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Acta Psychiatr Scand 2006: 113 (Suppl. 429): 73–80
Early detection and treatment ofschizophrenia: how early?
Riecher-Ro¨ssler A, Gschwandtner U, Borgwardt S, Aston J, Pﬂu¨ger M,
Ro¨ssler W. Early detection and treatment of schizophrenia: how early?
Acta Psychiatr Scand 2006: 113 (Suppl. 429): 73–80. ª 2006 Blackwell
1Psychiatric Outpatient Department, University HospitalBasel, Basel, Switzerland
Objective: Whereas early detection and therapy of schizophrenic
2Psychiatric University Hospital Zürich, Zürich,
psychoses until some time ago concentrated on frank schizophrenia,
during the last years some centres have also started to treat patientseven before a clear diagnosis could be established. This paper attemptsto discuss if and when this is justiﬁed in the light of recent research.
Method: Mini review of literature.
Results: The rationale for early detection and treatment of
Key words: early diagnosis, early intervention,
schizophrenia is based on several observations: diagnosis and
psychotic disorders, schizophrenia, risk factors,
treatment of schizophrenia are often seriously delayed. Consequences
of the disease are severe already in the early undiagnosed phase of the
Prof. Anita Riecher-Rçssler, MD, Psychiatric Outpatient
disorder and early treatment seems to improve the course of the
Department, University Hospital Basel, Petersgraben 4,
disease. It can therefore be stated quite safely that patients should be
treated as early as possible. However, the question of how early has not
been suﬃciently answered up to now.
Parts of this paper were in a preliminary version read at
Conclusion: We are at the moment in an ethical dilemma between either
the 3rd International Zurich Conference on Clinical and
diagnosing and treating this disorder too late or too early. The only
Social Psychiatry, Zurich, September 25–27, 2003. The
way and prerequisite for solving this dilemma is a more reliable
symposium as well as publication of this supplement
identiﬁcation of individuals at risk and the beginning disease process.
were sponsored by Eli Lilly, Suisse.
detection already in this phase of beginning schi-
Early detection and therapy of schizophrenic psy-
Thus, one of the main questions is, whether and at
choses has become a widely accepted goal in
what stage early intervention such as treatment with
psychiatry. Centres for early detection and inter-
low-dose atypical neuroleptics is indicated. This
vention have been set up worldwide. For example,
question confronts researchers and clinicians with
the UK Government has decided to systematically
the ethical dilemma between diagnosing/treating
invest in early detection and intervention as Ôthe
this disorder either too late or too early. On the one
rationale for early intervention is overwhelmingÕ (1).
hand the disease process can be very devastating
Whereas until some time ago early diagnosis
already in the early prodromal stages, as we have,
and intervention in schizophrenia concentrated on
for example, shown in our ABC Study [Age, Begin
clear-cut, frank schizophrenia, during the last years
and Course of schizophrenia]; (2, 3). On the other
some centres have also started to treat patients
hand it is important not to diagnose/treat too early,
even before a clear diagnosis could be established.
because of the potential identiﬁcation of Ôfalse
The rationale behind this is that these disorders
positivesÕ, the stigma associated with the diagnosis,
often begin many years before ﬁrst clear symptoms
the potential side-eﬀects of treatment, etc. (4–9).
occur with quite unspeciﬁc changes and prodromiand/or very brief, transient or mild ÔattenuatedÕ(subthreshold) psychotic symptoms, but often have
deleterious consequences already in these early
This paper attempts to discuss the following key
stages. However, reliable methods for an early
i) Is there really a sound rationale for the early
quality of life is seriously impaired already at ﬁrst
detection and treatment of schizophrenic psy-
admission and associated with DUP (16).
ii) What are the problems of early detection and
Early treatment seems to improve the course of the
disease. There is a large body of evidence that early
iii) How could we improve early detection?
treatment of psychosis can substantially improvetreatment response, course and outcome of thedisease (7, 8, 10, 17–20). Thus, the majority of
studies found a statistically signiﬁcant correlation
A selective review of recent literature was per-
between long DUP and poor outcome. This is
formed to answer these key questions. We searched
especially true for short-term outcome, but also
Medline and PsycINFO (2000–2004) using mainly
applies to long-term outcome. While some authors
combinations of the key words: schizophrenia, ﬁrst
questioned a direct causal link between DUP and
episode, (high) risk, early diagnosis, risk factors,
outcome (21), several studies demonstrated that
prevention. In addition we used previous reviews
DUP consistently predicted outcome independ-
ently of other variables, and that it was not simplya proxy for other factors (19, 20, 22–25).
outcome could be multifold. Thus, ongoing psy-chosis could have direct ÔneurotoxicÕ eﬀects (26)
Rationale for early detection and treatment of schizophrenia
including molecular sensitization and neurodegen-
The rationale for early detection of schizophrenia
eration with symptomatic progression (27) and
cognitive deterioration (28), although there arealso studies questioning these theories (29–31).
