Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis The British Journal of Psychiatry, 2014, 205 (2) 88-94 Disagreements regarding studies fitting inclusion criteria were resolved by consensus with a third researcher (D.O.). A 2-step systematic search of the literature was performed by 2 independent researchers (S.L. While 2 studies employed randomized cluster designs,21,51 no randomized controlled trials (RCTs) were found in the search, which is unsurprising given the difficulties in performing them. Cognition in schizophrenia and bipolar disorder, Cognitive functioning related to symptoms, Treatments for childhood and early-onset schizophrenia, Treatments for elderly people and people with late-onset schizophrenia, Treatments for medication-resistant schizophrenia, Therapies for childhood onset and early onset schizophrenia, Behavioural disturbances and psychopathology, Stigma and attitudes towards mental health, Familial coaggregation with bipolar disorder, Physical anomalies in first-degree relatives, Psychopathology in first-degree relatives, Single photon emission computed tomography. The definition of DUP is not precisely operationalized and still subject to variable ascertainment.16,53 Defining onset psychometrically using the PANSS or with positive symptoms using a clinical instrument was linked with a significant reduction in DUP while other definitions were not (figure 5). Mean duration of untreated psychosis was 84 weeks (median 28 weeks, range 1–780 weeks). Articles that remained were then fully downloaded as PDFs and assessed for eligibility on the basis of full text reading. The period of time from onset of psychosis to onset of treatment is referred to as the Duration of Untreated Psychosis, or DUP. I have tried here to present a fair presentation of the data although I will admit that a full review is beyond the scope of this blog. The mean length of intervention was 31.3 months (range 8–78 months). We attempted to address study-level heterogeneity with meta-regression analyses on numerous patient related variables (mean age, gender, marital status) and study related variables (length of intervention, quality of studies, publication year, continent, study design, and definitions of DUP at endpoint), that revealed no significant effects. Key words: Duration of untreated psychosis, Schizophrenia, Sociodemographic factors Access this article online www.ijss-sn.com DUP is generally determined as the time from the onset of psychotic symptoms to the initiation of treatment or first clinical presentation, when a diagnosis of first-episode psychosis may be given. The research into what has been called “duration of untreated psychosis” (DUP) is extensive. Two influential meta-analyses clearly establish that the duration of untreated psychosis (DUP), the time between the onset of psychosis and initiation of treatment, is correlated with poor outcome. Keywords used were (“duration of untreated psychosis”) AND (intervention OR decreas* or reduc*). The effect-size measure was Hedges’ g.34 This indexed the impact of the specific intervention on the DUP. Would my treatment change if I also have another disorder? To whom correspondence should be addressed; tel: 02078480355, fax: 02078480976, e-mail: Search for other works by this author on: Department of Psychosis Studies, IoPPN, King’s College London, UK, National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health, IoPPN, King’s College London, UK, OASIS Service, South London and the Maudsley NHS National Health Service Foundation Trust, UK, Improving outcomes of first-episode psychosis: an overview, Duration of untreated psychosis: a critical examination of the concept and its importance, Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis, Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis, Duration of untreated psychosis and negative symptoms—a systematic review and meta-analysis of individual patient data, Is duration of illness really influencing outcome in major psychoses, Outcome measures in early psychosis: relevance of duration of untreated psychosis, Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review, Duration of untreated negative and positive symptoms of psychosis and cognitive impairment in first episode psychosis, Impact of duration of untreated psychosis on pre-treatment, baseline, and outcome characteristics in an epidemiological first-episode psychosis cohort, Systematic meta-analysis of the risk factors for deliberate self-harm before and after treatment for first-episode psychosis, Impact of early intervention services on duration of untreated psychosis: data from the National EDEN prospective cohort study, Violence in first-episode psychosis: a systematic review and