Clinical and demographic predictors of continuing remission or relapse following discontinuation of antipsychotic medication after a first episode of psychosis. A systematic review
Introduction
The first episode of psychosis (FEP) is a clinical presentation that warrants unique treatment guidelines; those affected are typically young, drug naïve, require lower doses of antipsychotic medication, and are more sensitive to side effects (Alvarez-Jimenez et al., 2016). Early intervention services provide treatment tailored to the needs of these individuals and such specialist services have now been established in multiple cities around the world. Many such programs provide care to individuals experiencing their first episode of either affective or non-affective psychotic disorders (Conus et al., 2017, Fusar-Poli et al., 2013a, Kane et al., 2016).
Antipsychotic medications are effective in treating the positive symptoms of psychotic disorders (Leucht et al., 2009). However, the long-term use of antipsychotic medications carries significant morbidity and mortality implications (Correll et al., 2009). Potential physical health complications include weight gain, dyslipidemia and diabetes, and possible structural brain changes (Fusar-Poli et al., 2013b). In the acute setting, early induction of an atypical antipsychotic at the minimum effective dose is the standard recommendation in most guidelines (Buchanan et al., 2010, Early-Pychosis-Guidelines-Working-Group, 2010, Taylor and Kapur, 2011). With antipsychotic treatment, symptomatic remission is achieved by as many as 80% of individuals affected by a FEP (Malhi et al., 2010). Following remission, most guidelines recommend maintenance treatment with an atypical antipsychotic medication at minimum effective dose, for a duration of one to two years (Taylor and Kapur, 2011).
However, more recently, the benefits of long-term maintenance treatment have been questioned, with there being a call for more research to guide treatment duration (Emsley et al., 2016, Moncrieff, 2015, Wunderink et al., 2013). Contrary to clinical guidelines, up to 70% of individuals disclose that they ceased their medications less than twelve months following remission (McEvoy et al., 2007). Interestingly, this practice appears to be supported by the majority of clinicians, with less than one third believing that antipsychotic medication should be continued for over a year post remission (Alvarez-Jimenez et al., 2016, Thompson et al., 2016).
Whilst there are risks associated with the long-term use of antipsychotic medication, there are also risks associated with discontinuation, as high relapse rates have been observed (Zipursky et al., 2014). Relapse may hinder or reverse gains made in social and vocational functioning whilst on maintenance treatment (Kam et al., 2015). There are also concerns that individuals may not respond as effectively to antipsychotic medication following relapse as in the first episode (Lieberman et al., 1996). Yet, not all those who discontinue antipsychotic medication will experience relapse. There would be clinical utility in being able to identify individuals who are likely to be able to discontinue antipsychotics and sustain remission after a FEP.
Considerable research has been undertaken to identify factors predictive of either relapse, or continuing remission amongst individuals who receive ongoing maintenance treatment. Commonly accepted predictors of relapse amongst such individuals are poor medication adherence, male sex, a longer duration of untreated psychosis (DUP), substance misuse, poorer premorbid adjustment, and a greater severity of negative symptoms at baseline (Alvarez-Jimenez et al., 2012). However, some have suggested that factors predictive of relapse or sustained remission may differ between those who continue medication, and those who discontinue (Hui et al., 2013). A key question is whether predictors of outcome amongst individuals receiving maintenance treatment are similarly predictive when applied to a discontinuation cohort.
As such, we aimed to conduct a systematic review of published reports that identified demographic and clinical predictors of outcome following antipsychotic discontinuation in individuals affected by a FEP. There is considerable heterogeneity amongst individuals cared for by specialist early psychosis services. Thus, an analysis of the total FEP cohort, including individuals affected by affective and non-affective psychoses, is necessary for clinical applicability and allows for inclusion of final diagnosis as a potential predictor. In this review, we specifically aimed to identify factors predictive of either continuing remission or of relapse. We also aimed to examine whether findings were replicated between studies.
Section snippets
Literature search
The study aimed to determine predictors and it was expected that multiple demographic and clinical variables would appear across studies. The following databases were systematically searched: PubMed, CINAHL, and PsychInfo. Ancestry searching was also conducted.
Keywords used
The search terms included: (determinant* OR predict*) AND (success* OR relapse OR fail OR recurrence OR outcome) AND (discontinu* OR cease OR stop OR cessation) AND (schizo* OR first episode OR psychosis) AND (antipsychotic OR
Results
Database searching yielded 1042 records. An additional two articles were identified through ancestry searching. After removal of duplicates, 783 articles remained. Following title screening, 578 articles were excluded. A review of abstracts excluded a further 138 articles. A total of sixty-four articles were reviewed in full, and a further fifty-three excluded. The process resulted in the identification of eleven articles (pertaining to ten cohort populations) for inclusion in the present
Rates of relapse
Within the present study, rates of relapse range from 19.4% to 97% across studies (Emsley et al., 2014, Emsley et al., 2012, Landolt et al., 2016). It is important to acknowledge that relapse rates reach high levels with long term follow up. However, research suggests that, even at a decade's follow up, not all individuals will experience relapse after a FEP, and many achieve prolonged periods of remission (Morgan et al., 2014). Further, with a lack of a uniform definition of relapse in the
Conflicts of interest
The authors have no conflicts of interest.