Diagnosis and treatment of schizophrenia are often
A delay of treatment on the contrary can have
very severe consequences. Thus, it has been notedthat a longer DUP was associated with an incom-
i) Duration of untreated psychosis (DUP):
plete remission of symptoms (19, 20), with a worse
patients suﬀer from productive psychotic symp-
long-term prognosis (32, 33), a higher overall
toms, such as delusions or hallucinations, for an
dosage of neuroleptics (34), a worse compliance,
average of 1–3 years before this disorder is
higher burden for the family and higher expressed
diagnosed and treated for the ﬁrst time.
emotion level (35), a higher rate of rehospitaliz-
ii) Duration of untreated illness (DUI): even
ations (36) and higher overall treatment costs (37).
before that, patients suffer from an Ôunspeciﬁc
We also have to expect an enhanced risk of
prodromal phaseÕ for an average of 2–5 years [for
depression, suicide and substance abuse if there is
a long phase of untreated disease (35).
One of the ﬁrst studies which could show this
It can therefore be stated quite safely that
delay on a methodologically sound basis was the
patients should be diagnosed and treated as early
ABC Study (2, 3). In this study, we could
as possible. The question, however, is: how early?
retrospectively show that the initial signs on aver-age became apparent approximately 4.6 years
Problems of early detection and treatment
prior to ﬁrst admission and diagnosis. Firstpsychotic
Early detection of schizophrenia? An early diagnosis
2.1 years before ﬁrst admission (14).
of ÔschizophreniaÕ before the diagnostic criteria arefulﬁlled, might be possible retrospectively, but is
Consequences of the disease are very severe already in
Ôper deﬁnitionÕ not possible prospectively.
the early preclinical, undiagnosed phase of the disor-der. One of the further major ﬁndings of the ABC
Early detection of psychosis? Researchers and clini-
Study was that before ﬁrst admission most patients
cians have, therefore, concentrated on the early
already suﬀered from serious impairments and
diagnosis of ÔpsychosisÕ using well-deﬁned criteria
losses in various social domains such as education,
for psychotic breakdown [mainly the criteria of
work, partnership or independent living (15).
Yung et al. (38)]. Early treatment of patients who
Especially as the disease often strikes individuals
fulﬁll these criteria aims at reducing the DUP. It
when they are still very young and in the midst of
seems quite clear that early treatment should start
their developmental years, consequences for the
at least as soon as frank psychosis has occurred, as
diﬀerent social roles are often deleterious. Thus,
this can substantially ameliorate symptoms and
shorten psychotic episodes (10) and thereby avoid
What domains are these? What predictors for
or at least ameliorate the immediate negative
developing schizophrenia do we know? To answer
psychological and social consequences.
this, we did a comprehensive search of the literaturewith a special focus on patients who had been
Early detection of Ôbeginning illness’? Early detection
investigated before full-blown schizophrenia had
of Ôat-risk status’? However, a reliable detection of
occurred. Retrospectively, such patients are descri-
the disorder even before frank psychotic break-
bed in ﬁrst episode studies, prospectively in genetic
down is still not possible prospectively. At this
high-risk studies and birth-cohort studies. We also
stage of a presumed illness, we are not yet able to
looked at cross-sectional data of ﬁrst episode
diagnose a disorder (schizophrenia) or a syndrome
patients hypothesizing that the abnormalities they
(psychosis). And there is not even enough evidence
show in diﬀerent domains such as neuropsychology
for a reliable detection of an Ôat-risk statusÕ, let
or neuroradiology might already start before the
alone a prodromal phase of the disease.
ﬁrst psychotic episode. Based on these results, we
Treatment of such individuals, thus, raises many
found that early identiﬁcation of a beginning disease
or individuals at risk should theoretically be possible
answered as yet, especially ethical ones (39, 40).
in several domains, mainly the following:
Thus we cannot exclude to identify and treat Ôfalse
i) early risk factors for schizophrenia (genetic
positivesÕ. These individuals would have to cope
with the information on their risk which might be
reasonable and comparable to other risk assess-
iii) other indicators of beginning disease (social
ments and patient education in medicine. Never-
theless, we have to be aware of the special stigma
associated with schizophrenia and – as a conse-
quence of this – the special stress we put on the
individuals confronted with this presumed risk.