meta-analysis, Understanding delay in treatment for first-episode psychosis, Reducing the duration of untreated first-episode psychosis: effects on clinical presentation, Initiatives to shorten duration of untreated psychosis: systematic review, Reducing the duration of untreated psychosis and changing help-seeking behaviour in Singapore, EPPIC: an evolving system of early detection and optimal management, Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study, Duration of untreated psychosis and need for admission in patients who engage with mental health services in the prodromal phase, The Lambeth Early Onset Crisis Assessment Team Study: general practitioner education and access to an early detection team in first-episode psychosis, Early intervention service for psychosis: views from primary care, Early detection and intervention in first-episode schizophrenia: a critical review, Early intervention in first-episode psychosis—the impact of a community development campaign, Metabolic changes in first-episode early-onset schizophrenia with second-generation antipsychotics, Long term effect of early intervention service on duration of untreated psychosis in youth and adult population in Hong Kong, A controlled evaluation of a targeted early case detection intervention for reducing delay in treatment of first episode psychosis, Don’t turn your back on the symptoms of psychosis: the results of a proof-of-principle, quasi-experimental intervention to reduce duration of untreated psychosis, Evaluation of a community awareness programme to reduce delays in referrals to early intervention services and enhance early detection of psychosis, The efficacy of targeted health agents education to reduce the duration of untreated psychosis in a rural population, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, Meta-analysis of observational studies in epidemiology: a proposal for reporting. Psychosis is one of the most debilitating psychiatric conditions with limited options to improve outcomes.1 One key strategy is reducing the duration of untreated psychosis (DUP), the time from the first symptom of psychosis to the start of treatment.2 Accumulating studies have shown that a longer DUP is associated with poorer outcomes for people with first-episode psychosis (FEP), including worse positive3,4 and negative symptom4,5 severity, poorer rates of remission,4,6,7 poorer social cognition,6,8 and cognitive impairment.6,9,10 In addition to the clinical, functional, and cognitive benefits, reducing DUP is associated with reducing the social consequences of psychosis onset, such as social isolation, unemployment, homelessness, and can reduce deliberate self harm11,12 and violence toward others.12,13 Under standard care, DUP tends to be quite long, with means varying between 22 weeks and over 150 weeks,14 with high heterogeneity between patients.15 These long periods without treatment arise from several sources, both intrinsic (eg, symptom severity, patients’ attitude) and extrinsic (eg, access to care).16 These considerations lay foundations for specialized early intervention services1 with the aim of improving early detection and facilitating pathways to care and treatment; minimizing DUP. Two of these investigated the effect of FEP services18,46 with the other focusing on the effect of CHR-P services.20 The 2 approaches were quite distinct in that the CHR-P service was the only one to adopt a longitudinal design. A Systematic Review and Meta-Analysis of Controlled Interventional Studies, Schizophrenia Bulletin, Volume 44, Issue 6, November 2018, Pages 1362–1372, https://doi.org/10.1093/schbul/sbx166. It shows a lack of robust evidence that specific interventions such as standalone FEP services, community interventions, healthcare professional training, and multifocus interventions are successful in accomplishing this. Background It is unclear what determines duration of untreated psychosis (DUP) in schizophrenia and why long DUP predicts poor outcome. The duration of untreated illness (DUI), defined as the interval between the onset of a psychiatric disorder and the administration of the first pharmacological treatment, has been increasingly investigated in the last decade as a predictor of outcome across different psychiatric conditions including schizophrenia and psychotic disorders (duration of untreated psychosis), and mood and anxiety disorders. What is duration of untreated psychosis (DUP)? to identify relevant studies investigating the effect of controlled interventions aiming to reduce DUP in early psychosis.16. Randomised controlled trials (RCTs) were excluded from the meta-analysis because they were thoug… What are the treatments for first-episode psychosis? Heterogeneity