Treating schizophrenia earlier in life and the potential for prevention

Schizophrenia is a serious mental disorder, often with a chronic and debilitating course. Treating the disorder earlier in a patient’s life and in the life of the disorder may result in better outcome. The potential for prevention in the postonset phase (ie, tertiary prevention) could be achieved either by reducing the duration of untreated psychosis (DUP) or by introducing more effective interventions. The preponderance of evidence continues to suggest a relationship between shorter DUP and better short-term outcome. Prevention in the pre-onset phase is either by intervention in the premorbid phase to reduce the incidence (primary prevention), or intervention in the prodromal phase to reduce the prevalence (secondary prevention). However, the positive predictive power for psychosis for markers in the premorbid phase is low. In contrast, there has been substantial progress in identifying risk prospectively in the prodromal phase. The present clinical instruments identifying the prodrome have demonstrated good inter-rater reliability and predictive validity. There are also attempts to enhance the accuracy of identifying true positive prodromal patients by using genetic analysis, neuropsychologic testing, and neuroimaging studies. Two randomized clinical treatment trials have been conducted in prodromal patients and are discussed.     

Pharmacological intervention in the initial prodromal phase of psychosis.

Early identification and treatment of schizophrenia may alleviate the symptoms, delay the onset and improve the outcome of psychosis. Thus, detection of individuals at risk during the prodromal phase is an important task. Universal approaches to screen the general population or healthy subjects at risk have not proven possible to-date. However, clinical criteria for detecting ultra-high risk individuals have been developed for specialized settings, with their implementation in interventional studies. This article examines the rationale for early detection and intervention of psychosis, along with a review of some of the current studies. These target prevention using psychological and/or pharmacological intervention strategies have demonstrated promising results in high risk individuals. The German Research Network on Schizophrenia (GRNS) is conducting two multicenter early intervention studies; one with early psychological intervention in subjects who manifest early prodromal symptoms; with the second trial applying clinical management and pharmacological early intervention in subjects experiencing late prodromal symptoms (high risk subjects). Despite the promising results, many of the current studies have small sample sizes with study durations of a short period. The full benefits of early detection and intervention should be revealed once larger and longer studies are conducted.     

Durée de psychose non traitée : état des lieux et analyse critique

IntroductionPrognosis of schizophrenia has not significantly improved despite extensive research. There is often a relatively long delay between onset of symptoms and treatment initiation. Lately, duration of untreated psychosis (DUP), the time between the onset of psychosis and initiation of treatment, has been one of the most studied variables in patients presenting for a first psychotic episode in order to evaluate the impact of early intervention on the prognosis of schizophrenia. In the literature, a variety of criteria have been used to define both transition to psychosis and initiation of treatment. Furthermore, the dating of both of these variables is usually retrospective, further complicating the measurement of DUP.MethodsWe conducted a comprehensive review about DUP using Pubmed and Google Scholar databases up to January 2015 using the following keywords “schizophrenia”, “duration of untreated psychosis”, “duration of untreated illness” and “early intervention”. Papers were included if they were published in French or English.ResultsThe mean DUP was found to be 2 years but it can vary according to multiple factors such as denial of illness by the patient and family, withdrawal and isolation from friends and relatives, diagnostic errors, paranoid views of the mental health treatment systems, or negative symptoms. Long DUP may also be a correlate of poor premorbid functioning or of an insidiously unfolding psychosis. Considerable discrepancies exist in the way that DUP is estimated in different studies. Although the clinical interview remains the most common way of measuring DUP, so far there is no evidence for favoring one method over another. Regardless of measurement method, a longer DUP is found to be associated with poorer outcome in schizophrenia in both the short and long-term across a number of domains: symptoms severity, remission rates, the risk of relapse, global functioning and quality of life. Its role in functional outcome appears to be mediated largely by negative symptoms, for which there is still no effective treatment. A recent meta-analysis has shown that shorter DUP is associated with less severe negative symptoms at short and long-term follow-up, especially when DUP is shorter than 9 months. The mechanism of the relationship between DUP and outcome is still undefined. A hypothesis is that the shorter the DUP, the more likely the intervention is being applied during the period in which neurobiological deficit processes in schizophrenia are most active.DiscussionA study of the duration of untreated illness (DUI), which is defined as the DUP and the prodromal phase, seems necessary because results of studies evaluating the effect of early detection and intervention in individuals with clinical high risk for psychosis are promising. A number of interventions such as omega 3 fatty acids and integrated psychosocial interventions seem to delay transition in the at-risk population. However, replication studies are lacking, and a great proportion of at high-risk individuals will spontaneously remit or develop diseases other than chronic psychosis, making us question the advantages and disadvantages of a treatment. Taking into consideration the high prevalence of comorbidities in individuals referred for clinical high-risk state and their effect on the individual's functioning, future interventions in the field need to address not only the preventative efficacy on psychosis transition but also their effectiveness in improving the functioning of this population and their effect on the outcome of schizophrenia when transition to psychosis has occurred.ConclusionDespite the huge advances in the field of schizophrenia, many questions remain unanswered and huge efforts are still necessary to understand the pathophysiology of this illness in order to improve its outcome.     