And, more importantly, we expose those individ-
In the following, the results of our literature
uals to potential risks and side-eﬀects of therapy
review will be brieﬂy summarized with an emphasis
and medication. Nevertheless, during the last years
on new ﬁndings from the last years.
some centres have started treatment in this unspe-ciﬁc prodromal phase, aiming not any more at
Early risk factors for schizophrenia. Apart from the
reducing DUP as has been tried so far, but at
well-known genetic risk, other early risk factors
reducing DUI (41–43); for reviews see (6, 44).
such as obstetric complications (45) or develop-
In our opinion this might be still too early. The
mental and behavioural problems in childhood
prerequisite for such a very early ÔdiagnosisÕ and
have been described. Davidson and Weiser (46) in
intervention would – in our opinion – be a more
a review of high-risk studies, birth-cohort studies
reliable assessment of the at-risk status and also of
and retrospective and follow-back studies report
the early stages of the beginning disease. That
that future schizophrenic patients present with
means the decision for such very early treatment
delayed developmental milestones, speech and
should be based on more and better empirical
behavioural diﬃculties and lower IQ scores than
evidence. This clearly needs more research.
non-cases. Recent publications have conﬁrmed
But what possibilities for enhancing the reliab-
earlier studies. Thus, for example, Isohanni et al.
ility of such a very early ÔdiagnosisÕ do we have?
(47) analysing a large birth-cohort, found that the
ages at learning to stand, walk or become potty-trained each related to subsequent incidence ofschizophrenia and other psychoses. Also, in a
Improvement of early detection: possible approaches
birth-cohort study, Cannon et al. (48) found signi-
Early identiﬁcation of individuals at risk and
ﬁcant impairments in neuromotor and cogni-
detection of the very early phases of the disease
tive development as well as that of receptive
language, furthermore, they found emotional prob-lems and interpersonal diﬃculties among children
i) identifying more reliable risk factors and
later diagnosed as having schizopreniform disor-
der. Erlenmeyer-Kimling et al. (49) in oﬀspring of
ii) using different levels of investigation; and
schizophrenic patients found childhood deﬁcits
iii) combining these different risk factors/indica-
in verbal memory, gross motor skills and atten-
tors for a comprehensive Ômultidomain risk
tion to predict schizophrenia-related psychoses in
adulthood. Niemi et al. (50) in a recent review
et al. (53, 54) have recently also conﬁrmed the
found amongst others the following factors in
importance of a decline of social functioning for
childhood and adolescence to predict schizophre-
nia: problems in motor and neurological develop-ment, deﬁcits in attention, poor social competence,
Neuropsychological and motor deﬁcits. Recent stud-
positive formal thought disorder-like symptoms
ies conﬁrmed ﬁndings about neuroleptic-free ﬁrst
and severe instability of early rearing environment.
episode schizophrenic patients and individuals at riskhaving generalized neuropsychological deﬁcits, espe-
Psychopathology. Studies have also conﬁrmed the
cially concerning (sustained) attention, abstraction,
importance of early psychopathological abnormal-
(verbal) learning, (verbal) memory and executive
ities and so-called prodromal symptoms. Looser-
function [for review see (55–57)].
Ott et al. (51) followed children of schizophrenic
Regarding individuals at risk Byrne (58) repor-
patients into adulthood within the New York High
ted on 157 individuals at risk (at least two family
Risk Project. They rated video tapes of these
members with schizophrenia) from the Edinburgh
children and found thought disorder as well as
High Risk Study. When compared with 34 controls
negative symptoms in those children who went on
and the general population they showed a poorer
performance on tests of intellectual function,
Klosterko¨tter et al. (52) investigated the predic-
especially verbal IQ, executive function and
tive value of prodromal symptoms. They used the
memory. They suggest that what is inherited is
Bonn Scale for the Assessment of Basic Symptoms
not the disorder itself but a state of vulnerability
to predict schizophrenic disorder in a sample of
manifested by neuropsychological impairment,
385 patients. After a mean period of 9.6 years, 79
which although subtle, could distinguish those at
(49.4%) of 160 patients, who could be re-exam-
risk from control subjects. Egan et al. (59) showed
ined, had in fact developed schizophrenia. The
attention deﬁcits in siblings of schizophrenia
original presence of prodromal symptoms predic-
patients, if index patients suﬀered from severe
ted schizophrenia with a probability of 70%
attention deﬁcits themselves. In our Basel FePsy
(speciﬁcity 0.59, false positive predictions 20%).