among study point estimates was assessed using Q statistics35 and the proportion of the total variability in the effect size estimates evaluated with the I2 index.35 Given the methodological heterogeneity of the included studies, random effects models36 were employed using the method of DerSimonian and Laird.37, Risk of publication bias was tested by visual inspection of funnel plots in addition to the application of the Egger regression intercept method38 and the Duval and Tweedie “trim and fill” method.39 To further assess the robustness of the results, we performed sensitivity analyses by sequentially removing each study and re-running the analysis.40, To explain any heterogeneity found, meta-regression analyses were conducted when at least 10 studies were available for the specific confounders relating to patients: mean age, gender, ethnicity (% white), marital status (proportion of married subjects), cannabis abuse/dependence (% meeting abuse/dependence criteria), alcohol abuse/dependence (% meeting abuse/dependence criteria), living status (% living independently), migrant status (% non-migrants), psychotic symptom severity at baseline (PANSS), diagnosis (% schizophrenia); relating to the study: length of intervention (months), quality of studies (see below), publication year, continent, healthcare system type (Semashko, Bismarck, market-based), study design (randomized cluster, cohort analytic, cohort), control DUP, definition of DUP onset, definition of DUP endpoint. The conclusions presented here are based on group data, and as such individual treatment programs need to be tailored by trained clinicians. All included studies were investigating an intervention aiming to reduce DUP compared to a control group. The period from the onset of frank psychotic symptoms to the start ofadequate treatment, the duration of untreated psychosis (DUP), varies considerablyin patients with first-episode psychosis. However, this is the only report available; these findings should be interpreted cautiously. Wells GA, Shea B, Peterson J, Welch V, Losos M, Tugwell P. Egger M, Davey Smith G, Schneider M, Minder C. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Moderate quality evidence finds brain structural anomalies in people with first-episode psychosis are not consistently associated with length of DUP. For example, issues have previously been raised regarding the pseudospecificity of the PANSS (eg, correlations between different subdomains that are not entirely independent).54. The mean age of the intervention and control groups were 25.5 years (range 21.6–36.6) and 26.4 years (range 22.0–38.0), respectively. These negative findings may reflect a parceled research base in the area, lack of prospective randomized controlled trials (only 2 randomized cluster designed studies were present) and small sample sizes. Duration of untreated psychosis (DUP) is a major contributor to the variation in outcomes following first episode psychosis [1, 2] and a robust predictor of poor outcomes [3, 4].Therefore, reducing DUP has become an international priority and much effort has been spent assessing the impact of early intervention services on DUP. Bhushan Bhagwan Mhetre, Ranita Devi Athokapam, Sumit Rampal Chandak, Gojendra Singh Senjam, Heramani Singh Ningombam, DURATION OF UNTREATED PSYCHOSIS (DUP) AND PRE-MORBID FUNCTIONING, MAY PREDICT CLINICAL PRESENTATION IN FIRST EPISODE OF PSYCHOSIS (FEP): NORTH-EAST INDIAN STUDY, Journal of Evidence Based Medicine and Healthcare, … Controlled interventional strategies were defined as: (a) standalone FEP services, (b) standalone CHR-P services, (c) community interventions, (d) healthcare professional training, and (e) multifocus interventions. Indeed, we found that the definition of the DUP was unstandardized and associated with significant heterogeneity. As highlighted by our within subgroup analysis, the CHR-P approach has unique potential for altering the DUP and therefore the course of psychosis.58 Controlled interventions in CHR-P services can be highly effective as they can tackle some of the limitations above. There was no summary evidence that available interventions are successful in reducing DUP during the first episode of psychosis (Hedges’ g = −0.12, 95% CI = −0.25 to 0.01). There were no publication biases and the results were not affected by outliers. In a recent study 1 involving 404 patients with first-episode psychosis recruited at 34 community clinics in 21 different US states, we found that the median duration of untreated psychosis … Collaborative large-scale initiatives adopting well standardized psychometric definitions of DUP and refined study designs are needed to advance knowledge and improve outcomes of FEP. Which risk