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Acta Psychiatr Scand 2001: 103: 323–334 Copyright # Munksgaard 2001
Printed in UK. All rights reserved
ACTA PSYCHIATRICA
SCANDINAVICA
ISSN 0001-690X

Review article
Early detection and intervention in first-
episode schizophrenia: a critical review
Larsen TK, Friis S, Haahr U, Joa I, Johannessen JO, Melle I, T. K. Larsen1, S. Friis1, U. Haahr2,
Opjordsmoen S, Simonsen E, Vaglum P. Early detection and I. Joa3, J. O. Johannessen3,
intervention in first-episode schizophrenia: a critical review. I. Melle4, S. Opjordsmoen1,
Acta Psychiatr Scand 2001: 103: 323–334. # Munksgaard 2001. E. Simonsen3, P. Vaglum1
1
University of Oslo, Norway, 2Roskilde County
Objective: To review the literature on early intervention in psychosis and Psychiatric Hospital Fjorden, Denmark, 3Rogaland
to evaluate relevant studies. Psychiatric Hospital, Norway and 4Ullevål Hospital,
Method: Early intervention was defined as intervention in the prodromal Oslo, Norway
phase (primary prevention) and intervention after the onset of psychosis,
i.e. shortening of duration of untreated psychosis (DUP) (secondary
prevention).
Results: We found few studies aimed at early intervention, but many
papers discussing the idea at a more general level. We identified no
studies that prove that intervention in the prodromal phase is possible
without a high risk for treating false positives. We identified some studies
aimed at reducing DUP, but the results are ambiguous and, until now, no Key words: schizophrenia; first-episode psychosis;
follow-up data showing a positive effect on prognosis have been prevention; early intervention
presented. Tor K. Larsen MD, PhD, University of Oslo, Rogaland
Conclusion: Early intervention in psychosis is a difficult and important Psychiatric Hospital, Armauer Hansensv. 20, N-4011
challenge for the psychiatric health services. At the time being reduction Stavanger, Norway
of DUP seems to be the most promising strategy. Intervention in the
prodromal phase is more ethically and conceptually problematic. Accepted for publication October 9, 2000

Introduction (22–26). The distribution of the DUP is often skewed,

Schizophrenia is a serious disorder that often affects
quite young people. The outcome is often poor,
associated costs and burden are extensive, and it stills
remains a fact that approximately 25% of first-
episode patients have a very poor outcome (1–6).
Recently, the idea of early detection and intervention
has been launched as a new and promising approach.
The rationale for early intervention in schizophrenia
has been discussed in a considerable number of
papers and research strategies have been proposed.
The starting-point for considerations regarding
early intervention strategies is the observation that
most patients who develop schizophrenia have had a
period with unspecific, non-psychotic prodromal
symptoms before the onset of psychosis (7–21). The
prodromal period has been reported to last, on
average, 1–2 years. Another finding across studies is
that the period from onset of a manifest psychosis to
onset of adequate treatment (the Duration of
Untreated Psychosis (DUP)) is long, with a mean
of 1–2 years and a median of approximately 26 weeks
with some patients having very long DUPs. The
majority of studies show a statistically significant
correlation between long DUP and poor outcome
(22, 27–41), even though others have not found this
correlation (41–44). Wyatt (28) reviewed 22 studies in
which patients were or were not given neuroleptics at
specific times during their course of illness. He
concluded that ‘early intervention with neuroleptics
in first break schizophrenic patients increase the
likelihood of an improved long-term course’.
Although very few studies present scientific evidence
to support the hypothesis that an experimentally
achieved earlier intervention will lead to a better
outcome for the patients, a number of authors have
supported the idea enthusiastically. There is a danger
that our lack of effective treatment strategies for
psychosis may weaken our critical attitude towards
new ideas that are marketed strongly.
The title of our paper is ‘Early intervention in
first-episode schizophrenia’, but due to the duration
criteria in schizophrenia (6 months in DSM-IV and
1 month in ICD-10) early intervention must focus

323
Larsen et al.
on the more general syndrome of psychosis. We
have, therefore, chosen to include syndromes that
can be pre-stages to schizophrenia, i.e. non-
affective psychosis.
