The European Prediction of Psychosis Study (EPOS): integrating early recognition and intervention in Europe

Abstract

This paper provides the rationale and design of the European Prediction of Psychosis Study (EPOS), the first European prospective transnational field study of the prodrome and moderating risk/resilience factors of psychosis. As different health systems provide different structures of care, prevention programmes will only be successfully implemented and sustained system-wide, if they can be adapted to the system's special opportunities and needs. EPOS will provide a sound data base for a future evidence-based prevention of psychosis. Data on the recruitment of subjects and on the distribution of the four clinical criteria for an at-risk mental state for psychosis are given.

The European Prediction of Psychosis Study (EPOS) is the first European multicentre investigation focusing on early detection of persons at risk for psychosis, particularly schizophrenia, and was designed as a prospective, longitudinal, naturalistic field study. Originally designed by centres in Germany, Finland, The Netherlands, UK and Spain, the study is carried out in Cologne, Berlin, Turku, Amsterdam, Birmingham and Manchester, which together cover a catchment area of approximately 7.5 millions inhabitants.

EPOS addresses four main issues which are important in current research on early detection of psychosis:

• Pathways to care: How do persons at risk for psychosis access their health care system, and how does this vary between the different European Union healthcare settings? A systematic retrospective assessment of pathways to care and onset of symptoms, and an evaluation of delays and obstacles to adequate treatment will form an empirical database to design awareness and prevention programmes for the community in order to reduce the duration of untreated illness.

• Prediction of psychosis: What should be assessed in order to predict transition to psychosis? The predictive validity of past and present symptoms and deficits, of risk indicators and of personality, neurocognitive and neurobiological measures, as well as their possible synergisms, is evaluated.

• Disabilities: When and how do social, educational, vocational and other functional impairments start in prodromal patients, and what is their course? The systematic prospective assessment of disabilities and quality of life of persons at risk for psychosis aims at operationalized definitions of their deficits and needs in the prodromal stages of the illness. EPOS is the first study designed to reveal the onset, prevalence and determinants of disabilities in the prodromal stages of psychosis, which is a precondition for an early and targeted rehabilitation.

• Early interventions: What kinds of interventions are applied in at-risk individuals, by whom, and what is their cost-effectiveness? Any intervention such as psychotherapy or medication and institutional/non-institutional support offered to persons at risk for psychosis in the participating regions is monitored and evaluated for its cost-effectiveness and benefits to the person. The aims are an assessment of the possible applications and chances of success of early detection and intervention, and the provision of an empirical basis for the development of a common European framework for the care of people at risk for psychosis.

METHODS

Design

EPOS includes a comprehensive baseline assessment and two follow-ups, at nine and 18 months. All persons between 16 and 35 years of age presenting to any participating centre are being screened for the presence of four psychopathological inclusion criteria (Table 1). If at least one inclusion criterion is fulfilled and the person provides his/her informed consent, the baseline clinical examination as well as the neurocognitive, neurophysiological and magnetic resonance (MR) volumetric measures are performed. If inclusion criteria are not fulfilled, the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID, 1) and the Structured Interview for Prodromal Syndromes (SIPS, 2) are performed to complete the clinical assessment, thus establishing two control groups (see below). These groups will be re-examined only after 18 months to record any transitions to psychosis.

Table 1.

Inclusion criteria for the EPOS core group

Attenuated positive symptoms (APS)
Presence of at least one of the following SIPS symptoms with a score between 3 and 5 and an appearance of several times per week for a period of at least one week:
•	Unusual thought content / delusional ideas (P1)
•	Suspiciousness / persecutory ideas (P2)
•	Grandiosity (P3)
•	Perceptual abnormalities / hallucinations (P4)
•	Disorganized communication (P5)
•	Odd behaviour or appearance (D1)
Brief limited intermittent psychotic symptoms (BLIPS)
Presence of at least one of the following PANSS symptoms that resolve spontaneously in 7 days and an interval between episodes with these symptoms of at least one week (two episodes of BLIPS separated by less than one week are considered as being one episode; if the total duration then becomes more than one week, the transition criterion is fulfilled):
•	Hallucinations (PANSS P3 score ≥ 4)
•	Delusions (PANSS P1, P5, P6 score ≥ 4)
•	Formal thought disorder (PANSS P2 score ≥ 4)
Familial risk plus reduced functioning
A change in mental state or functioning leading to a reduction of 30% or more on the Global Assessment of Functioning scale for at least one month within the last year compared to the highest level of previous functioning, plus at least one of the following risk indicators:
•	One first- or second-degree relative with a history of any DSM-IV psychotic disorder (not due to a medical factor or substance induced)
•	A schizotypal personality disorder of the index person according to DSM-IV
Basic symptoms
Presence of at least two of the following symptoms from the cluster “cognitive disturbances” for more than one year, with a BSABS-P score ≥ 3 during the last three months:
•	Inability to divide attention (A.8.4)
•	Thought interferences (C.1.1)
•	Thought pressure (C.1.3)
•	Thought blockages (C.1.4)
•	Disturbances of receptive speech (C.1.6)
•	Disturbances of expressive speech (C.1.7)
•	Disturbances of abstract thinking (“concretism”; C.1.16)
•	Unstable ideas of reference (“subject-centrism”; C.1.17)
•	Captivation of attention by details of the visual field (C.2.9)

SIPS – Structured Interview for Prodromal Syndromes; PANSS – Positive and Negative Syndrome Scale; BSABS-P – Bonn Scale for the Assessment of Basic Symptoms - Prediction List

Subjects

A minimum number of 250 persons fulfilling at least one of the inclusion criteria listed in Table 1 ("core group") are to be recruited across the six participating centres. The inclusion criteria for EPOS are partly in line with the "ultra-high risk" (UHR) criteria used by the Melbourne and Yale groups (3,4). In addition, the basic symptom cluster "cognitive disturbances" is used as a fourth criterion (5,6). Moreover, the genetic risk criterion is extended to second-degree relatives with a psychotic disorder. Differently from the Melbourne criteria, brief limited intermittent psychotic symptoms (BLIPS) are not operationalized using the Brief Psychiatric Rating Scale, but using the Positive and Negative Syndrome Scale (PANSS, 7), which has the advantages of a more reliable item scoring and of the correspondence to the SIPS.

The control group I includes subjects suffering from attenuated positive symptoms (APS) or BLIPS or any of the 21 cognitive, perceptual and motor disturbances included in the Bonn Scale for the Assessment of Basic Symptoms - Prediction List (BSABS-P, 8), but not fulfilling the inclusion criteria listed in Table 1 (i.e., APS/BLIPS not within the last three months but within the last year, or basic symptoms below threshold concerning number, cluster or time frame).

The control group II includes subjects who seek help, but throughout their lifetime have never experienced any APS, BLIPS or BSABS-P symptoms and do not currently fulfil the inclusion criterion of familial risk and reduced functioning.

Only if inclusion criteria are fulfilled, exclusion criteria are assessed. These are given in Table 2.

Table 2.

Exclusion criteria for the EPOS core group

•	Previous psychotic episode for more than one week
•	Symptoms are due to substance abuse:
	-	for cannabis, if a symptom has not been definitely present before the use of the substance, there has to be a drug-free period (if the symptom is still present during the drug-free period, the subject can be included). If a symptom was definitely present before the use of cannabis, the subject can be included despite a present abuse.
	-	for other hallucinogens and amphetamines, the drug-free period has to be three months, i.e. new symptoms have to be still present after this period. An ongoing use of these drugs is an exclusion criterion.
	Alcohol dependence is an exclusion criterion, but alcohol abuse is not.
•	Symptoms are due to an organic mental disorder (such as intoxication or neurological disorders)
•	Verbal IQ below 85

As a continuation of the BLIPS definition, a transition to psychosis is defined by the presence of psychotic symptoms - i.e. hallucinations (PANSS P3 score ≥4), delusions (PANSS P1, P5 or P6 score ≥ 4) or formal thought disorders (PANSS P2 score ≥4) - for more than one week.

Assessments

To fulfil the four main objectives of EPOS, a thorough multi-level assessment of past and present psychopathology, personality, neurocognitive, neurophysiological and structural brain abnormalities is being carried out. Pathways to care, disabilities, and quality of life are also assessed. Treatment will be documented and direct and indirect costs of the illness will be calculated.

Socio-demographic data and general psychopathology

A Basic Data Form (9), which was developed for the purpose of EPOS, briefly reviews the person's sociodemographic background, physical health, obstetric and family history, as well as premorbid adjustment, social functioning and disability by psychiatric symptoms. For the latter, the Premorbid Adjustment Scale (PAS, 10) and the Prognostic Scale (S&CPS, 11) were incorporated into the Basic Data Form.

The SCID (1) is applied to rule out present or past psychosis and to evaluate comorbid conditions. Parts of the Composite International Diagnostic Interview (CIDI, 12) are used to assess substance use/abuse, that is considered to be an environmental factor eliciting psychotic relapse (13,14).

Prodromal symptoms

The SIPS (2) is used as a comprehensive diagnostic tool designed specifically for the assessment of a broad spectrum of prodromal signs and symptoms. The BSABS-P (9) is used to assess 21 self-experienced cognitive, perceptual and motor disturbances found to be predictive for a transition into psychosis (5,15). The PANSS (7) is used to assess the severity of BLIPS and to extend the SIPS regarding negative symptoms and global psychopathology. After transition, it is applied to assess the severity of the psychotic state.

Lifetime psychopathology and duration of untreated illness are determined with the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS, 16). All symptoms of the inclusion criteria are assessed with a special Course of Screening Symptoms sheet with regard to first onset as well as course and subjective burden during the last 12 months.

Pathways to care

The previous history of contacts with the health care system, the pathways to care and the delays are assessed with a specifically developed instrument based on the multicentre World Health Organization study on the pathways to care in primary health care (17,18). The updated EPOS - Pathways to Care questionnaire is used to collect information on key issues related to previous contacts with helping agencies, such as presenting symptoms, reasons for the decision to seek care and reasons for delay.

Disability and quality of life

The Global Assessment of Functioning scale (GAF-M, 19) is used to assess the reduction in social functioning as being part of the inclusion criterion "familial risk plus reduced functioning". The World Health Organization - Disability Assessment Schedule II (WHO-DAS II, 20) is used to assess difficulties in maintaining personal care, performing occupational tasks and functioning in relation to the family and the broader social context due to a mental disorder. The revised version of the Modular System for Quality of Life (MSQL-R, 21) is used to evaluate subjective quality of life in several areas: physical health, vitality, material satisfaction, spare time, partnership, family and occupation, as well as psychosocial, affective and general quality of life.

Treatment and cost-effectiveness

The Treatment Documentation Sheet (TDS, 22) is used to document in detail all contacts with health care agencies related to mental health problems, i.e. hours of psychological intervention, number of contacts with health care professionals, dosage of psychopharmacological treatments. It has been developed on the basis of a systematic review of the literature and a systematic, comprehensive collection of treatment settings, modalities and interventions available in the participating areas.

The Client Service Receipt Inventory (CSRI, 23), a wellestablished instrument for the assessment of direct and indirect costs of illness and cost-effectiveness of interventions, used successfully in European schizophrenia research (24,25), has been adapted for the needs of EPOS.

Additional measures

A screening for DSM-III-R personality disorders is performed with the revised version of the Personality Diagnostic Questionnaire (PDQ-R, 26). Schizotypal personality traits, which have been repeatedly shown to be a risk factor for schizophrenia (15,27,28), are systematically assessed with the Schizotypal Personality Questionnaire (SPQ, 29), whose positive dimension seems to reflect the genetic vulnerability to schizophrenia (30) as well as nonfamilial psychosis-proneness (31).

The Level of Expressed Emotion Scale (LEE, 32), a selfrating used to assess the person's interactions with his/her most significant other, has been included, because a high expressed emotion level is regarded as a risk factor for psychotic relapses in schizophrenia and may trigger the onset of a first psychotic breakdown in at-risk persons (33-37). Furthermore, its earlier and repeated assessment during the prodromal period will help to clarify the still unclear question of whether a high expressed emotion level in families of schizophrenics should be regarded as a general communication style or the family's reaction to the (developing) illness.

Recollections of trauma during lifetime are reviewed by means of the Trauma and Distress Scale (TADS, 38), because an accumulation of traumatic events were found among schizophrenic patients (39), with a possible, yet unclear contribution to the development of the disorder.

The Beck Depression Inventory (BDI, 40) is included as a self-report scale to review the course and severity of depressive symptoms during prodromal stages and interventions, since depression was retrospectively reported to be the most frequent earliest sign of illness in first-episode schizophrenic patients (41).

Life events are reviewed and evaluated for the 12 months prior to inclusion by a chart adapted for EPOS from the Munich Life Event List (MEL, 42) that also includes an assessment of the appraisal of the event and the degree of subjective burden.

Neurocognitive assessments

The various stages of information processing are monitored with a set of well-established neuropsychological instruments.

The identical pairs version of the Continuous Performance Test (43) is used to measure sustained attention. It has been repeatedly shown to indicate genetic liability to schizophrenia unrelated to schizotypy (44-46).

The Auditory Verbal Learning Test (47) is used to investigate whether at-risk persons show a mnestic profile which is distinguishable, yet similar to that of schizophrenic patients. It assesses recall and recognition of learnt materials, progression in learning, proactive and retroactive inhibition, primacy and recency effects.

The Verbal Fluency Test (48) is used to assess verbal fluency abnormalities, which are regarded as a familial trait marker for schizophrenia (49).

The Finger Tapping Test (50) is used to measure psychomotor abnormalities, since previous research suggested that central aspects of motor aberrations are associated with a liability to psychosis (51).

The assessment of spatial working memory is done by a computerized version of the Spatial Memory Test by Cannon et al (52), that requires remembering a sequence of spatial locations over a brief delay, since spatial working memory impairments are discussed as a possible endophenotypic marker for schizophrenia (53,54).

Biological investigations

High-resolution, three-dimensional T1 and T2 weighted MR scans will be performed. A voxel-based morphometry for significant regions will be done using statistical parametrical mapping (55). As a second step, a region of interest (ROI) based approach will be used. The neurophysiological dimension of information processing and its disturbances will be studied by quantitative EEG and eventrelated potentials, i.e. mismatch negativity (56) and P300.

RESULTS

By July 2004, 953 persons were screened for inclusion criteria, of which at least one was fulfilled by 340 (35.7%) in the absence of any exclusion criterion. Two hundred thirty-six (69.4%) of these 340 subjects gave informed consent to participate in the study and entered the core group of EPOS. Seventy-one (7.4%) screened persons entered the control group I; 175 (18.4%) entered the control group II. Three hundred sixty-seven (38.5%) persons were excluded, more than 50% of them because of a present or past psychotic episode. One hundred thirty (55.1%) of the core group subjects were male. The mean age of this sample was 22.5 (±5.1) years (range 15-35 years, median 21 years), with no significant difference between males (22.3±4.7 years) and females (22.9±5.6 years).

Among the 236 core group subjects, most reported APS (81.6%). This was closely followed in frequency by at least two basic symptoms of the cluster "cognitive disturbances" (65.5%), whereas BLIPS (12.6%) and the family risk plus reduced functioning criterion (16.2%) were met more infrequently. Thereby, the majority met one (44.2%) or two inclusion criteria (37.8%), seldom three (16.2%) and rarely four (1.8%); 13.5% were included on the basis of cognitive disturbances alone.

DISCUSSION

Prevention programmes, in principle, can follow three different approaches - a universal, a selective and/or an indicated one (57) - which reflect segments of the population as well as levels of risk (58). A universal prevention that targets the general population unspecifically as a whole is obviously not appropriate for a rare disorder of yet unknown, but certainly multi-factorial aetiology (59). Furthermore, a selective prevention approach to schizophrenia aiming at a segment of the population which is clinically healthy, but at a high risk for the disease (e.g., because of a genetic liability) would result in too many false positive and false negative cases. Therefore, an indicated prevention has currently the best prospects of success for schizophrenia, because it targets on persons who already show clinical signs and are possibly in a prodromal state. Thus, when referring to early detection and intervention projects, we focus on an indicated approach in a help seeking population with signs and symptoms associated with a relatively high risk of transition to psychoses and schizophrenia. This practice oriented approach is hitherto regarded most appropriate to examine hypothesized risk and resilience factors, which may increase the accuracy in predicting a transition to psychosis (60).

Current studies focus on two main aims: an evaluation of criteria to define and operationalize the prodrome and an evaluation of therapeutic interventions for treating present signs and symptoms and preventing frank psychosis (3,4,5,15,61-70). Trying to estimate the possibilities of and opportunities for an early detection and/or intervention, these studies had to focus rather strictly on their respective topic, e.g. on the evaluation of a limited number of potentially prodromal symptoms. EPOS not only adapts the UHR concept for the prediction of psychosis, but also uses a basic symptom criterion, "cognitive disturbances", which has been shown to be highly predictive for schizophrenia (5,6). A first analysis of baseline data demonstrates that the "cognitive disturbances" criterion allows the detection of some at-risk subjects who do not meet UHR criteria. Further follow-ups within EPOS will show whether this is an additional group or is detected earlier in course, before the development of APS or BLIPS. In line with other studies (71), most subjects recruited for EPOS exhibited APS.

As a broader approach should improve prediction even at a clinical level, EPOS comprises not only a thorough assessment of the course of symptoms, comorbidity and drug con- sumption, but also elaborated investigations of potential risk or resilience factors, e.g. personality traits, premorbid adjustment, trauma, development of social and vocational functioning, life events, family atmosphere and quality of life. Furthermore, the possible contribution of biological and neurocognitive aberrations, e.g. disturbances of information processing, has to be tested. In addition to a comprehensive tool for prediction, for the subsequent development of an evidence based prevention programme, data about the current support and interventions in and costs of the prodromal phase are needed. This step does not only serve the economic analysis of current costs, but also meets the demand for a comparative evaluation of costs, cost-effectiveness and costbenefit of evidence-based prevention programmes (58).

As different health systems provide different structures of care, prevention programmes will only be successfully implemented and sustained system-wide, if they can be adapted to the system's special opportunities and needs (58). In the European context, this strategy is of special importance, as European policy has an increasing impact on public health. Paying tribute to these aspects, EPOS is a hitherto unique project to provide essential data for a future evidence-based prevention of psychosis.

APPENDIX

The EPOS Group is formed by Joachim Klosterkötter, Stephan Ruhrmann, Frauke Schultze-Lutter, Heinrich von Reventlow, Heinz Picker, Katarina Savic, Meike Neumann, Anke Brockhaus and Ralf Pukrop (University of Cologne, Germany); Raimo K.R. Salokangas, Markus Heinimaa, Jyrki Korkeila, Tanja Suomela, Anna-Mari Heinisuo, Jyrki Heikkilä, Tuula Ilonen, Terja Ristkari, Jaakko Rekola, Jukka Huttunen, Jarmo Hietala and Erkka Syvälahti (University of Turku, Finland); Don Linszen, Peter Dingemans, Hiske Becker, Dorien Nieman, Reinoud van de Fliert and Maurice Niessen (University of Amsterdam, The Netherlands); Max Birchwood, Paul Patterson, Amanda Skeate, Leslie Harrison and Chris Jackson (University of Birmingham, UK); Andreas Heinze, Georg Juckel, Henning Witthaus, Seza Ozgürdal, Yehonala Gudlowski and Frank Forstreuter (University of Berlin, Germany); Anthony Morrison, Paul French and Helen Stevens (University of Manchester, UK). The International Advisory Board includes Patrick D. McGorry, Thomas H. McGlashan, Shôn Lewis and Martin Knapp.