Role of the funding source
Professor PD McGorry is supported by a Research Fellowship from the National Health and Medical Research Council of Australia and is an NHMRC Senior Principal Research Fellow. Professor E Killackey is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia.
References (46)
- et al.
Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies
Schizophr. Res.
(2012) - et al.
Predictors of favourable outcome in young people with a first episode psychosis without antipsychotic medication
Schizophr. Res.
(2017) - et al.
A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia
Schizophr. Res.
(2014) - et al.
Outreach and support in south London (OASIS), 2001–-2011: ten years of early diagnosis and treatment for young individuals at high clinical risk for psychosis
Eur. Psychiatry
(2013) - et al.
Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies
Neurosci. Biobehav. Rev.
(2013) - et al.
Revisiting the relapse predictive validity of prodromal symptoms in schizophrenia
Schizophr. Res.
(2007) - et al.
Predictors for symptom re-exacerbation after targeted stepwise drug discontinuation in first-episode schizophrenia: results of the first-episode study within the German research network on schizophrenia
Schizophr. Res.
(2016) - et al.
Early warning signs of relapse following a first episode of psychosis
Schizophr. Res.
(2005) - et al.
Predicting 1-year risk for relapse in patients who have discontinued or continued quetiapine after remission from first-episode psychosis
Schizophr. Res.
(2013) - et al.
Predictors of discontinuation of antipsychotic medication and subsequent outcomes in the European First Episode Schizophrenia Trial (EUFEST)
Schizophr. Res.
(2016)
Psychobiologic correlates of treatment response in schizophrenia
Neuropsychopharmacology
Duration of untreated psychosis: a state-of-the-art review and critical analysis
L'Encéphale
Risk of symptom recurrence with medication discontinuation in first-episode psychosis: a systematic review
Schizophr. Res.
Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF
Beyond clinical remission in first episode psychosis: thoughts on antipsychotic maintenance vs. guided discontinuation in the functional recovery era
CNS Drugs
Predicting relapse in schizophrenia: the development and implementation of an early signs monitoring system using patients and families as observers, a preliminary investigation
Psychol. Med.
The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements
Schizophr. Bull.
Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial
BMJ [Br. Med. J.]
Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents
JAMA
The relapse rate and predictors of relapse in patients with first-episode psychosis following discontinuation of antipsychotic medication
Early Interv. Psychiatry
Predictors of outcome in early-onset psychosis: a systematic review
NPJ Schizophr.
Australian Clinical Guidelines for Early Psychosis
Symptom recurrence following intermittent treatment in first-episode schizophrenia successfully treated for 2 years: a 3-year open-label clinical study
J. Clin. Psychiatry
Cited by (50)
First-episode psychosis
2023, Medicine (Spain)Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study
2023, European NeuropsychopharmacologyRole of de novo lipogenesis in insulin resistance in first-episode psychosis and therapeutic options
2022, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Although patients with first-episode psychosis (FEP) may display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for psychosis and cognitive dysfunction (Steiner et al., 2017; Chouinard et al., 2019). Evidence suggests that insulin resistance may deteriorate further following exposure to antipsychotic drugs as evident by increase in dyslipidemia, obesity and diabetes, which are major factors associated with premature antipsychotic withdrawal and relapse in schizophrenia (Freyberg et al., 2017; Bowtell et al., 2018; Tomasik et al., 2019; Chouinard et al., 2019). Although oxidative stress and inflammation, which are considered as the pathological hallmarks of schizophrenia, have been shown to trigger the development of insulin resistance (Kennedy et al., 2009; Keane et al., 2015; Fraguas et al., 2019; Upthegrove and Khandaker, 2020; Dunleavy et al., 2022), underlying mechanism(s) in schizophrenia remains to be conceptualized.
Clinical and treatment predictors of relapse during a three-year follow-up of a cohort of first episodes of schizophrenia
2022, Schizophrenia ResearchCitation Excerpt :The most relevant results from our study were: (1) The rate of first relapse after achieving remission of a first episode of non-affective psychosis was 49.6%, happening mainly in the first year; (2) Previous sociodemographic, non-modifiable variables (such as age, gender, urbanicity, employment etc.) did not show significant associations with relapses; (3) 22% of the patients that finished the 3-year follow-up without relapsing had discontinued antipsychotic treatment; (4) Taking antipsychotic polytherapy, higher antipsychotics dosage, mood stabilizers and benzodiazepines was more frequent in the group of patients that relapsed, while the proportion of patients with clozapine was notably higher in the group that did not relapsed; (5) The proportion of subjects that reported treatment-related side effects was higher in the group of patients with a relapse; (6) A higher proportion of patients that presented a relapse were receiving psychological treatment; and (7) Cannabis consumption during the follow-up was significantly associated with present a relapse. The relapse rate that we found was similar to the reported in other studies with a comparable design, though comparison across studies remains complex due to the lack a uniform definition of relapse in the literature, together with different lengths of follow-up, diagnosis of the sample and characteristics of the setting (Bowtell et al., 2018b). Pelayo-Terán et al. reported a rate of 48.68% in a three-year follow-up study of FEP in an early intervention program in the Spanish region of Cantabria (Pelayo-Terán et al., 2017).