This paper is primarily a critical review of the ‘early
intervention in psychosis’ literature. The concept
‘early intervention’ is ambiguous and we need a
definition in order to carry out a meaningful review.
The concept ‘early’ is related to an idea of what is
‘usually’ the situation. Usually the treatment is given
after development of psychosis and even after long
DUPs, therefore ‘early’ means ‘earlier than usual’.
Two types of early intervention strategies are
possible: (a) early intervention in the prodromal
phase and (b) early intervention after the onset of
psychosis. These possible types of early intervention,
related to the phases that schizophrenia often
develops from, are presented in Fig. 1.
Early intervention in the prodromal phase means
primary prevention and should lead to a decrease in
the incidence of the disorder. The most general form
of primary prevention consists of prevention strate-
gies aimed at the total population or universal
prevention (e.g. immunizations, the use of seat-
belts), followed by prevention strategies aimed at
high-risk subgroups (e.g. mammography in females
with a family history of breast cancer) (45).
Fig. 1. The early course of schizophrenia.
324
Identifying and treating symptoms that are precur-
sors to a more serious disease in order to prevent
outbreak of the disease is called indicated prevention.
Treatment of prodromal symptoms to psychosis may
be labelled as indicated primary prevention (46–48).
Early intervention after the onset of psychosis means
that treatment is given as soon as possible after the
psychosis is present. This equals a reduction of DUP
and should lead to a reduction in the prevalence of the
disorder (secondary prevention). As shown in Fig. 1,
onset could be defined as related not only to positive
or negative symptoms, but also to the onset of a
syndrome with specific criteria of symptom combi-
nations and duration. The onset of positive symp-
toms has been reported to be more reliable than
negative symptoms (12), but thorough studies of the
early course of illness have shown that about 70% of
the patients with schizophrenia develop negative
symptoms before positive symptoms (49). In the
literature the general recommendation has been to
use positive symptoms in order to define onset of
psychosis (9, 23), but the possibility of using other
definitions should be recognized.
Tertiary prevention means that effective treat-
ment is given for a long enough period of time
after the onset of psychosis (50, 51) including the
prevention of relapse (51). According to our

definition of early intervention, tertiary prevention
is not an early intervention strategy. Tertiary
prevention has more to do with the timing,
duration and content of adequate treatment.
Recently, extensive reviews have been published
regarding the effectiveness of different treatment
programmes for psychosis; see, for example, the
Schizophrenia Patient Outcomes Research Team
(PORT) (52).
Another research strategy for identifying early
symptoms of psychosis is to carry out so-called
high-risk studies. In these studies offspring of
patients with schizophrenia have been followed
prospectively for long periods of time to study not
only to what degree they develop psychosis, but also
what the early signs of psychosis look like. We
recognize that these studies play an important role
in the development of early identification strategies,
but the rate of offspring with severe mental disorder
is generally low. Only a few patients (approx. 15%)
with schizophrenia have close relatives with schizo-
phrenia and the generalizability of such studies is
not high (53–56). Therefore, these studies are not
reviewed here.
This review addresses in particular the following
two questions: first, do the results of the studies
indicate that the described intervention pro-
grammes have managed to achieve early interven-
tion, and secondly, are there indications that the
earlier intervention was followed by an improve-
ment in outcome?
Review strategies
We will first discuss projects aimed at early
intervention in the prodromal phase and then
early intervention after the onset of psychosis.
For each study we will present design, results and
our evaluation. Studies will be classified as to their
validity of knowledge according to the criteria used
by APA (57). Studies were identified through search
in Medline, Embase and PsychLit. In total, we
looked at 116 papers, and 113 papers relevant for
this review were identified. Thirty-eight of these 113
we characterized as ‘general’ and 19 as describing
the relationship between precursors and outcome,
none of these presenting any original data relevant
for our review. We thus identified 56 papers
describing 13 studies relevant for this review. We
will not review every paper, but review each of the
relevant studies based on the papers published so
far. Since there is a lack of studies, we have also
tried to identify ongoing projects and their pre-
liminary results through personal contact with the
research teams leading these programmes.
Early detection and intervention in schizophrenia
General papers
The idea of early intervention is discussed in a
number of papers that present little primary data on
the topic (8, 10, 58–79). In the books The recognition
and management of early psychosis — a preventive
approach by McGorry and Jackson (80), Early
intervention in psychosis: a guide to concepts, evidence
and interventions by Birchwood, Fowler and Jackson
(81) and Early intervention and treatment of schizo-
phrenia by Jørgensen, Larsen and Rosenbaum (in
Danish) (82), these perspectives are discussed in
detail.
Studies of primary prevention
The Buckingham project
The Buckingham study from 1984–88 (8, 83, 84) is a
pioneer study in primary prevention. To our
knowledge it was the first study to organize a very
early detection of psychosis. Due to its dramatic
results it has had a major impact on the field.
Design.The study was carried out in the county of
Buckinghamshire, England, during 1984–88. The
project teams established a mental health service
system with close connection to the existing
primary health services. The four teams had a total
staff of 12 nurse therapists, two psychiatrists, one
psychologist, one social worker, one occupational
therapist and two secretaries. The general practi-
tioners in the area (population 35 000, number of
GPs 16) were trained in detecting early cases of
psychosis with the use of a checklist for prodromal
symptoms similar to the prodromal symptoms in
DSM-III-R (85). Patients with possible prodromal
symptoms were referred immediately to specialized
mental health assessment. The treatment given
consisted of low-dose medication, crisis-orientated
family intervention, with an emphasis on problem-
solving, and social skills training. Specifically, the
patients and the families were given ‘education
about the nature of schizophrenia’ (83).
Results. During this 4-year period, 16 patients with
prodromal symptoms were detected; only one of
these definitely had schizophrenia and she was
treated with low-dose neuroleptics for 3 weeks and
then went into remission. Epidemiological studies
carried out 10 years earlier indicated an incidence
of 2.5 new cases per year. The authors draw the
conclusion that a 10-fold reduction in the annual
incidence of schizophrenia, from 7.4/100 000 to
0.75/100 000 total population, had been achieved.
325
Larsen et al.

Evaluation. The Buckingham study could be
classified as a prospective clinical trial according to
the APA coding system, the intervention being the
early identification with the previous epidemio-
logical study acting as a historical control. The
study has several methodological shortcomings.
The authors report no study of their diagnostic
reliability. There was no follow-up of the patients
which ensured that intervention actually prevented
the outbreak of psychosis and not just delayed it.
As with all historical control studies, there is no
control for natural changes in the incidence of
the disorder (cohort effects). The most critical
limitation is, however, the uncertain compar-
ability with the historical control. Was the first
epidemiological study also based on GP
populations only? Are the two patient groups
drawn from the same patient populations? If this is
not the case, the prevalence figures are probably
non-comparable.
The most remarkable finding in this study is that
no first-episode cases with long DUP were identi-
fied. Most other studies of first-episode schizo-
phrenia report that about 50% of the patients have
been psychotic for quite a long time at the time of
inclusion. In a later paper from 1996 regarding this
particular issue, Falloon describes how their con-
cern regarding this question made them look for
‘hidden cases’ afterwards. Falloon writes: ‘A review
was conducted of all persons in the area who were
regularly prescribed psychoactive drugs’ (p. 279)
(84). This identified six additional cases of schizo-
phrenia. Falloon continues: ‘All the individuals had
experienced onset of the disorder before the study
period; in four, the onset was more than five years
earlier’ (p. 279). Were these actually the long DUP
cases that for some reason were not detected by the
system for early detection of prodromal symptoms?
If so, we will argue that these patients should have
been included in the incidence figures, resulting in
an incidence of seven new cases, i.e. within the
expected range. This study also raises a number of
ethical questions regarding ‘false positive’ cases.
The use of concepts such as ‘prepsychosis’ or
‘preschizophrenia’ may create a stigma that causes
unnecessary problems for the patients. The study
does not give unambiguous evidence that primary
intervention can be achieved through identification
of prodromal states. This is also recognized by the
author, who regarded the study as ‘preliminary’.
The ‘PACE’ study
The Personal Assessment and Crisis Evaluation
Service (PACE) is a clinical service established in
Melbourne, Australia, in connection with the Early
Psychosis Prevention and Intervention Centre
(EPPIC) services (see description later). McGorry
and his colleagues have been a major driving force
in the development of international collaboration in
the field of early intervention of psychosis.
Design. The focus of PACE is to look for
precursor factors which occur just prior to
psychosis, i.e. to try to identify individuals who in
the absence of treatment run a high risk of
becoming psychotic in the short term (11, 61,
86–91). Three types of prodromal states are
defined (Table 1).
The PACE service is located at a generalist out-
patient service and health promotion centre for
adolescents. All patients are help-seeking and
experience some kind of psychiatric symptoms.
Patients between the ages of 16–30 with one or more
of the predefined prodromal states are followed
with monthly ratings of psychopathology. The
study defines transition from prodromal states to
psychosis as:
1) Presence of at least one of the following
symptoms:
(i) hallucinations defined by a score of 3 or
more on the hallucination scale of the BPRS;
(ii) delusion as defined by a score of 4 or more
on the unusual thought content scale of the
BPRS or a score of 4 or more on the
suspiciousness scale of the BPRS, or it is held
with strong conviction, as defined by a score of
3 or more on the CASH rating scale for
delusions; and
(iii) formal thought disorder, as defined by a
score of 4 or more on the conceptual
disorganisation scale BPRS.

Table 1. PACE criteria for ‘at risk mental states’

Attenuated psychotic symptoms Patients who demonstrate a recent onset of at least one attenuated psychotic symptom from the following DSM-IV schizotypal
personality disorder criteria: ideas of reference, odd beliefs or magical thinking, perceptual disturbance, odd thinking and speech,
paranoid ideation, and odd behaviour or appearance (92)
Transient psychotic symptoms Patients who demonstrate transient psychotic symptoms, i.e. DSM-IV hallucinations, delusions, or disorganized speech, for
less than 1 week before spontaneous resolution
Trait plus state risk factors for psychosis
Genetic risk Patients who have non-specific anxiety and/or depressive symptoms, a recent loss of at least 30 Global Assessment of
Functioning points (GAF), and a first-degree relative with a DSM-IV schizophrenia spectrum disorder

326

2) Frequency of symptoms is at least several times
a week.
3) Duration of mental state change is longer than
1 week.
Results. During the first 16-month period 119
referrals were assessed and 49 patients met the
criteria for prodromal syndromes. In a publication
from 1998, 20 patients had been followed for at
least 6 months. Forty per cent of these developed
psychosis (46), 5% within the first month of follow-
up. A comparison between those who developed
psychosis (N=8) and those who did not (N=12)
showed that the psychosis group initially had
significantly higher BPRS total scores, more
negative symptoms and more signs of depression
and poorer quality of life and lower GAF scores.
In a randomized non-blind clinical trial with 60
patients fulfilling criteria for at-risk mental states,
the 6-month follow-up data have been presented
(87). The treatment group (N=32) received anti-
psychotics (risperidone 1–2 mg/day), antidepres-
sants and anxiolytics in combination with
cognitive behavioural therapy. The control group
(N=28) received basic support, antidepressants and
anxiolytics. In the treatment group 12.5% converted
to psychosis, compared to 36% in the control group
(P<0.05).
Evaluation. At the PACE clinic a prospective
longitudinal study was carried out where subjects
are followed without any specific intervention. The
statement that 40% of the patients identified in a
possible prodromal stage of psychosis developed
psychosis within the first year of follow-up is, in
our view, problematic. The duration criteria for
transition to psychosis in the PACE clinic (longer
than a week) may represent a higher threshold than
the DSM-IV diagnostic criteria for brief psychosis
(more than a day) or psychosis NOS (no duration
criteria). The patients labelled prepsychotic may
thus have met the DSM-IV criteria for brief
psychosis or psychosis NOS at their inclusion into
the study. For this type of patient it could be
argued that the term ‘transition into psychosis’ is
ambiguous, since they already could be labelled
‘psychotic’.
The study has several other methodological
weaknesses. No data on the reliability of for example
the presence versus absence of prodromal states are
presented. Additionally, no data on comorbidity are
presented. In particular, the lack of information on
the prevalence of borderline or schizotypal person-
ality disorder in the screened population and how
these patients were dealt with is a matter for concern,
as patients with severe personality disorders would
Early detection and intervention in schizophrenia
regularly meet the PACE criteria for prodromal
states. The PACE project, however, focuses on a very
important topic: the threshold between psychotic,
prodromal and non-psychotic states. These concepts
are not well defined in existing diagnostic manuals.
The PACE study can provide data that clarify these
borderlines which have become increasingly impor-
tant in recent years. One of the study’s main strengths
is that their detailed description of definitions enable
readers to make up their own minds.
The findings from the randomized clinical trial
with use of antipsychotics in the prodromal phase is
interesting, but replication with a double-blind
placebo-controlled design is needed in order to
understand the significance of these findings.
The ‘Bonn Early Recognition’ study
In Germany, early symptoms of schizophrenia have
been labelled basic symptoms (BS). This concept
comprises the very early self-experiences that
schizophrenic patients have before they develop
psychosis. BS was first described by Huber et al. (93,
94) and are developed within the tradition of Kurt
Schneider. BS represent subjective experiences of
the early neurophysiological changes that patients
go through before they develop symptoms of
psychosis. Klosterkoetter has described BS as ‘the
subjective side of the pre-existing neurophysiologi-
cal deficit’ (95). The BS are described in detail in the
Bonn Scale for the Assessment of Basic Symptoms
(BSABS) (96, 97).
Design. The study included patients with a
DSM-III-R diagnosis of personality, mood,
somatoform and anxiety disorders drawn from all
patients attending the psychiatric departments of
the German university clinics in Ulm-Wesseinau,
Lübeck and Bonn (98). Patients were referred from
psychologists, psychotherapists and neurologists
with a request for further diagnostic clarification.
The frequency of BS at baseline was recorded and
patients were followed-up after 8 years. The aim of
the study was to record the transition rate to
psychosis, and the relationship between BS
symptoms and the development of psychosis.
Results. Ninety-six patients were included; 81% of
these had at least one BS at baseline. At 8-year
follow-up 58% had developed schizophrenia. One-
quarter of the patients with baseline BS did not
develop schizophrenia. Statistically significant
predictors of the transition to schizophrenia were
the BS’s ‘cognitive thought’, ‘perception’ and
‘motor disturbances’ and additionally the presence
of schizotypal personality disorder.
327
Larsen et al.
Evaluation. The study was longitudinal without
any specific intervention. The study population was
highly selected. Patients were referred from
psychologists, psychotherapists and neurologists
for further diagnostic classification. Several of the
patients had already received more or less effective
treatments. They all had a high baseline prevalence
of BS. The predictive power of BS may be weaker
in non-selected populations. It is not clear whether
any of the patients initially met the criteria for
other types of psychosis such as brief psychosis or
psychosis NOS, as the presence of DSM-III-R
schizophrenia was the only diagnostic exclusion
criteria. Replication studies are needed with less
selected samples.
Ongoing projects on primary prevention
There are a number of ongoing projects on primary
prevention of psychosis; they will be described
briefly here.
The PRIME (Prevention through Risk
Identification, Management, and Education) Clinic
is located at the Yale Medical School in New Haven,
Connecticut, United States. The aim is to test in a
double-blind study whether early treatment with an
atypical antipsychotic compared to placebo can
prevent or delay the onset of psychosis. Patients
between the age of 14–45 who fulfil criteria for a
prodromal state according to SIPS (Structured
Interview for Prodromal States) and SOPS (the
Severity Scale of Prodromal Symptoms) (99) are
included in a study with 1-year treatment and 1-year
follow-up. The treatment consists of randomization
to olanzapine or placebo (double-blind), and the
dependent variable is development of psychosis
according to specific criteria. All patients receive a
psychosocial intervention consisting of stress man-
agement and problem-solving skills training. The
study addresses specifically whether treatment with
olanzapine in a possible prodromal phase can prevent
development of psychosis. Preliminary data on the
first 35 patients who are judged to be at risk for
psychosis report that 24 patients have been rando-
mized into the clinical trial. The conversion to
psychosis rate as at January 1, 2000 is 33% (TH
McGlashan, personal communication, January 23,
2000).
The TOPP (early Treatment of Prepsychosis)
project is being carried out at Rogaland Psychiatric
Hospital, Stavanger, Norway as a part of an
ongoing international multisite study testing the
efficacy of Early Treatment and Intervention in
Psychosis (the TIPS study, see presentation later).
The TOPP project studies whether patients with
defined prodromal states (according to a Norwegian
version of the SIPS and SOPS scales) develop
328
psychosis within a 5-year follow-up period. The
treatment given consists of supportive psychother-
apy without use of antipsychotics. As at December
31, 1999 a ‘conversion to psychosis’ rate of 40% was
observed for 10 patients with a follow-up period of
approximately 1 year (100).
The DEEP (Detection of Early Psychosis) project
is being carried out in Turku, Finland. In this study
several groups are selected for a screening of pro-
dromal symptoms (with a Finnish version of the SIPS
and SOPS scales). One group consists of first-degree
relatives of discharged schizophrenic patients, other
groups are attending psychiatric open care, patients
of the adolescent unit and their first-degree relatives
and an unselected group of volunteers and controls
recruited from the general population. A 3-year
follow-up study in order to describe conversion into
psychosis is being carried out. As at December 20,
1999 121 first-degree relatives of schizophrenic
patients have been through the clinical interviews.
Eight of these people have been diagnosed with a
lifetime prodromal symptomatology. In the other
groups 143 cases have been screened and 36 fulfil
criteria for a prodromal state. All these patients are
currently being followed-up and no preliminary
data are available (personal communication, M.
Heinemaa, December 20, 1999).
Secondary prevention studies
The ‘EPPIC’ study
In Melbourne, Australia, a group of clinicians and
researchers have developed a psychiatric health
system with a strong emphasis on early detection
and early treatment of psychosis (101–105). For
more than a decade they have been working
towards the realization of a preventive approach
to first-episode psychosis. The Early Psychosis
Prevention and Intervention Centre (EPPIC) has
been established as a mental health service, provid-
ing both early detection and specialized treatment
for early psychosis and treatment-resistant psycho-
sis. The catchment area is the western metropolitan
region of Melbourne with approximately 800 000
inhabitants.
Design. Patients included in the EPPIC programme
from March to October 1996 were compared with a
matched group of patients detected during
1989–92, before the first EPPIC programme was
established. Patients with onset of psychosis
between the ages of 16 and 30 who were psychotic
according to specific definitions at their entrance
into the programmes were included. The aim of the
study was to ‘evaluate the effectiveness of the
EPPIC programme on 12 month outcome in first-

episode psychosis, in contrast to the previous
model of care’ (103) (p. 315).
Results. In a paper from 1996 51 patients were
included in both samples (103). The pre-EPPIC
sample was drawn from a sample of 200 patients
matched with the EPPIC group on the variables
age, sex, diagnosis, marital status and premorbid
functioning. The study compared baseline
characteristics and 1-year outcome. No significant
reduction in DUP was found. Mean DUP was 237
weeks (median 60) in the pre-EPPIC and 191
(median 52) in EPPIC. In 1999 larger groups were
compared: pre-EPPIC N=140 and EPPIC=110
(105). Even in this comparison no significant
reduction in DUP was reported, mean DUP was
226 (median 30) in the pre-EPPIC and 175 (median
52) in the EPPIC. Statistical tests (after log-
transforming the data in order to minimize
the effect of extreme outliers) indicated that DUP
was actually longer in the EPPIC sample. During
the 1-year follow-up period the EPPIC sample
experienced significantly fewer admissions, had
shorter periods as in-patients and had a reduction
in both acute and post-acute levels of neuroleptic
dosage. The patients in the EPPIC also had
significantly better Quality of Life Scores (QOS)
(106), and significantly less negative symptoms at
follow-up. This effect was strongest for patients
with a DUP of 1–6 months.
Evaluation. The EPPIC historical control studies
can be characterized as prospective clinical trials
with a historical control group. The studies did not
show that the EPPIC programme was able to
shorten DUP significantly. In both studies DUP
was in the same range as reported in international
studies during the last decades. The better 1-year
outcome in the EPPIC group is due probably
to an improved and more structured treatment
programme. It is an interesting finding that the
effect of better treatment programmes might be
strongest for patients with a DUP of 1–6 months.
Due to the low number of patients in the different
subgroups of DUP (DUP 1–6 months; preEPPIC;
N=42; EPPIC; N=31) these findings must be
interpreted with caution and replication studies are
needed.
The TIPS study
Design. The TIPS (Early Treatment and Inter-
vention of Psychosis) project is a prospective
clinical trial designed to test whether an earlier
treatment in first-episode psychosis can change the
natural course of the disorder. It is a multicentre
study with three participating sites: Rogaland
Early detection and intervention in schizophrenia
County, Norway (370 000 inhabitants), Ullevål
sector, Oslo, Norway (190 000 inhabitants) and
Roskilde County, mid sector, Denmark (100 000
inhabitants). Patients with first-episode non-
affective psychosis are treated with the same drug
and psychosocial treatment protocol at all three
sites. The patients are assessed with the same rating
instruments at baseline, 3 months, 1, 2 and 5 years.
The Rogaland centre has developed an extensive
education programme that use newspaper
advertisements, videos, lectures and information
brochures, etc. Specific subprogrammes have been
developed for the general population, schools
(pupils, teachers, nurses and psychologists) and the
primary care system (GPs, social workers, etc.)
(107). Ullevål and Roskilde rely on existing
detection and referral systems for first-episode
cases.
Results. The inclusion phase ends December 31,
2000. Until now, one interesting and potentially
important preliminary finding has been reported.
Patients with long DUPs are significantly more
reluctant to enter the study (108). This could be
an important bias in studies of DUP that needs to
be addressed.
The TIPS historical control study
During the prephase to the TIPS project in 1993–94,
a descriptive study of first-episode non-affective
psychosis patients was carried out in Rogaland
County, Norway (23, 109, 110). The aim of the
study was to describe ‘pathways to care’ with
emphasis on DUP. A 1-year follow-up study was
also carried out (35).
Design. The patients recruited during 1993–94,
when Rogaland had no early detection programme
(the historical control sample or HC), have been
compared with the patients recruited during the
first 2 years, 1997–98, of the TIPS study (the early
detection sample or ED). Both samples were drawn
from the same catchment area. The study addresses
the specific question whether an ED system can
reduce DUP in one sector.
Results. In the HC sample 43 patients were
included, compared to 51 patients in the ED
sample. A significantly shorter DUP was found in
the ED sample (mean: 114–18 weeks; median: 26–8
weeks). This was largely accounted for by a
reduction in DUP among males. The ratio
schizophrenia/schizophreniform disorder at base-
line had changed from 10.6 (HC) to 1.2 (ED).
There was a complementary reduction in the
329
Larsen et al.
frequency of a diagnosis of schizophrenia at
baseline from 32 (HC) to 20 patients (ED). ED
patients were also significantly younger, with
better premorbid adjustments and less severe
psychopathology. They had, however, more
substance abuse at first contact (111).
Evaluation. The study is a prospective clinical trial
with early identification and treatment as the
experimental intervention in one of the samples.
The historical control design has several major
methodological drawbacks, due mainly to our
inability to control for major variances in
study populations, diagnostic distributions, in
measurement and in treatment between the time
periods. Population studies have estimated that
approximately one-third of patients with disorders
in the schizophrenia spectrum never seek treatment
(38, 112). Patients with short DUP in the ED group
could go on to a rapid and complete recovery, and
represent a group that was not identified in the HC
period. The early detection effect may actually be
an intensive identification effect. It is impressive
that a reduction in schizophrenia cases at baseline
is reported, despite the fact that more patients are
detected in the ED group. However, it is difficult to
understand why cases with very long DUPs seem
to have disappeared during this process, as an
increase of long DUP cases was to be expected in
the initial phase of an earlier, more intensive
identification programme. Could very intensive
detection programmes repel the sickest patients?
The results need to be replicated before firm
conclusions can be drawn.
Ongoing studies of secondary prevention
At present, several studies aiming at earlier
identification of patients with first-episode psycho-
sis are being carried out.
The OPUS (early detection and assertive com-
munity treatment of young persons with untreated
psychosis) study in Denmark has established early
detection teams in one study sector and aims at
comparing with ‘detection as usual’ in the other
study sector. At present no results can be reported
from the study (personal communication, P. Munk-
Jørgensen, January 20, 2000).
The RAPP (Recognition and Prevention of
Psychological Problems) clinic at Hillside Hospital,
New York is an early intervention centre focusing on
patients between the ages of 12 and 25 with possible
prodromal symptoms or early symptoms of psycho-
sis (113, 114). At present no data are available.
The FETZ (Früherkennungs- und Therapie-
zentrum für psychotische Krisen) clinic in Cologne,
330
Germany also aims (115) at both primary and
secondary prevention. No preliminary results are
available.
Discussion
For the time being, no research projects have shown
beyond reasonable doubt that primary prevention
in psychosis is possible. Several ongoing studies
describe characteristics of prodromal states which
indicate increased risk of transition to psychosis.
The conversion rates reported from the early phases
of these studies lie between 33 and 58%. Even
though these findings are encouraging, the specifi-
city of prodromal states is still ambiguous and
caution must be taken to avoid unnecessary
stigmatisation and false positives (116). In the
case of intervention in supposedly prodromal
states, we believe that so far only patients who
worry over their symptoms and wish to receive
treatment should be included in treatment efforts. It
is a problem that treatments may carry the risks of
somatic or psychological side-effects, due to use of
antipsychotic medication or the use of labels such as
‘early schizophrenia’ or ‘prepsychosis’ (65, 77). On
the other hand, early follow-up data from the
PACE clinical trial study with use of antipsychotics
in at-risk mental states show a possible significant
reduction in conversion to psychosis within 6
months of treatment. Even though this study
needs replication with double-blind design, it
raises the question of whether not treating with
antipsychotics in these high-risk groups could
represent a larger ethical problem than the produc-
tion of false positives. More research is clearly
needed to answer these questions.
Regarding secondary prevention, we conclude
that it is still an open question if a reduction in DUP
leads to better outcome for first-episode patients.
We have not been able to find any well-designed
studies showing evidence that early identification
makes a difference for the outcome of the individual
patient. There are, however, ongoing studies that
are designed to answer this question, and we expect
that more scientific results will be presented in the
years to come. In the meantime there are several
good arguments for early intervention, regardless of
outcome. First, a shortening of the time period a
patient is overtly psychotic is obviously beneficial,
even if the long-term prognosis remains poor. A
parallel discussion is ongoing in somatic medicine in
relation to early treatment of rheumatoid arthritis
(117). It is a well-documented fact that many of the
homeless suffer from untreated schizophrenia (118,
119). If a reduction in DUP could be achieved, some
of these negative consequences could be reduced

(120, 121). It also seems reasonable to expect that it
must be easier to establish a good therapeutic
alliance in patients detected before their psychoso-
cial ‘breakdown’ is complete. The preliminary TIPS
results point in this direction, as the increased rate
of study participation refusal in long DUP patients
seemed to be paralleled by an increase in negative
attitude to treatment. Short-term effects might be
clinically significant even without improvements in
long-term outcome. Earlier intervention may affect
suicide rates. In one study, 24% reported that they
had had suicidal thoughts during the early phases
before treatment was administered (90). We do not
know how many people with completed suicides
that had experienced prodromal symptoms or suffer
from untreated psychosis. It seems likely that the
quality of life during the first years of illness will be
better when early treatment is achieved.
Early intervention programmes are difficult to
organize and expensive to carry out. Even if there
are several good arguments for early intervention in
first-episode psychoses it is still very important to
carry out studies with experimental design, that can
confirm or invalidate the hypothesis that early
intervention improves the course and outcome of
schizophrenia/first-episode psychosis. Studies that
can show how certain aspects of outcome such as
symptomatology, neurocognitive function, ability
to study or work and quality of life are affected by
early intervention, and studies that can identify
subgroups who will benefit more than others from
such intervention, are of particular value.
Acknowledgement
This study was supported by the NARSAD Young Investigator
Award (to Dr Larsen).
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