Treating early psychosis: who,what, and when?

Early intervention and prevention in schizophrenia is just over 10 years old. The assumption guiding this field is that intervention is likely to be most effective if it begins before psychosis sets in, ie, during the prodromal phase. Although a substantial number of prodromal treatment programs have been initiated around the world, three early programs have generated most of the intervention findings to date: Personal Assessment and Crisis Evaluation (PACE) in Australia, and the Prevention through Risk Identification, Management, and Education (PRIME) and Recognition and Prevention (RAP) programs in the USA. The data suggest that early intervention leads to a reduction in prodromal symptoms and clinical distress. However, prevention of psychosis remains an unresolved question. Other issues include defining who should be treated, with what, and when. In addition, treatment targets associated with functional disability, such as early prodromal negative symptoms and risk factors, continue to emerge. Newly identified targets, in turn, suggest the need for a variety of novel interventions and treatment strategies.     

A community intervention for early identification of First Episode Psychosis

Abstract Objective The aim of this study was to assess the impact of a community case identification program on duration of untreated psychosis (DUP) (a measure of delay in treatment) and characteristics of patients entering treatment for a first episode of psychosis. Method Using a quasi-experimental historical control design, patients within a defined geographic catchment area who met DSM-IV criteria for a first episode of a psychotic disorder (FEP) were assessed on a number of demographic and clinical variables including DUP, length of prodromal period and symptoms at initial presentation, for 2 years prior to and 2 years after the introduction of a community-wide Early Case Identification Program (ECIP). The ECIP was designed to promote early recognition and referral of individuals with a FEP from any possible source of referral including self-referrals. Treatment interventions offered were the same throughout the two phases. Results In all, 88 and 100 patients met criteria respectively in phases I and II. There were no significant differences in rates of treated incidence or DUP between the two phases. Patients recruited in phase II had significantly longer prodromal periods and higher level of psychotic and disorganization symptoms. There were no differences in level of negative symptoms or pre-morbid adjustment. Conclusion A community-wide approach to early case identification may not be the most effective way to reduce delay in treatment of psychosis, but may bring into treatment patients who have been ill for long periods of time and have a higher level of psychopathology. A more targeted approach directed at primary care and emergency services may achieve different results in reducing delay in treatment.     

Early detection and intervention in the initial prodromal phase of schizophrenia

Attenuated and transient psychotic symptoms as well as a combination of different risk indicators and a recent significant deterioration in global functioning are currently used as a preliminary definition of the initial prodromal or at-risk mental state by the vast majority of investigators in research on early psychosis detection and intervention. Recently published results demonstrated a mean progression to frank psychosis within one year in 36.7 % of cases showing emerging symptoms, indicating that these criteria already seem to provide a satisfying assessment for risk of an imminent psychosis. However, as functional decline often sets in before this time, detection in earlier prodromal stages seems necessary. In a prospective study, certain basic cognitive and perceptive symptoms showed good to excellent predictive accuracy for schizophrenic psychosis, thus potentially offering a reasonable approach for earlier detection. Early intervention is aimed at improving prodromal symptoms, avoiding functional deterioration, and suppressing or delaying transition to psychosis. Initial study results targeting an earlier or later prodromal phase are promising, but longer follow-ups and larger samples are needed.     

Treatment delay and response rate in first episode psychosis

OBJECTIVE: There is no consistent evidence of long duration of untreated psychosis (DUP) predicting long time to response (TTR) in first psychosis. This study aims to investigate the predictors of DUP and TTR in a first episode patient population. METHOD: An epidemiologically representative sample of 157 non-affective first psychotic episode patients was interviewed and followed-up for at least half a year. RESULTS: The mean DUP was 46 weeks, the median 31 days. Long DUP was associated with being unemployed before treatment and male gender. Short DUP, having a job, and living with a partner before treatment predicted early response. CONCLUSION: Early intervention likely improves short-term treatment response in first episode psychosis. The best strategy to reduce DUP probably is to direct attention to the substantial number of patients who do not engage in regular treatment.     

One year outcome in first episode psychosis: influence of DUP and other predictors

BACKGROUND: A number of studies have reported evidence of a relationship between longer duration of untreated psychosis (DUP) and poorer outcome at 1 year while others have failed to find such evidence. It is possible that several other predictors may confound this relationship and there may be different predictors for different dimensions of outcome. In the current study we examined relationship between DUP and several other predictors, and 1 year outcome on rate and level of remission as well as level of positive, negative, depressive and anxiety symptoms in a community cohort of first episode psychosis patients. METHOD: All potential cases of a first episode of non-affective psychosis were assessed and offered treatment in a comprehensive treatment program. Data were collected on all patients who completed 1 year of treatment on a number of predictor variables (DUP, length of the prodromal period, age of onset, gender, pre-morbid adjustment during childhood and adolescence, diagnosis) and outcome variables (level of remission, positive, negative, depression and anxiety symptoms based on ratings on SAPS, SANS, CDS and HAS, respectively). Data were analysed using an analysis of variance, bivariate correlations and hierarchical regression analysis. RESULTS: Of a total of 130 patients were offered treatment, 106 completed 1 year of treatment and complete data were available on 88 subjects, 80% of whom met criteria for schizophrenia spectrum psychosis. The rate and level of remission were significantly higher for patients with shorter DUP (<22 weeks). DUP was the only independent predictor of the level of remission as well as reality distortion at 1 year; for disorganization syndrome and negative symptoms it was the age of onset and level of premorbid adjustment in adolescence, respectively; while the level of anxiety was predicted by the length of the prodrome. Additional predictors increased the variance explained by each model. CONCLUSION: Our results confirmed the independent role of DUP in remission and positive symptom outcome at 1 year, thus providing support for the enthusiasm for early intervention. However, the model including DUP and premorbid adjustment in early adolescence explained a greater amount of variance in outcome on positive symptoms than DUP alone. On the other hand, outcome on negative symptoms, disorganization and anxiety are more likely to be influenced by longer term characteristics such as premorbid adjustment, earlier age of onset, gender and the length of the prodromal period, and therefore may not be as responsive to effects of early intervention.     

Duration of untreated psychosis and its correlates in first-episode psychosis in Finland and Spain

OBJECTIVE: To examine the association of duration of untreated psychosis (DUP) with early course characteristics in first-episode psychosis in Finland and Spain. METHOD: Eighty-six patients from Finland (49) and Spain (37) were evaluated on various early course characteristics. RESULTS: The mean value of DUP was 4.0 months (median 2 months) for the Finnish patients and 9.9 months (median 2 months) for the Spanish ones. In both groups, long DUP was associated with insidious onset, poor global functioning, and laboral incapability. Among the Finnish patients exclusively, long DUP correlated with a weak earlier social network, instability of professional identity, long duration of prodromal symptoms, psychological dependency on the family, and criticism by the parents of the patient. Among the Spanish patients only, longer DUP was associated with more severe positive symptoms at admission. CONCLUSION: There are universal psychosocial factors influencing DUP, but also cultural differences may have an impact on the treatment delay.     

Determining the chronology and components of psychosis onset: The Nottingham Onset Schedule (NOS)

The Nottingham Onset Schedule (NOS) is a short, guided interview and rating schedule to measure onset in psychosis. Onset is defined as the time between the first reported/observed change in mental state/behaviour to the development of psychotic symptoms. Onset is conceptualised as comprising of (i) a prodrome of two parts: a period of 'unease' followed by 'non-diagnostic' symptoms; (ii) appearance of psychotic symptoms; and (iii) a build-up of diagnostic symptoms leading to a definite diagnosis. Twenty consecutive cases of first-episode psychosis were administered the NOS schedule to determine its psychometric properties including inter-rater and test-retest reliability. Its clinical and research potential as a reliable measure of duration of untreated psychosis (DUP) was assessed in a cohort of 99 cases of first-episode psychosis (56 schizophrenia, 43 affective psychoses). NOS identified all prodromal symptoms previously reported in other studies. There was high degree of inter-rater and test-retest reliability for all components of NOS. Duration of untreated psychosis was significantly longer (p<0.05) in schizophrenia (mean 179 days, S.D. 344; median 52 days) than in affective psychosis (mean 15 days, S.D. 116; median 12 days) but there were no gender differences between lengths of prodrome or treatment delays. The NOS provides a standardised and reliable way of recording early changes in psychosis and identifying relatively precise time points for measuring several durations in emerging psychosis. The scale is easy to use and is not time-consuming or labour intensive. Onset, as measured by NOS, is significantly longer in schizophrenic disorders than in affective psychosis. A small proportion of schizophrenia cases have very long DUP. Some cases with schizophrenia receive anti-psychotics in the prodromal phase, prior to the emergence of frank psychotic symptoms.     

Early intervention in first-episode psychosis

OBJECTIVE: Substantial delays in providing access to treatment in first-episode psychosis have been well documented. The present study examines the impact of strategies aimed at improving access and reducing delays. METHOD: A pilot community education campaign was conducted with the aim of reducing the duration of untreated psychosis (DUP) in a geographically defined intervention sector located in the northwestern region of Melbourne, Australia. Utilising a quasi-experimental design, a comparison sector with similar demographics was selected from another part of the north-western region. A mobile early detection team and the same treatment system served both sectors. RESULTS: While there was no significant difference between the mean DUP for intervention and comparison sectors, the distributional features of DUP between the two regions were significantly different. In the intervention sector, disproportionately more cases with very long DUP were detected. When a small number of outliers were removed, the mean and median DUP in the intervention sector was reduced. CONCLUSION: These findings highlight the complexity of treatment access and delay and suggest that efforts to reduce DUP may have two effects, not one. Firstly, a different sample of cases is treated through the detection of hidden "long DUP" cases that otherwise may have remained untreated. Secondly, the DUP for the remainder may indeed be reduced. More research with larger samples and more potent campaign strategies is clearly required. It may also be worth considering whether there is a safe and ethical way to undertake a RCT of early versus delayed antipsychotic treatment to perhaps settle the DUP debate once and for all.     

Predictors of cognition in first episode psychosis

PurposeCognitive deficits are common in the first episode of psychosis (FEP) and may begin much earlier. While some evidence suggests that the decline in cognition occurs over the untreated symptomatic period, including the prodromal phase, others point to these deficits being present even earlier. We aimed to investigate the differential effect of untreated symptomatic and pre-morbid phases on cognition in a large sample of FEP.MethodsTwo hundred and sixty eight FEP patients, admitted into a specialized early intervention service, were administered neuro-cognitive tests. The Circumstances of Onset and Relapse Schedule (CORS) was administered for measurement of duration of untreated psychosis (DUP), the duration of untreated illness (DUI) and demographic factors. The Pre-morbid Adjustment Scale (PAS) was used to measure different domains of pre-morbid adjustment. Seventy three healthy controls were also recruited for neuro-cognitive comparison.ResultsWe observed no effect of DUP and a minimal effect of DUI on cognitive functioning in FEP. Instead, the early educational pre-morbid adjustment domain was most strongly associated with cognition and predicted both global cognitive and verbal memory outcome in FEP.ConclusionOur results suggest that symptoms associated with the symptomatic phase of a FEP do not influence cognitive functioning in FEP. Instead, cognitive deficits in FEP may predate illness onset and may indicate susceptibility to such illness.     

A case of prolonged duration of untreated psychosis: barriers to treatment and strategies to improve the outcome

Several factors may contribute to increase in duration of untreated psychosis (DUP). In most cases, early intervention, namely psychopharmacological or psychosocial intervention, is done after first-episode psychosis. It is important to know what factors can contribute to duration of untreated psychosis. During this phase, patients often display unspecific symptoms such as anxiety and depression, personality disorders, and abuse of alcohol or drugs. These symptoms could go unrecognized and, hence, cause a delay in seeking treatment. In addition, functional and social decline frequently occurs in the prodromal phase or in the early course of schizophrenia. The purpose of this paper is to highlight barriers that cause delay in treatment and to review early detection and specific treatment strategies that may help to improve outcomes leading to psychosocial recovery.     

Early intervention in patients at ultra high risk of psychosis: benefits and risks

Objective: Prediction of transition to psychosis in the prodromal phase of schizophrenia has raised interest in intervention prior to the onset of frank psychosis. The aim of this review was to examine whether interventions in the prodromal phase have a favourable benefit/risk ratio. Method: A literature search in PubMed, EMBASE and PsycINFO was performed. Results: Three randomized clinical trials with antipsychotic medication and/or cognitive behavioural therapy as clinical intervention suggested a positive effect at the end of treatment, but no significant differences were found at the end of follow‐up periods from 1 to 4 years. Naturalistic studies present a hypothesis about a possible preventive effect of antidepressive medication. The results of eight other studies are more difficult to interpret. Side‐effects of antipsychotic medication and non‐adherence with medication are essential problems. Conclusion: At the present time, the data concerning the benefits and risks do not justify prodromal intervention as standard clinical practice.     

Early recognition and early treatment of schizophrenia: chance or dilemma?

The early recognition and treatment of schizophrenia in children and adolescents is one of the most important therapeutic goals because of the postulated relation between delayed initiation of treatment and an unfavourable developmental course. The duration of untreated psychosis (DUP) seems to be significantly prolonged in adolescents compared to adults due to both a protracted development of psychotic features and the failure of families and health workers to take seriously the initial signs of psychosis. The idea of primary prevention is criticized since the unspecificity of prodromal signs precludes any specific intervention to prevent schizophrenia. The tree hit model of pathogenesis is outlined and strategies of risk evaluation in early psychotic phases on the basis of the biopsychosocial model are promoted.     

Long-term effects of a community intervention for early identification of first-episode psychosis

Objective: To assess whether an Early Case Identification Program (ECIP) for first‐episode psychosis (FEP), which showed no significant short‐term effects, has a delayed impact on duration of untreated psychosis (DUP). Method: Using a historical control design, FEP patients were assessed on clinical variables over three consecutive phases, 2 years prior, 2 years during and 3 years after implementation of the ECIP. Additional analyses were conducted on non‐affective and schizophrenia spectrum psychoses cases only. Results: There was no overall significant difference in DUP across the three phases. For cases treated within the first year of illness a nonsignificant reduction in DUP to less than 2 months observed during the active phase was sustained post‐ECIP. Conclusion: In some jurisdictions community‐wide early case detection may fail to have an immediate or delayed effect on DUP, especially for cases who normally present for treatment with DUP >1 year.     

The outcome of early intervention in first episode psychosis

Abstract

The last 20?years have seen an increased focus on early intervention in psychotic disorders in research and clinical practice. Interventions have typically aimed at either reducing the duration of untreated psychosis (DUP), or developing specialized treatment facilities for patients with first episode psychosis (FEP). This review presents an overview of the most important trials and meta-analytic evidence within this field. The possibilities for reducing DUP and elements included in specialized early intervention treatment are discussed. Further, it examines long-term outcomes of early interventions and results from prolonged early intervention trials. Lastly, it analyses possible interactions between DUP and specialized early intervention treatment. In conclusion, both elements appear necessary in order to develop an integrated service that can provide the optimal treatment for patients with FEP. The aim of this article is to provide an overview over the most important trials and evidence regarding the outcome of early intervention in first episode psychosis.     

Early detection and secondary prevention of psychosis: facts and visions*

Abstract. As effective and practical approaches to primary and universal prevention of psychosis are lacking, intervention efforts are targeted at the early stages of schizophrenia to prevent (by way of secondary prevention) or postpone psychosis onset, reduce severity of illness or at least ameliorate the social consequences involved. Early intervention requires early detection and early recognition (diagnosis) of persons at risk and early prediction of psychosis. Within the German Research Network on Schizophrenia (GRNS) awareness programmes are being carried out in several German cities, and these efforts are already improving utilisation of early-recognition and early-prediction services by at risk persons. The empirical basis of developing a two-step early-recognition inventory and strategies of application will be discussed. This instrument is supplemented by a set of cognitive tests, prospectively validated in the GRNS. Results from preliminary analysis of data covering a two-year period demonstrate that the inventory and the cognitive tests are readily accepted. When used for screening in non-specialist settings and at the next level, i. e. at early-recognition centres, they seem to permit identification of at-risk persons. Early intervention is being tested 1) in a randomised controlled multi-centre trial consisting of a specially developed cognitive-behavioural therapy in the early (prepsychotic) prodromal state and 2) on additional treatment with appropriate doses of amisulpride in the late prodromal (early psychotic) state. Preliminary data from Study 1 covering 16.3 months show significantly fewer transitions to psychosis and from Study 2 reduced positive and negative symptoms and improved global functioning compared with controls who had received normal clinical treatment. As a result, both the early-recognition inventory plus cognitive tests and the two therapy strategies are feasible. We hope that the favourable trend indicated by the preliminary data will be confirmed in the final analysis planned for 2005 and the objective of implementing effective and practical secondary prevention of psychosis and its consequences will be attained.* This paper was written within the framework of the German Research Network on Schizophrenia and was funded by the German Federal Ministry for Education and Research BMBF (grant 01 GI 0236).     

Duration of untreated psychosis: a proposition regarding treatment definition

Aim: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first‐episode psychosis cohort to assess the impact of the choice of definition on DUP estimation. Methods: The DUP of 117 patients admitted in the Treatment and Early Intervention in Psychosis Program Psychosis in Lausanne was measured using the following sets of criteria to define treatment onset: (i) initiation of antipsychotic medication; (ii) entry into a specialized programme; and (iii) entry into a specialized programme and adequate medication with a good compliance. Results: DUP varied greatly according to definitions, the most restrictive criteria leading to the longest DUP (median DUP1 = 2.2 months, DUP2 = 7.4 months and DUP3 = 13.6 months). A percentage of 19.7 of the patients who did not meet these restrictive criteria had poorer premorbid functioning and were more likely to use cannabis. Longer DUP3 was associated with poorer premorbid functioning and with younger age at onset of psychosis. Conclusion: These results underline the need for a unique and standardized definition of the end of DUP. We suggest that the most restrictive definition of treatment should be used when using the DUP concept in future research.     

Duration of untreated psychosis: Impact of the definition of treatment onset on its predictive value over three years of treatment

BackgroundWhile reduction of DUP (Duration of Untreated Psychosis) is a key goal in early intervention strategies, the predictive value of DUP on outcome has been questioned. We planned this study in order to explore the impact of three different definition of “treatment initiation” on the predictive value of DUP on outcome in an early psychosis sample.Methods221 early psychosis patients aged 18–35 were followed-up prospectively over 36 months. DUP was measured using three definitions for treatment onset: Initiation of antipsychotic medication (DUP1); engagement in a specialized programme (DUP2) and combination of engagement in a specialized programme and adherence to medication (DUP3).Results10% of patients never reached criteria for DUP3 and therefore were never adequately treated over the 36-month period of care. While DUP1 and DUP2 had a limited predictive value on outcome, DUP3, based on a more restrictive definition for treatment onset, was a better predictor of positive and negative symptoms, as well as functional outcome at 12, 24 and 36 months. Globally, DUP3 explained 2 to 5 times more of the variance than DUP1 and DUP2, with effect sizes falling in the medium range according to Cohen.ConclusionsThe limited predictive value of DUP on outcome in previous studies may be linked to problems of definitions that do not take adherence to treatment into account. While they need replication, our results suggest effort to reduce DUP should continue and aim both at early detection and development of engagement strategies.