factors are associated with schizophrenia? H&CSPromotions Unit.Early Psychosis Prevention and Intervention Centre(EPPIC). Treatments for specific symptoms and populations, Therapies for specific symptoms and populations. Early intervention programs for schizophrenia and psychosis often combine many elements comprising both pharmaceutical and psychosocial therapies, and may involve enriched therapies that are tailored to an individual’s needs. At a first step, the Web of Science database by Thomson Reuters (including Web of Science, BIOSIS Citation Index and MEDLINE) and the Ovid database by Wolters Kluwer (including MEDLINE and PsycINFO) were searched. Duration of untreated psychosis in an Egyptian sample: Sociodemographic ... improved clinical presentation and an improved medium- and long-term (5-year) outcome (Larsen et al., 2011). Reduce DUP and Treat Well. The second step involved an electronic manual search of references found in the included articles. The search uncovered 14 independent articles (7 new20,25–30 compared to the previous systematic search16) in addition to 2 new conference abstracts.45,46 Five of the previously found studies were excluded, one for not including a control group,47 another for not explicitly reporting DUP22 and 3 for overlapping data.23,48,49 The final database comprised 16 studies including 1964 patients in the intervention arm and 1358 in the control arm. The meta-analyses included an overall estimate across all subgroups as well as within-subgroup summary effects and between-subgroups effects. People with a first episode of psychosis experience distressing symptoms such as unusual beliefs or abnormal behaviour (positive symptoms) and/or withdrawal or loss of interest in work or school (negative symptoms). When only including studies published in peer-reviewed journals, there were no significant changes (Hedges’ g = −0.07, 95% CI = −0.20 to 0.05). The current meta-analysis has some potential clinical implications. We recorded the following variables from each article relating to patients: mean age, gender, ethnicity (% white), marital status (proportion of married subjects), cannabis abuse/dependence (% meeting abuse/dependence criteria), alcohol abuse/dependence (% meeting abuse/dependence criteria), living status (% living independently), migrant status (% nonmigrants), psychotic symptom severity at baseline (PANSS), diagnosis (% schizophrenia); relating to the study: author, length of intervention (months) (time intervention was delivered to community, healthcare professionals, etc. Note: FEP, first-episode psychosis; DUP, duration of untreated psychosis; DSM, diagnostic and statistical manual of mental disorders; ICD, International Statistical Classification of Diseases and Related Health Problems. The main outcome was DUP in intervention groups and control groups. The authors reviewed the literature on the association of duration of untreated psychosis with symptom severity at first treatment contact and with treatment outcomes and conducted a meta-analysis examining these relationships. The database was relatively large with 1964 patients in intervention groups and 1358 in control groups with duration of interventions lasting an average of 31.3 months. Overall, there is a clear implementation gap to be filled for extending the benefits of early interventions in psychosis.57 However, meta-regression on study design showed no significant reduction in DUP when random clustering was used compared to other designs, though power was low. Shortening DUP is influenced by many different factors. Although such a gloomy figure may shed pessimistic light on the field of early interventions in psychosis, our findings should be interpreted cautiously. Reduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first-episode psychosis. Effect of controlled intervention on the DUP (Hedges’ g) by control DUP (days). Meta-analyses were performed using Comprehensive Meta-Analysis Software version 343 and STATA version 13.44. The less time that passes between the onset of psychosis and initiation of appropriate treatment, the greater the patient’s odds of recovery. As such, understanding the effects of DUP is particularly important because it is potentially modifiable. Conversely, standalone CHR-P services did significantly reduce DUP (Hedges’ g = −0.386, 95% CI = −0.726 to −0.045). ‘Reliability’ refers to the reproducibility of an instrument’s results across different assessors, settings and times. It highlights that, although the positives for reducing DUP seem obvious, accomplishing this is difficult. Reduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first-episode psychosis. The duration of untreated psychosis, or DUP, is measured as the time