in the design or conduct of this study; in the collection, management, analysis, or interpretation of data; in the writing of the manuscript; or in the preparation, review, approval, or decision to submit this manuscript for

Contributors

MA-J and A-P performed the literature search, extracted data from the selected articles and wrote the first draft of the manuscript. SE-H independently extracted data from the selected studies. SE-H, S-B, E-K, A-P, PD-M and JF-G contributed to the design of the study, participated in the consensus process, and critically revised the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors report no additional financial or other affiliation relevant to the subject of this article.

Acknowledgements

The authors wish to thank investigators who provided additional information including Prof Stephen Wood, Dr Helene Verdoux, Prof Ross Norman, Prof Jean Addington, Prof Ashok Malla, Prof Wolfgang Wolwer, Dr Attila Sipos and Prof Swaran Singh.

References (56)

M. Alvarez-Jimenez et al.
Prevention of antipsychotic-induced weight gain with early behavioural intervention in first-episode psychosis: 2-year results of a randomized controlled trial
Schizophr. Res.
(2010)
M. Alvarez-Jimenez et al.
Prediction of a single psychotic episode: a 7.5-year, prospective study in first-episode psychosis
Schizophr. Res.
(2011)
M. Birchwood et al.
Early intervention in psychotic relapse
Clin. Psychol. Rev.
(2001)
R. Emsley et al.
Remission in early psychosis: rates, predictors, and clinical and functional outcome correlates
Schizophr. Res.
(2007)
J.F. Gleeson et al.
A systematic review of relapse measurement in randomized controlled trials of relapse prevention in first-episode psychosis
Schizophr. Res.
(2010)
R.M. Norman et al.
Social support and three-year symptom and admission outcomes for first episode psychosis
Schizophr. Res.
(2005)
V. Novak-Grubic et al.
Predictors of noncompliance in males with first-episode schizophrenia, schizophreniform and schizoaffective disorder
Eur. Psychiatry
(2002)
J.K. Patel et al.
Metabolic profiles of second-generation antipsychotics in early psychosis: findings from the CAFE study
Schizophr. Res.
(2009)
S. Rajkumar et al.
Factors affecting relapse in schizophrenia
Schizophr. Res.
(1989)
J. van Os et al.
High expressed emotion: marker for a caring family?
Compr Psychiatry
(2001)

J. Ventura et al.

Self-efficacy and neurocognition may be related to coping responses in recent-onset schizophrenia

Schizophr. Res.

(2004)

S. Almond et al.

Relapse in schizophrenia: costs, clinical outcomes and quality of life

Br. J. Psychiatry

(2004)

M. Alvarez-Jimenez et al.

Differential predictors of critical comments and emotional over-involvement in first-episode psychosis

Psychol. Med.

(2010)

M. Alvarez-Jimenez et al.

Preventing the second episode: a systematic review and meta-analysis of psychosocial and pharmacological trials in first-episode psychosis

Schizophr. Bull.

(2011)

APA

Diagnostic and Statistical Manual of Mental Disorders

(1994)

P. Bebbington et al.

The predictive utility of expressed emotion in schizophrenia: an aggregate analysis

Psychol. Med.

(1994)

R.P. Bentall et al.

Social predictors of psychotic experiences: specificity and psychological mechanisms

Schizophr. Bull.

(2008)

M. Bodnar et al.

Cognitive markers of short-term clinical outcome in first-episode psychosis

Br. J. Psychiatry

(2008)

H.E. Cannon-spoor et al.

Measurement of premorbid adjustment in chronic schizophrenia

Schizophr. Bull.

(1982)

C.M. Cassidy et al.

Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years

Schizophr. Bull.

(2010)

E.L. Coldham et al.

Medication adherence of individuals with a first episode of psychosis

Acta Psychiatr. Scand.

(2002)

A. Cougnard et al.

Pattern of health service utilization and predictors of readmission after a first admission for psychosis: a 2-year follow-up study

Acta Psychiatr. Scand.

(2006)

T.J. Craig et al.

Is there an association between duration of untreated psychosis and 24-month clinical outcome in a first-admission series?

Am. J. Psychiatry

(2000)

R.J. Drake et al.

Insight as a predictor of the outcome of first-episode nonaffective psychosis in a prospective cohort study in England

J. Clin. Psychiatry

(2007)

M. Egger et al.

Bias in meta-analysis detected by a simple, graphical test

BMJ

(1997)

W. Gaebel et al.

Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial

Neuropsychopharmacology

(2011)

P.A. Garety et al.

Implications for neurobiological research of cognitive models of psychosis: a theoretical paper

Psychol. Med.

(2007)

M. Gitlin et al.

Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia

Am. J. Psychiatry

(2001)

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ReviewRisk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Data sources

Results

Comment

Summary

Role of funding source

Contributors

Conflict of interest

Acknowledgements

Schizophr. Res.

Schizophr. Res.

Clin. Psychol. Rev.

Schizophr. Res.

Schizophr. Res.

Schizophr. Res.

Eur. Psychiatry

Schizophr. Res.

Schizophr. Res.

Compr Psychiatry

Schizophr. Res.

Relapse in schizophrenia: costs, clinical outcomes and quality of life

Br. J. Psychiatry

Differential predictors of critical comments and emotional over-involvement in first-episode psychosis

Psychol. Med.

Preventing the second episode: a systematic review and meta-analysis of psychosocial and pharmacological trials in first-episode psychosis

Schizophr. Bull.

Diagnostic and Statistical Manual of Mental Disorders

The predictive utility of expressed emotion in schizophrenia: an aggregate analysis

Psychol. Med.

Social predictors of psychotic experiences: specificity and psychological mechanisms

Schizophr. Bull.

Cognitive markers of short-term clinical outcome in first-episode psychosis

Br. J. Psychiatry

Measurement of premorbid adjustment in chronic schizophrenia

Schizophr. Bull.

Testing definitions of symptom remission in first-episode psychosis for prediction of functional outcome at 2 years

Schizophr. Bull.

Medication adherence of individuals with a first episode of psychosis

Acta Psychiatr. Scand.

Pattern of health service utilization and predictors of readmission after a first admission for psychosis: a 2-year follow-up study

Acta Psychiatr. Scand.

Is there an association between duration of untreated psychosis and 24-month clinical outcome in a first-admission series?

Am. J. Psychiatry

Insight as a predictor of the outcome of first-episode nonaffective psychosis in a prospective cohort study in England

J. Clin. Psychiatry

Bias in meta-analysis detected by a simple, graphical test

BMJ

Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial

Neuropsychopharmacology

Implications for neurobiological research of cognitive models of psychosis: a theoretical paper

Psychol. Med.

Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia

Am. J. Psychiatry

Review
Risk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies