The Basel early-detection-of-psychosis(FEPSY)-study – design and preliminaryresults

Riecher-Rossler A, Gschwandtner U, Aston J, Borgwardt S, Drewe M,Fuhr P, Pfluger M, Radu W, Schindler Ch, Stieglitz R-D. The Baselearly-detection-of-psychosis (FEPSY)-study – design and preliminaryresults.

Objective: Early detection and therapy of schizophrenic psychoseshave become broadly accepted aims in psychiatry, recently even in veryearly stages of the disorder when clear diagnostic criteria are not yetfulfilled. However, reliable and widely applicable methods do not yetexist. This study aims at contributing to the improvement of the earlyassessment of psychosis.Method: Individuals potentially at risk are identified by a newlydeveloped stepwise screening procedure. Identified subjects are thenexamined extensively and followed-up for at least 5 years to detectactual transition to psychosis.Results: Of 50 subjects who have been followed up for 1–5 years bynow, 16 have progressed to frank psychosis, 12 of them during the first12 months of follow-up.Conclusion: At this stage, our approach seems to be promising for theearly detection of psychosis. Further results from this ongoing studywill hopefully permit us to optimize the assessment procedure.

A. Riecher-Rçssler1,U. Gschwandtner1, J. Aston1,S. Borgwardt1,2, M. Drewe1,P. Fuhr3, M. Pfl�ger1, W. Rad�4,Ch. Schindler5, R.-D. Stieglitz1

1Psychiatric Outpatient Department, University HospitalBasel, Petersgraben, Basel, Switzerland, 2Institute ofPsychiatry, Denmark Hill, London, UK, 3Department ofNeurology, University Hospital Basel, Petersgraben,4Department of Neuroradiology, University HospitalBasel, Petersgraben, and 5Institute for Social andPreventive Medicine, Steinengraben, Basel, Switzerland

Key words: psychosis; psychotic disorders; riskassessment; schizophrenia; early diagnosis

Anita Riecher-Rçssler, Psychiatric Outpatient Depart-ment, University Hospital Basel, Petersgraben 4-6,CH-4031 Basel, Switzerland.E-mail: ariecher@uhbs.ch

Accepted for publication May 11, 2006

Significant outcomes

• Early detection of psychosis and of at risk mental states is possible in a stepwise enrichment strategyusing a screening procedure.

• This approach is feasible for specialised early detection centres with well trained psychiatrists and thecapacity to perform broad information and awareness campaigns.

• In the usual clinical setting a major aim of early detection remains the early diagnosis of frankpsychosis which is obviously still underdiagnosed and the differential diagnosis of these disorders.

Limitations

• At this stage of the ongoing study, only preliminary data are available.• Sample size is still small, and follow-up is ongoing.• Definite conclusions and recommendations can only be made after completion of the study.

Introduction

The early diagnosis and treatment of schizophrenicpsychoses have become widely accepted aims inpsychiatry. While previous efforts to improve earlydiagnosis and intervention concentrated on mani-fest schizophrenia, some centres have meanwhile

started to treat patients well before a cleardiagnosis is established.The rationale for that is based on several

observations. On the one hand, it has been recog-nized that the true onset of schizophrenic psychosesis often many years before the first manifestation ofclear schizophrenic symptoms. In fact, schizophre-

Acta Psychiatr Scand 2007: 115: 114–125All rights reservedDOI: 10.1111/j.1600-0447.2006.00854.x

Copyright � 2006 The AuthorsJournal Compilation � 2006 Blackwell Munksgaard

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nic disorders often begin with unspecific changesand �prodromal� symptoms or very brief transientor subthreshold psychotic symptoms. But thedisease often has particularly serious consequencesfor the patients already in these early stages. Earlytreatment on the other hand seems to improve theshort-term and long-term course of these psychoses[for review see (1–6)].Concerning the delay of diagnosis and treat-

ment, we can distinguish between duration ofuntreated psychosis (DUP) and duration ofuntreated illness (DUI). Regarding DUP, patientssuffer from productive psychotic symptoms suchas delusions or hallucinations for, on average,1–3 years before this disorder is diagnosed andtreated for the first time. And, even before that,individuals often suffer from a so-called �unspecificprodromal phase�, which makes DUI last 2–5 yearson average [for review see (6, 7)].This delay of treatment can have severe conse-

quences [for review see (6, 7)]. Thus, it has beennoted that the delay was associated with anincomplete remission of symptoms, a worse long-term prognosis, a higher overall dosage of neuro-leptics over time, a worse compliance, a higher rateof rehospitalizations, higher overall treatmentcosts and an enhanced risk for depression, suicide,substance abuse and delinquency. There are alsooften very negative consequences for the psycho-logical and the social development of the individ-uals. Especially, as the disease often starts at a veryyoung age in the midst of the developmentalprocesses of adolescence and young adulthood,important social roles can often not be attained. Inthe higher age group, there is often a marked socialdecline with loss of employment, partnership orindependent living. With all these negative conse-quences in mind, it can thus be stated quite safelythat a patient should be treated as early as possible.However, the question is: How early?The problems of a very early detection and

treatment of the disorder are evident. Thus, an�early diagnosis� of schizoprenia before the diag-nostic criteria are fulfilled might be possible retro-spectively, but is not possible prospectively �perdefinition�. Researchers and clinicians have there-fore concentrated on early diagnosis of �psychosis�in individuals at risk (IR) by using well definedcriteria for psychotic breakdown. They begintreatment when the patient’s psychotic symptomsare severe enough to fulfil these criteria.In the meantime, however, one of the key

questions is, whether a very early interventionsuch as treatment with low-dose atypical neuro-leptics is indicated even before that – for example inpatients with very brief or subthreshold psychotic

symptoms or with severe other symptoms suspectedto be prodromes of schizophrenia.Researchers and clinicians are faced with the

ethical dilemma of diagnosing and treating thisdisorder either too late or too early [see e.g. (5), forreview see (6)]. On the one hand, we know that itcan be very devastating already in the earlyprodromal stages. On the other hand, it is alsoimportant not to diagnose/treat too early, becauseof the potential identification of �false positives�,the stigma associated with the diagnosis, thepotential side effects of treatment. The only wayand pre-requisite for solving this dilemma is a morereliable identification of IR and of the beginningdisease process.However, reliable and widely applicable meth-

ods for early detection already in this early phaseof beginning schizophrenia respectively for identi-fying IR are still not available, although valuablework has been done [see e.g. (8–12), for review see(4, 6, 7, 13)]. Several predictors of transition topsychosis have been identified in these studies suchas certain prodromes, attenuated and brief limitedpsychotic symptoms, genetic risk or social decline.

Aims of the study

With the aim of facilitating and improving theearly assessment of beginning psychoses respect-ively of the risk for psychosis in 1999 we initiatedthe FEPSY (Fruherkennung von Psychosen ¼early detection of psychosis) study.In this paper, we describe the principles of the

ongoing study and report the first results obtainedfrom subjects recruited between 1 March 2000and 28 February 2003 and followed-up until 28February 2005.

Material and methods

The FEPSY study is an open, prospective clinicalstudy in all consecutive referrals to our specializedclinic for the early detection of psychosis (FEPSYClinic). Figure 1 shows the study design. Individ-uals potentially in an early stage of schizophreniaare identified using a newly developed screeningprocedure. This procedure is based on variableswhich have been shown to be predictors ofpsychosis by other groups, such as �attenuated� orbrief limited psychotic symptoms, negative symp-toms, prodromal symptoms, genetic risk, or socialdecline (12). In a next step, each individualidentified as being at risk is thoroughly examinedin different assessment modalities covering furtherimportant potential predictors of schizophreniawhich we had derived from the literature and

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recently reviewed in the Acta Psychiatrica Scandi-navica (6).All IR are then followed up for a minimum of

5 years. By comparing those subjects who in factdevelop manifest psychosis during the period offollow-up with those who do not, the study seeks apost hoc validation of the risk factors and indicatorsassumed a priori based on the literature. With theaim of identifying the signs and symptoms, andcombinations of them, with the best predictivepower, all instruments and assessments from screen-ing and the entry examination will be analysed.The specificity of these predictors will addition-

ally be tested by comparing control groups of first-episode (FE) patients on a cross-sectional andretrospective basis (Fig. 1). On the basis of theresults of this study, we hope to improve ourscreening and assessment procedure, which will infuture hopefully facilitate and improve the identi-fication of patients at risk and/or with a beginningdisease.

Hypotheses

The FEPSY-study is based on the followinghypotheses:

i) Our newly developed screening procedurebased on risk factors, prodromes and otherindicators of beginning schizophrenia is suit-able to identify individuals at an early stage ofschizophrenia and/or IR.

ii) Early assessment and detection can beimproved by identifying more specific predic-tors, or combinations of predictors of subse-quent psychosis by comparing the baselinevariables of the subjects who progress to psy-chosis with those of the subjects who do not.

Setting and recruitment

Subjects are recruited into this study via theFEPSY Clinic at the Psychiatric Outpatient

Department of the University Hospital Basel,which was set up specifically to identify patientsin the early stages of a beginning psychoticdisorder and to assess the risk of developingpsychosis in the putative prodromal stage.To encourage early, low-threshold referrals, we

organize regular information campaigns withscientific symposia and teaching courses for generalpractitioners, psychiatrists, social service staff, etc.In addition, we alert the public to this facility byarticles published in local newspapers and a specialwebsite. To facilitate identification of individualswho should be referred to us we distribute a one-page checklist, to be used by potential referrers orlay people. The checklist is based on prodromalsymptoms of schizophrenia, social decline, geneticrisk, drug abuse and age. The main source ofreferrals is our own Psychiatric Outpatient Depart-ment, which serves an area of about 200 000inhabitants. Other referrals come from the abovenamed professionals and from relatives, or are self-referrals.The study was approved by the local ethics

committee of the University of Basel and writteninformed consent is obtained from each partici-pant.

Screening procedure

For screening, we use the Basel Screening Instru-ment for Psychosis (BSIP), a more extensive 46-item checklist we specifically developed for thispurpose (A. Reicher-Rossler et al., in preparation).This checklist is based on DSM-III-R – prodromalsymptoms (14) and other prodromi as derived fromliterature, social decline, drug abuse, previouspsychiatric disorders and genetic risk (seeTable 1) (6). It is used in combination with theBrief Psychiatric Rating Scale [BPRS, expandedversion (15, 16)] to rate (pre-) psychotic phenom-ena. In combination with the four psychosis itemsof the BPRS, it allows to classify patients� risk for

Referrals from outside + from Psychiatric Outpatient Department

Screening:- Basel Screening Instrument for Psychosis, BSIP- BPRS

Exclusion according to criteria

I. Individuals without risk for psychosis

II. Individuals at risk for psychosis: full entry examination

III. Patients with manifest psychosis→ controls of first episode patients:full entry examination

Follow-up once after5 years for verificationof diagnosis (i.e. no psychosis)

Follow-up every 1–3 months(depending on risk and observation time) during thefirst 3 years, then yearly

No transitiontopsychosis

Transitionto psychosis

Fig. 1. Design of the FEPSY Study.

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psychosis according to the criteria established byYung et al. (17). All assessments are conducted byexperienced psychiatrists who undergo regulartraining. Interrater reliability was substantial (7)for the main outcome category �at risk forpsychosis�.The BSIP was constructed as a screening check-

list to identify those at risk and is followed by amore extensive early detection interview in a nextassessment step. It is not a screening instrument tobe used in the general population, but in helpseek-ing populations and has to be performed byexperienced psychiatrists. So far there exist fourother screening instruments for the investigation ofthe prodromal state of schizophrenia: the Prod-screen (18), the Prodromal Questionaire (19), theY-PARQ (20) and the SIPS screen (21) [for reviewsee (22)]. But as to our knowledge these screeninginstruments have so far only been tested for theirvalidity in predicting a prodromal state as definedby other, more comprehensive instruments, but notregarding their validity for predicting actual trans-ition to psychosis.

Inclusion criteria for individuals at risk (IR, main study population)

Subjects are included as IR if they meet thefollowing inclusion criteria based on our screeninginstrument and the BPRS [version Lukoff et al.(15) and Ventura et al. (16)]:

i) Prepsychotic category [according to Yunget al. (17) and BPRS version/scale Lukoffet al. (18)]

�attenuated� psychotic symptoms: psychoticsymptoms below transition cut off (BPRSscales: hallucinations 2–3, unusual thought con-tent 3–4, suspiciousness 3–4) at least several times

per week, in total persisting for>1 week; or BriefLimited Intermittent Psychotic Symptoms(BLIPS): psychotic symptoms over transitioncut-off (BPRS scales: hallucinations ‡4, unusualthought content ‡5, suspiciousness ‡5, concep-tual disorganisation ‡5), but each symptom<1 week before resolving spontaneously.

ii) Genetic risk category: first or second degreerelative with psychotic disorder and at leasttwo further risk factors according to screeninginstrument.

iii) Unspecific risk category: minimal amount andcombination of certain risk factors accordingto screening instrument.

Precondition for all categories: criteria of trans-ition to psychosis not fulfilled.Criteria i) and ii) correspond to those of Yung

et al. (17). Criterium iii) additionally permits theinclusion of individuals at lower risk, i.e. ofpatients without pre-psychotic symptoms or gen-etic risk who only exhibit a combination of certainunspecific risk factors and indicators such asprodromal symptoms or marked social decline(unspecific risk group).

Inclusion criteria for first-episode patients and criteria fortransition to psychosis

Patients with first-episode psychosis (FE, controlgroup) are those who at intake already fulfil thecriteria for transition to psychosis as defined by theMcGorry Group (17):

• At least one of the following symptoms:Suspiciousness (BPRS ‡5): says others are talk-ing about him/her maliciously, have negativeintentions or may harm him/her (incidents morethan once a week OR partly delusionalconviction).Unusual thought content (BPRS ‡5): full delu-sion(s) with some preoccupation OR some areasof functioning disrupted (not only ideas ofreference/persecution, unusual beliefs or bizarreideas without fixed delusional conviction).Hallucinations (BPRS ‡4): occasional halluci-nations OR visual illusions >2/week or withfunctional impairment (not only hearing of ownname, non-verbal acoustic or formless visualhallucinations/illusions).Conceptual disorganisation (BPRS ‡5): speechdifficult to understand due to circumstantiality,tangentiality, neologisms, blockings or topicshifts (most of the time OR three to fiveinstances of incoherent phrases).• Symptoms at least several times a week.• Change in mental state lasting >1 week.

Table 1. Basel Screening Instrument for Psychosis (BSIP) – domains

PsychopathologyProdromal symptoms according to DSM-III-R (first occurrence within the last5 years and persisting up to now)Other prodromal signs as derived from literature (first occurrence within the last2 years and persisting up to now)(Pre-) psychotic symptoms (previous or current)

Social declineMarked deterioration of psychosocial functioning with serious consequences forwork, education, relationships (occurrence during the last 5 years and persistingup to now)

Drug abuseRegularly within the last 2 years

Psychiatric historyPrevious psychiatric disorders and treatments

Genetic riskSchizophrenia/psychoses in first or second degree relatives

At-risk ageAge below 30 years in women, below 25 years in men

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These first episode �FE� patients have beenincluded as a control group from the second yearof our study onwards.

Exclusion criteria

Age below 18 years, insufficient knowledge ofGerman, IQ < 70, previous episode of schizo-phrenic psychosis (treated with major tranquillisersfor >3 weeks), psychosis clearly due to organicreasons or substance abuse, or psychotic sympto-matology within a clearly diagnosed affectivepsychosis or borderline personality disorder.

Entry examination

All subjects selected for the study by the screeningthen undergo an extensive entry examinationcomprising known potential risk factors and indi-cators of a beginning schizophrenic disorder, i.e. amore detailed assessment of present and previouspsychopathology and further risk factors andindicators of beginning disease, as well as neuro-psychological testing, neurophysiological measure-ments, and neuroimaging.

Instruments at study entry

Instruments and assessment domains were selectedbased on our comprehensive review of the litera-ture regarding important predictors of schizophre-nia (6). Here, we only report on the instruments forwhich we present results in this paper. This is – inaddition to our screening instrument and the BPRS– only the Scale for the Assessment of NegativeSymptoms (SANS) (23) for assessing negativesymptoms.

Follow-up and transition to psychosis

Each IR is followed-up for 5 years. Transition topsychosis is monitored by means of the transitioncriteria based on the BPRS. The scale is applied atregular intervals with the frequency depending onthe estimated risk of developing psychosis. Duringthe first year of follow-up, high-risk individuals areassessed monthly, while low-risk individuals areassessed at 3-monthly intervals. During the secondand third years, all individuals are assessed3-monthly and thereafter once a year.

Statistical analysis

spss for Windows (SPSS version 12) was used. Forcategorical variables such as gender, chi-square orFisher’s exact test was used. For quantitative

variables such as age or BPRS scores, we usedthe Mann–Whitney U-test. The Jonckheere–Terp-stra-Trend Test was performed to assess thehypothesis that the frequency of psychopatholog-ical symptoms at study entry is lowest among IR-patients without later transition to psychosis,intermediate in IR-patients with later transitionand highest in first episode patients. Time totransition to psychosis data were graphically rep-resented by survival curves estimated by theKaplan–Meier method since this variable hascensored values (IR were included successively, afew subjects have dropped out, and not all IRmade the transition by the end of the observationperiod).

Results

Here, we present the first preliminary results of theongoing study.

Sample characteristics

Our sample comprises the study subjects recruitedduring the first 3 years (from 1 March 2000 to 28February 2003) who were followed-up until 28February 2005. During this inclusion period, 206individuals were screened (Fig. 2).Of these 206 individuals, 98 met our criteria for

being at risk. Of the 98 IR, 58 (34 men and 24women) consented to take part in our study. Afurther 76 subjects screened already suffered fromfrank psychosis according to our transition criteriaand were diagnosed as FE patients. From thesecond year of the study onwards, we started toexamine these FE patients as controls. During thesecond and third years, 36 (69%) of a total of 52FE patients agreed to participate in our study.There was no significant difference between parti-cipants and refusers regarding age or gender(Table 2).Overall, 32 subjects did not meet the criteria for

being at risk of psychosis. These subjects were notincluded, but they are nevertheless subjected tofollow-up monitoring (at least once after 5 years)to identify any false negatives.During the follow-up period, seven of the 58 IR

dropped out. One further patient was excludedbecause he had received neuroleptic medicationfrom an external psychiatrist due to negativesymptoms. Such treatment would have impededthe detection of transition to psychosis. At the cut-off date for this preliminary report (28 February2005), 50 IR (20 women and 30 men) had beenfollowed-up for a period ranging from 2 to 5 years(Fig. 2).

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At initial assessment, none of the 58 IR receivedany neuroleptic medication, but 14 of the subjectswere treated with antidepressants. All were offeredsupportive counselling and clinical management.Of the 36 FE patients, one received neurolepticmedication and two were treated with antidepres-sants at study entry.

Results in relation to our hypotheses

Hypothesis I �Our newly developed screening pro-cedure is suitable to identify IR� was confirmed intwo ways:First, we showed that the individuals identified

as being at risk were comparable with FE patients

in many respects. Table 3 shows the risk factors,prodromal symptoms and other indicators of abeginning disease as assessed with our screeninginstrument BSIP. The IR showed risk factors andearly indicators of psychosis similar to those of theFE, both in terms of the type and extent of thesigns.On the other hand, IR had significantly lower

BPRS symptom scores than FE patients (Table 4).This was true for the BPRS global score as well asfor the four subscores of the BPRS with psychoticsymptomatology, which is consistent with the factthat they had not made the transition to psychosisat this stage.Main proof of validity of our screening proce-

dure is, however, the actual transition to psychosisof many IR. By the cut-off date, 16 (32%) of the 50IR who were followed-up had made the transitionto psychosis according to our predefined criteria.Most (n ¼ 7) transitions had occurred during thefirst 6 months after study entry. Using survivalanalysis (Kaplan–Meier method), the 6 monthtransition rate was estimated to be 0.13 [95% Cl0.05–0.21] (Fig. 3). At 12 months after study entry,five further IR had become psychotic. The12-month transition rate was 0.23 [95% Cl 0.13–0.33].In the second year of follow-up (between 12 and

24 months after study entry) only one further IRbecame psychotic, the 24-month transition ratebeing 0.25 [95% Cl 0.15–0.35]. A further three IRdeveloped psychosis after the first 2 years of

Fig. 2. FEPSY samples at study entry and follow-up.

Table 2. Comparison of participants and refusers within the groups of individualsat risk and first episode patients

Participants Refusers Significance

Individuals at riskTotal, n (%) 58 (59.2) 40 (40.8)Mean age (SD) 26.8 (8.9) 26.4 (7.5) U ¼ 1097.5,

P ¼ 0.651, n.s.GenderMale, n (%) 34 (58.6) 23 (57.5) v2 ¼ 0.01, d.f. ¼ 1,

P ¼ 0.912, n.s.Female, n (%) 24 (41.4) 17 (42.5)First episode patientsTotal, n (%) 36 (69.2) 16 (30.8)Mean age (SD) 31.1 (7.0) 30.3 (9.7) U ¼ 254.5,

P ¼ 0.506, n.s.GenderMale, n (%) 26 (72.2) 10 (62.5) v2 ¼ 0.49, d.f. ¼ 1,

P ¼ 0.483, n.s.Female, n (%) 10 (27.8) 6 (37.5)

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follow-up (transition rates not calculated as not allindividuals have been observed for longer than2 years).To test hypothesis II and identify predictors of

transition to psychosis, we compared the baselinedata of the 16 IR who had made the transition topsychosis with those of the 34 IR who had notbecome psychotic during the evaluation period.When comparing the variables age and gender,

we did not find any significant differences. Themean age of the 16 patients with transition was26.8 years (SD ¼ 7.6), compared with a mean ageof 26.5 years (SD ¼ 9.6) for the 34 subjects with-out transition (U ¼ 251.5; P ¼ 0.669). Six (30.0%)of 20 women and 10 (33.3%) of 30 men made thetransition (v2 ¼ 0.06; d.f. ¼ 1; P ¼ 0.804). Thus,there was no obvious gender difference for thelikelihood to progress to psychosis.In a next step, we compared the groups regard-

ing psychopathology. We hypothesized that sub-

jects who will progress to psychosis show moreprepsychotic and other psychiatric symptomsalready at study entry than do subjects who donot progress to psychosis, but show less severesymptoms than do FE patients. This hypothesiscould be confirmed by the Jonckheere–TerpstraTrend Test (24) (for P-values see Fig. 4). In fact,the 16 patients who subsequently made the trans-ition to frank psychosis were with their baselineBPRS scores between the subjects who did notdevelop psychosis, and the FE patients (Fig. 4).This was not only true for the four subscalesmeasuring psychotic symptomatology, but also forthe BPRS global score measuring overall psycho-pathology.In addition, we analysed negative symptoms at

study entry based on the SANS. Among thesubjects who subsequently developed psychosis,anhedonia and asociality at study entry showed atendency to be more frequent than in the subjects

Table 3. Risk factors, prodromal symptoms, andother indicators of beginning psychosis in individu-als at risk vs. first episode patients – based onBSIP*

Individuals at risk[n ¼ 58, n (%)]

First episode[n ¼ 36, n (%)] P-value� P-value�

Prodromal symptoms according to DSM-III-RSocial isolation 29 (50.9) 26 (72.2) 0.052 0.551Impaired role functioning 43 (74.1) 32 (88.9) 0.114 0.837Peculiar behaviour 8 (13.8) 9 (25.0) 0.182 0.951Impairment in personal hygiene 5 (8.8) 5 (14.3) 0.497 �1.000Blunted or inappropriate affect 24 (42.9) 12 (33.3) 0.390 0.999Disturbances of speech 14 (24.6) 16 (44.4) 0.068 0.652Odd beliefs 26 (44.8) 25 (71.4) 0.018 0.238Unusual perceptual experiences 26 (44.8) 21 (60.0) 0.200 0.965Lack of initiative 40 (70.2) 25 (73.5) 0.813 �1.000

Other unspecific prodromal signs 50 (90.9) 32 (91.4) �1.000 �1.000(Pre-) psychotic symptoms (previous or current) 43 (74.1) 34 (94.4) 0.014 0.191Social decline 42 (75.0) 28 (80.0) 0.620 �1.000Drug abuse (regularly in the last two years) 25 (44.6) 19 (52.8) 0.523 �1.000Previous psychiatric disorder 26 (61.9) 13 (50.0) 0.450 �1.000Genetic risk [first or second degree relative

with (suspected) psychosis]12 (22.6) 6 (17.1) 0.598 �1.000

Inclusion 1 March 2000 to 28 February 2003; discrepancies in n/percentages are due to missing data.*BSIP, Basel Screening Instrument for Psychosis.�Fisher's exact test, two-tailed.�Adjusted for multiple testing.

Table 4. Brief Psychiatric Rating Scale (BPRS) sub-scores with psychotic symptomatology and BPRSglobal score in individuals at risk and first episodepatients at study entry

Individuals atrisk (n ¼ 58)

First episodepatients (n ¼ 36) Significance

n Mean (SD) n Mean (SD)Mann–Whitney

U-test P-value� P-value�

BPRS-subscoresHallucinations 58 1.5 (0.9) 34 3.6 (1.6) 279.0 <0.001 <0.001Unusual thought content 58 2.0 (1.2) 34 3.6 (1.7) 482.0 <0.001 <0.001Suspiciousness 57 2.3 (1.3) 34 3.4 (1.7) 622.0 0.003 0.014Conceptual disorganization 58 1.6 (0.9) 36 2.2 (1.2) 750.5 0.012 0.046

BPRS global score 57 40.3 (11.0) 35 52.6 (13.3) 424.5 <0.001

Inclusion 1 March 2000 to 28 February 2003; discrepancies in n/percentages are due to missing data.�Mann–Whitney U-test, two-tailed.�Adjusted for multiple testing.

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who did not develop psychosis during the evalua-tion period. Moreover, most single items of theanhedonia-subscale showed higher values in thosewith than those without later transition (Table 5).The SANS-summary-score or the other SANS-subscale scores did not show significant differences.Thus, anhedonia and asociality may also bepredictors of psychosis.

Discussion

There is growing interest in early detection andintervention in schizophrenia. Some centres haveeven started treatment in individuals suspected tobe in a very early stage of the disease, withouthaving clear criteria to reliably predict the risk ofactual transition to psychosis. This ethical dilemmais controversially discussed in the scientific com-munity (3, 4, 25–27).Our study attempts to contribute to solving this

dilemma by facilitating and improving the methodsfor early detection and risk assessment. In order todo this, we identify IR for developing psychosiswith a stepwise enrichment strategy including anewly developed screening procedure, and then,after inclusion, conduct a broad multi-modalityassessment.

Screening

Our screening instrument was designed not only toallow the inclusion of individuals at �ultra high risk�as, e.g. Yung et al. (12), but hopefully also toidentify individuals with solely unspecific riskfactors and prodromi similar to those describedby Klosterkotter et al. (10). In contrast to thegenetic high-risk studies (9), genetic risk is not aprerequisite for the inclusion of these individuals inour study. Instead, a combination of certainunspecific risk factors and indicators of beginningpsychosis can also lead to inclusion as an IR. Thisapproach seems justified in a disorder that beginswith unspecific or negative symptoms in as many asapproximately 73% of patients (28) and is not

0 10 20 30 40 50 60Number of months from entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n n

on

-psy

cho

tic

58 42 34 22 8 1 0Numberat risk

Fig. 3. Transition to psychosis – Kaplan–Meier estimates(survival curve).

Fig. 4. Symptomatology (BPRS) at study entry individuals in at risk (IR) with and without later transition to psychosis and in first-episode (FE) patients.

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bound to a genetic risk in many patients. Thecombination of different risk factors is necessary asthe early changes are often unspecific and can beclassified as �prodromal� only retrospectively.

Stepwise enrichment strategy for early detection

We have opted for a stepwise enrichment strategybecause rare conditions, such as schizophrenia, donot justify unselective screening of the generalpopulation. Our efforts to educate both the publicand professionals likely to encounter subjects atrisk of developing schizophrenia and the distribu-tion of our �Brief Psychosis Risk Checklist� resultedin the timely referral of appropriate individuals toour specialized clinic.Thus, 98 (47%) of 206 individuals referred to us

fulfilled our predefined criteria for being at risk. Afurther 76 (36.9%) individuals already sufferedfrom clear psychosis at screening. Enrolment ofsubjects was facilitated by the fact that ourdepartment is fully responsible for a definedcatchment area. External psychiatrists as well asthose of our Psychiatric Outpatient Department,who see most psychiatric emergencies of ourcatchment area, were well trained and referredmany subjects at potential risk to the FEPSYClinic.

Methodological standards

Our information campaigns have the aim to reachas many IR as possible within our catchment area.Although certain potential IR or patients withpreviously undiagnosed psychosis will inevitablyhave escaped our attention, recruitment success

was high, with an annual referral rate of about 29per 100 000 inhabitants, which is roughly twice ashigh as the documented yearly incidence of schi-zophrenia (29).Our refusal rates (30.8% for the FE patients and

40.8% for the IR) seem low for such highlysuspicious populations. We cannot compare theserates to those of other studies, as these rates havehardly been reported so far. However, the refusersdid not significantly differ from the participantsregarding age and sex, which seems to indicate thatat least there was no crude selection taking place atthis point.We purposely allowed for the inclusion of

patients with organic comorbidity or drug abuse,if their psychotic symptoms were not clearly andexclusively due to this condition. We feel that suchpatients should not be excluded initially, butshould rather be analysed as subgroups sincevaluable information can be gained from them.This especially concerns the many cannabis abuserswho exhibit prodromal and/or (pre-)psychoticsymptoms.The 32 subjects in whom we could not identify

any risk for psychosis (other diagnoses, see Fig. 1)will be followed-up at least once after 5 years toidentify any false negatives.Because of the close monitoring of our study

participants, the dropout rate during follow-upwas low [8 (13.8%) of 58 IR]. One of these subjectshad to be excluded because he received neurolep-tics for severe negative symptoms from his privatepsychiatrist. Transition to psychosis was thus notto be expected anymore. This case at the same timeillustrates one of the limitations and difficulties ofstudies such as ours, which concern the main

Table 5. Anhedonia/asociality (SANS*) at studyentry in individuals at risk with later transition vs.individuals at risk without later transition to psy-chosis

Anhedonia–Asociality

Individuals at risk

Significance

Withouttransition(n ¼ 34)

With latertransition(n ¼ 16)

n Mean (SD) n Mean (SD)Mann–Whitney

U-test P-value� P-value�

Subscale score 34 4.6 (4.6) 16 7.6 (4.2) 158.5 0.017 0.082Single items

Recreational interests and activity 34 1.7 (1.6) 16 2.7 (1.4) 178.5 0.046 0.230Sexual interest and activity 21 1.0 (1.5) 6 2.3 (1.0) 23.0 0.014 0.070Ability to feel intimacy and closeness 29 1.1 (1.5) 10 2.6 (1.6) 70.0 0.011 0.057Relationship with friends and peers 34 1.4 (1.5) 14 2.7 (1.2) 116.0 0.004 0.022Global rating of anhedonia-asociality 34 1.4 (1.5) 16 2.6 (1.5) 156.5 0.014 0.069

Inclusion 1 March 2000 to 28 February 2003, follow-up until 28 February 2005; discrepancies in n/percentages are dueto missing data.*Scale for the Assessment of Negative Symptoms, Andreasen et al. 1989.�Mann–Whitney U-test, two-tailed.�Adjusted for multiple testing.

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outcome criteria. When our study was designed in1999, the criterion �transition to psychosis� roughlycorresponded to the criterion �in need of neurolep-tic treatment� as stated by Yung et al (17). In themeantime, we have neuroleptics supposed to bealso efficacious in the treatment of negative andcognitive symptoms. Consequently, it has becomeincreasingly difficult to withhold neuroleptic treat-ment from patients with these symptoms, even ifthey have not yet made the transition to frankpsychosis.

Transition rate

The relatively high transition rate in our studysuggests that our enrichment and screening proce-dure are valid in principle. Sixteen of 50 IR whohad been followed-up for 2–5 years by the cut-offdate had actually developed frank psychosis duringthis time. This corresponds to an overall transitionrate of 32%.Nevertheless, the transition rate in the first

12 months of our study was with 23.0% lowerthan the 34.6% reported by the McGorry group inan earlier study (12). This discrepancy may beexplained by the divergent study populations.While the McGorry group mainly included �ultrahigh-risk� patients who already showed somepsychotic symptoms or had at least an affectedfirst-degree relative, we also included lower riskpatients, i.e. patients with a certain number andcombination of prodromal symptoms or patientswith an affected second degree relative and prodro-mal symptoms. Moreover, McGorry’s study pop-ulation is much younger than ours and especiallythe inclusion of subjects below the age of 18 yearsmay have increased the overall transition rate (30).In a prospective study in 160 individuals with

relatively unspecific prodromal symptoms,Klosterkotter et al. (10) reported that 49.4% ofsubjects developed schizophrenia during a meanfollow-up of 9.6 years. Thus, our annual transitionrate lies well within the expected range.For the subjects who have not (yet) progressed

to psychosis during the evaluation period, itremains uncertain whether these were correctlyidentified as IR in our screening procedure. How-ever, the finding that at study entry our IRexhibited the same sort and extent of risk factorsand prodromal symptoms as FE patients seems toshow that we have correctly classified them. Wespeculate that some of these individuals maydevelop psychosis at a later stage of follow-up. Infact, some of these subjects might have beenprotected by the unspecific support they receivedin our project.

On the basis of the results of our study, we planto further improve our assessment procedure byplacing more emphasis on the variables shown todiffer between individuals who did progress andthose who did not progress to psychosis. However,this will only be possible after completion of thestudy. More sophisticated statistical analyses toidentify individual predictors will then be warran-ted.Variables that have emerged so far as potential

predictors include certain negative and positivesymptoms and global symptomatology as assessedby the BPRS. These results correspond well tothose of Yung et al. (12). The finding that the IRwho subsequently developed psychosis had shownmore anhedonia-asociality at baseline is in goodagreement with Yung et al. (12) who found negat-ive symptoms to be predictors of transition topsychosis. Retrospective studies, such as our ABC-Study, had also revealed that negative symptomsfrequently occur before the first psychotic episode(28). Consequently, it is to be expected that apartfrom subthreshold psychotic symptoms also neg-ative symptoms will play a role in the prediction ofpsychosis.

Multi-modality assessment

To optimize the prediction of psychosis, also otherdomains are assessed. Specific variables suspectedto be relevant predictors of developing schizophre-nia as reviewed in our previous paper (6) areinvestigated, including the patient’s psychiatrichistory and certain aspects of current neuropsy-chology, neurophysiology, and neuroimaging.Clearly, such extensive assessment is feasible onlywithin a research programme, but we hope that therisk factors and indicators, or combinations ofthem, with the highest predictive power, emergingfrom our and other studies can ultimately beintegrated into stepwise risk assessment proce-dures. We have reported first results from ourFEPSY-study on neuropsychology, fine motorfunctioning and eye-movements (31, 32) and neu-roimaging (33) in other papers.

Patients previously undiagnosed with psychosis

Another clinically relevant result of our study isthe high proportion of referred patients whoalready suffered from frank psychosis but hadnot previously been diagnosed or treated. Manyof these patients had suffered from psychoticsymptoms for quite some time and might havegone unnoticed for longer in the absence of ourFEPSY-clinic.

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Differential diagnosis

Our study also showed the importance of differen-tial diagnosis in patients suspected to be at risk ofdeveloping psychosis. Thus, we diagnosed severeorganic brain diseases, such as chronic subduralhaemorrhage (34), encephalitis and other condi-tions among the patients referred to us because ofsuspected risk of psychosis.To conclude, our preliminary data in line with

other authors suggest that subjects at risk ofdeveloping schizophrenic psychosis can be identi-fied, before symptoms of frank psychosis arepresent. Various early signs, and combinations ofthem, are emerging as potential predictors ofdeveloping psychosis. We hope to optimize ourscreening and assessment procedures in response tothe results emerging in this ongoing study and theresults of other studies.

Acknowledgements

This project is being supported by the Swiss National ScienceFoundation no. 3200-057216.99, no. 3200-057216.99 and no.PBBSB-106936, the Nora van Meeuwen-Haefliger Stiftung,Basel (CH) and by unconditioned grants from the NovartisFoundation, Bristol-Myers Squibb GmbH (CH), Eli Lilly SA(CH), AstraZeneca AG (CH), Janssen-Cilag AG (CH), andSanofi-Synthelabo AG (CH).

Declaration of interests

All authors except M. Drewe and Ch. Schindler have had someconnections with several pharmaceutical companies as lectur-ers or advisers with honoraria, receiving invitations tocongresses or unconditional research grants (see also Acknowl-edgements).Statistical analyses were performed by the three co-authors:Dr phil. Marlon Pfluger, Prof. R.-D. Stieglitz, both psychol-ogists, and Dr C. Schindler, statistician. The protocol canbe obtained from the first author Anita Riecher-Rossler(ariecher@uhbs.ch).

References

1. Harrigan SM, Mcgorry PD, Krstev H. Does treatmentdelay in first-episode psychosis really matter? Psychol Med2003;33:97–110.

2. Larsen TK, Friis S, Haahr U et al. Early detection andintervention in first-episode schizophrenia: a criticalreview. Acta Psychiatr Scand 2001;103:323–334.

3. Mcgorry PD. Early psychosis reform: too fast or too slow?Acta Psychiatr Scand 2002;106:249–251.

4. Norman RM, Malla AK. Duration of untreated psychosis: acritical examination of the concept and its importance.Psychol Med 2001;31:381–400.

5. Pelosi AJ, Birchwood M. Is early intervention for psychosisa waste of valuable resources? Br J Psychiatry2003;182:196–198.

6. Riecher-Rossler A, Gschwandtner U, Borgwardt S, Aston J,Pfluger M, Rossler W. Early detection and treatment of

schizophrenia: how early? Acta Psychiatr Scand Suppl2006;113:73–80.

7. Drake RJ, Lewis SW. Early detection of schizophrenia.Curr Opin Psychiatry 2005;18:147–150.

8. Drake RJ, Haley CJ, Akhtar S, Lewis SW. Causes andconsequences of duration of untreated psychosis inschizophrenia. Br J Psychiatry 2000;177:511–515.

9. Johnstone EC, Ebmeier KP, Miller P, Owens DG, Lawrie SM.Predicting schizophrenia: findings from the EdinburghHigh-Risk Study. Br J Psychiatry 2005;186:18–25.

10. Klosterkotter J, Hellmich M, Steinmeyer EM, Schultze-

Lutter F. Diagnosing schizophrenia in the initial prodro-mal phase. Arch Gen Psychiatry 2001;58:158–164.

11. Mcgorry PD, Yung AR, Phillips LJ. ��Closing in�� whatfeatures predict the onset of first-episode psychosis withinan ultra-high-risk group? In Zipursky RB, Schulz SC, eds.The Early Stages of Schizophrenia. Washington DC,London: American Psychiatric Publishing Inc., 2002: 3–31.

12. Yung AR, Phillips LJ, Yuen HP, Mcgorry PD. Risk factorsfor psychosis in an ultra high-risk group: psychopathologyand clinical features. Schizophr Res 2004;67:131–142.

13. Olsen KA, Rosenbaum B. Prospective investigations of theprodromal state of schizophrenia: review of studies. ActaPsychiatr Scand 2006;113:247–272.

14. American Psychiatric Association. Diagnostic and Statis-tical Manual of Mental Disorders DSM-III-R, 3rd edn –revised. Washington DC: American Psychiatric Associa-tion, 1987.

15. Lukoff D, Nuechterlein KH, Ventura J. Manual for theexpanded brief psychiatric rating scale. Schizophr Bull1986;12:594–602.

16. Ventura J, Lukoff D, Nuechterlein KH, Liberman RP, Green

M, Shaner A. Training and quality assurance with the briefpsychiatric rating scale: ��The Drift Busters��; Appendix 1The Brief Psychiatric Rating Scale (expanded version). IntJ Meth Psychiatric Res 1993;3:221–224.

17. Yung AR, Phillips LJ, Mcgorry PD et al. Prediction ofpsychosis. A step towards indicated prevention of schizo-phrenia. Br J Psychiatry Suppl 1998;172:14–20.

18. Heinimaa M, Salokangas RK, Ristkari T et al. PROD-screen– a screen for prodromal symptoms of psychosis. Int JMeth Psychiatr Res 2003;12:92–104.

19. Loewy RL, Bearden CE, Johnson JK, Raine A, Cannon TD.The prodromal questionnaire (PQ): preliminary valid-ation of a self-report screening measure for prodromaland psychotic syndromes. Schizophr Res 2005;77:141–149.

20. Ord LM, Myles-Worsley M, Blailes F, Ngiralmau H.Screening for prodromal adolescents in an isolated high-risk population. Schizophr Res 2004;71:507–508.

21. Miller TJ, Cicchetti D, Markovich PJ, Mcglashan TH,Woods SW. The SIPS screen: a brief self-report screen todetect the schizophrenia prodrome. Schizophr Res2004;70(Suppl.):78.

22. Olsen KA, Rosenbaum B. Prospective investigations of theprodromal state of schizophrenia: assessment instruments.Acta Psychiatr Scand 2006;113:273–282.

23. Andreasen NC. The scale for the assessment of negativesymptoms (SANS): Conceptual and theoretic foundations.Br J Psychiatry 1989;155:49–52.

24. Fisher LD, Van belle G. Biostatistics – a methodology forthe health sciences. New York: John Wiley & Sons, Inc.,1993.

25. Malla AK, Norman RM. Early intervention in schizo-phrenia and related disorders: advantages and pitfalls.Curr Opin Psychiatry 2002;15:17–23.

Riecher-Rossler et al.

124

26. Mcgorry PD. The recognition and optimal management ofearly psychosis. An evidence-based reform. World Psy-chiatry 2002;1:76–83.

27. Verdoux H, Cougnard A. The early detection and treatmentcontroversy in schizophrenia research. Curr Opin Psychi-atry 2003;16:175–179.

28. Hafner H, Maurer K, Loffler W et al. The ABC Schizo-phrenia Study: a preliminary overview of the results. SocPsychiatry Psychiatr Epidemiol 1998;33:380–386.

29. Rossler W, Joachim SH, Van OSJ, Riecher-Rossler A. Size ofburden of schizophrenia and psychotic disorders. EurNeuropsychopharmacol 2005;15:399–409.

30. Amminger GP, Leicester S, Yung AR, Phillys LJ, Berger

GE, Francey SM, Yuen HP, McGorry PD. Early onset ofsymptoms predicts conversion to non-affective psychosisin ultra-high risk individuals. Schizophr Res 2006; 84:67–76.

31. Gschwandtner U, Aston J, Borgwardt S et al. Neuropsy-chological and neurophysiological findings in individualssuspected to be at risk for schizophrenia: preliminaryresults from the Basel early detection of psychosis study –Fruherkennung von Psychosen (FEPSY). Acta PsychiatrScand 2003;108:152–155.

32. Gschwandtner U, Pfluger M, Aston J et al. Fine motorfunction and neuropsychological deficits in individuals atrisk for schizophrenia. Eur Arch Psychiatry Clin Neurosci2005;EPub ahead of print.

33. Borgwardt SJ, Radu EW, Gotz K et al. Radiological find-ings in individuals at high risk of psychosis. J NeurolNeurosurg Psychiatry 2006;77:229–233.

34. Gschwandtner U, Borgwardt S, Aston J, Drewe M, Radu

EW, Riecher-Rossler A. [Chronic subdural hemorrhage in apatient with suspected schizophrenia prodrome]. Nerve-narzt 2004;75:691–693.

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