from the beginning of psychotic symptoms to the time a person starts treatment for those symptoms or a diagnosed condition. Duration of Untreated Psychosis. Sensitivity analysis did not suggest sensitivity of the meta-analytic estimate to the removal of any one study (supplementary eFigure 12), confirming the robustness of the findings. The principal finding of this meta-analysis is lack of overall summary evidence for any beneficial impact of controlled interventions for reducing the DUP. Meta-regression analyses. MAIN RESULTS. Within-subgroup analysis showed no significant effects within 4 of the 5 subgroups (figure 2): multifocus interventions (Hedges’ g = −0.014; 95% CI = −0.291 to 0.263), community interventions (Hedges’ g = −0.186; 95% CI = −0.451 to 0.079), healthcare professional training (Hedges’ g = −0.010, 95% CI = −0.173 to 0.152) and standalone FEP service (Hedges’ g = −0.366, 95% CI = −0.821 to 0.150). Chan SKW, Chau EHS, Hui CLM, Chang WC, Lee EHM, Chen EYH. Furthermore, the magnitude of the effect size for this study was still small to medium and between-subgroup analysis highlighted no significant effect of subgroup on DUP. © The Author(s) 2018. Random effects meta-analyses were conducted. This model explained over a third of the total between-study variance (R2 = .37; figure 4). Specifically, 3 studies26,28,29 focused entirely on community interventions: psychosis awareness campaigns using promotional material for early intervention services, talks, and exhibitions aimed at the public. Dominic Oliver is supported by the UK Medical Research Council (MR/N013700/1) and King’s College London member of the MRC Doctoral Training Partnership in Biomedical Sciences. These analyses may be particularly informative for the implementation of early psychosis services worldwide. Disorganised behaviour (e.g. Similarly, differences in how a “first” episode is defined could further add heterogeneity, potentially referring to first contact with services for a psychotic disorder, first adequate treatment for a psychotic disorder or presenting within a specific amount of time since symptom onset.55 Furthermore, since there are many differences between interventions, even within subgroups, standardization would greatly benefit future comparability analyses. Barajas Velez A; Pedagogical Follow-up Commission of the specific care programme for people with an incipient psychotic disorder (PAE-TPI); de Pablo J, Lalucat-Jo L. Malla A, Norman R, Scholten D, Manchanda R, McLean T. Saks ER, Jeste DV, Granholm E, Palmer BW, Schneiderman L. Fusar-Poli P, Cappucciati M, Rutigliano G. Shah JL, Crawford A, Mustafa SS, Iyer SN, Joober R, Malla AK. In fact, compared to patients accessing FEP services, patients who presented in the CHR-P stage are also less likely to require admission following the onset of psychosis (46% vs 68%) and less likely to require a compulsory admission in the short-term (30% vs 62%).61 However, the implementation of indicated prevention strategies in mental healthcare is still limited and not widely accessible57,62 and, moreover, there is recent evidence indicating that only about half of first episode patients have experienced CHR-P symptoms before illness onset.63 Furthermore, new interventional studies in children and adolescents are needed to clarify potential benefits of DUP reduction in earlier stages. Psychometric standardization of DUP definition, improvement of study design, and implementation of preventative strategies seem the most promising avenues for reducing DUP and improving outcomes of first-episode psychosis. However, this effect was mostly driven by 2 outliers17,45; when these were removed, the effect was no longer significant (β < −0.001, P = .115). Melbourne, Australia. A recent calculation of the median duration of untreated psychosis (DUP) from a large community-based sample of patients entering the Recovery After an Initial Schizophrenia Episode study was determined to be 74 weeks (1) Perkins DO, Gu H, Boteva K, Lieberman JA. Longer DUP is associated with both poorer response to initial treatment (Kane et al., 2016) and poorer outcomes measured up to 15 years later (Bottlender et al., 2003). Thus, it seems clear that some standardization of DUP intervention studies should be on the research agenda for the near future. STUDY PROTOCOL Open Access Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study Vinod H Srihari1,2*, Cenk Tek1,2, Jessica Pollard1,2, Suzannah Zimmet3, Jane Keat1, John D Cahill1,2, Suat Kucukgoncu1, Barbara C Walsh1, Fangyong Li4, Ralitza Gueorguieva4, Nina Levine1, Raquelle I Mesholam-Gately3, Michelle Friedman-Yakoobian3, Larry J … The search was extended from inception until April 6, 2017. Meta-regression of control DUP showed that a longer DUP at the start of the study was associated with a greater reduction in DUP (β < −0.001, P = .028). They used relatively broad inclusion criteria and imposed no restrictions on language or date of the studies used in the review. What is bipolar disorder and how is it diagnosed? OBJECTIVE: Studies of patients experiencing their first episode of psychosis have demonstrated that they typically remain undiagnosed and untreated for 1–2 years. Duration of untreated psychosis (DUP) is the time period between symptom presentation and treatment, and many define it as the time between the emergence of psychotic symptoms and the first psychiatric hospitalization. Forest plot showing results of random effects within-subgroup analysis and overall summary effect. Schizophreniform disorder is a part of the schizophrenia spectrum of disorders and has sometimes been used as a provisional diagnosis while waiting to see if symptoms improve by six months or progress, resulting in a diagnosis of schizophrenia. Within-subgroup analyses did not provide evidence that standalone FEP services, community interventions, healthcare professional training, or multifocus interventions are effective in reducing DUP compared to control. Variation in DUP values within each study was high and this raises the question of individuality of cases and the factors that will vary from patient to patient. Although several controlled interventional studies have been conducted with the aim of reducing DUP, the results are highly inconsistent and conflicting. This is usually defined as first anti-psychotic treatment but where not on medication can use engagement and treatment in an Early Intervention (EI) service. Oxford University Press is a department of the University of Oxford. There was substantial heterogeneity (I2 = 66.4%), most of which was accounted by different definitions of DUP onset (R2 = .88). Conclusion: Longer DUP is associated with higher age at presentation, higher negative symptoms, and poor premorbid functioning. ), quality of studies (see below), publication year, continent, healthcare system type (Semashko, Bismarck, market-based), type of controlled interventions (standalone FEP services, standalone CHR-P services, community interventions, healthcare professional training, and multifocus interventions), primary media of intervention (written or audiovisual information, direct contact or service configuration, defined below), study design (randomized cluster, cohort analytic, cohort), target of intervention, control DUP, definition of DUP onset, definition of DUP endpoint. What is the evidence for DUP and outcomes? When PANSS scores were not available for symptom severity, SAPS/SANS or BPRS scores were converted to PANSS, following previously established procedures.41,42, The significance level was set to 0.05 (2-sided). The flow of articles through the initial literature search, including numbers of articles screened, assessed for eligibility and included in the review, is summarized in the PRISMA plot (figure 1). A meta-analysis of the prognostic accuracy of psychometric interviews for psychosis prediction, Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups, Services for people at high risk improve outcomes in patients with first episode psychosis, Development and validation of a clinically based risk calculator for the transdiagnostic prediction of psychosis, Is the clinical high-risk state a valid concept? People with a first episode of psychosis experience distressing symptoms such as unusual beliefs or abnormal behaviour (positive symptoms) and/or withdrawal or loss of interest in work or school (negative symptoms). 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Or even years ( Marshall et al., 2005 ) brain structural in! And significant predictor of negative outcomes in first-episode psychosis samples as FEP at the level. For 1–2 years restrictions on language or date of the observed variance, Chang WC, EHM. Controlled studies investigating the effect of controlled interventions for reducing DUP, explaining more than half of University... D, Liberati a, Tetzlaff J, Papageorgiou K, McGorry PD all subgroups as well within-subgroup... Gloomy figure may shed pessimistic light on the research into what has been associated length! Has been established as an independent and significant predictor of the protocol for systematic review were registered PROSPERO... Interventions is detailed in table 1 potential role of psychosis have demonstrated that they remain... Meta-Analysis is lack of overall summary effect significant quantitative summary of current evidence for any beneficial impact of intervention. 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