(Fru¨herkenung von Psychosen) study we compared
Yung et al. (53) prospectively examined the
32 individuals at risk for schizophrenia with 32
predictive power of certain mental state and illness
healthy controls and found impairments in diﬀer-
variables. They included symptomatic individuals
ent neuropsychological test parameters, mainly
with either a family history of psychotic disorder,
with prolonged reaction times in individuals at
schizotypal personality disorder, subthreshold psy-
chotic symptoms or brief transient psychotic
Also neurological abnormalities, such as dyskin-
symptoms. Of a total sample of 49, 40.8% devel-
esias, Parkinsonian signs and neurological soft
oped a psychotic disorder within 12 months.
signs have been found in neuroleptic-naı¨ve schizo-
Highly signiﬁcant predictors of transition to psy-
phrenia patients [for review see (56, 57, 61)].
chosis were: long duration of prodromal symp-
Dazzan and Murray (62) in a review report that
toms, poor functioning at intake, low-grade
ﬁrst episode patients show an excess of neurolog-
psychotic symptoms, depression and disorganiza-
ical soft signs especially in the areas of motor
tion. Combining some predictive variables yielded
co-ordination and sequencing, sensory integration
a strategy for psychosis prediction with good
and developmental reﬂexes. Mohr et al. (63) in
sensitivity (86%), speciﬁcity (91%), positive pre-
addition to an increased frequency of soft signs
dictive value (80%) and negative predictive value
showed correlations between the soft signs and
(94%). These results, the authors state, Ôlay the
groundwork for the development of targeted
In individuals at risk delayed motor development,
intervention or indicated prevention modelsÕ.
poor motor skills and also increased rates of
They recently (54) published the results of an
neurological soft signs have been described (61). It
even larger sample of 104 Ôultra high-riskÕ young
has therefore been suggested that motor abnor-
people and again reached a speciﬁty of 93%, but
malities may constitute markers of vulnerability
(61). Lawrie et al. (64) detected a signiﬁcantamount of Ôsensory integration abnormalitiesÕ in
Other indicators of the disease. In addition to
individuals at risk (at least two close relatives with
psychopathology, other indicators of beginning
schizophrenia) compared with healthy controls. In
schizophrenia such as changes of social behaviour
our own study (60) individuals at risk showed a
or deterioration in the fulﬁlment of social roles
signiﬁcant impairment of dexterity and of arm/
have also been identiﬁed as important (15). Yung
Previous studies also documented deﬁciencies in
psychosis which had shown reduced hippocampal
eye movements in individuals at risk and patients
with ﬁrst episode schizophrenia [for review see
These recent ﬁndings conﬁrm that very early
(65)]. Gooding et al. (66) found individuals at risk
detection can in fact become more reliable, if in
(identiﬁed by the Chapman Psychosis-Proneness
addition to clinical prodromi other risk factors and
Scale) to have more aberrant smooth pursuit eye
early indicators of vulnerability and/or beginning
tracking than controls. We found an increased
number of correction saccades in smooth pursuiteye movements (60). Also in relatives of patients
with schizophrenia, deﬁcits of the saccadic systemand
Early detection and treatment of schizophrenia is
important and possible. It should in future notonly concentrate on the early detection of schizo-
phrenia and frank psychosis, but also on the
is on the one hand used to exclude organic
identiﬁcation of individuals at risk and especially
psychosis, on the other hand to identify EEG-
on that subgroup of at-risk individuals who
characteristics in schizophrenia. In a review,
already show signs of a beginning disease. In
Torrey (56) reanalysed 65 studies of individuals
these individuals a reliable prediction of psychotic
with schizophrenia and found that the percentage
breakdown should be a major goal. As ﬁrst studies
of abnormal EEGs in never medicated patients
have shown this might be possible, but the empir-
with schizophrenia ranged between 23% and
ical basis for this still has to be improved.
44%, in healthy controls between 7% and 20%.
Early detection clinics would for the moment thus
Especially quantitative EEG may be of value in a
multidomain approach when correlated with other
i) First, early detection and treatment of clear
parameters such as psychopathology or magnetic
schizophrenia and frank psychosis to reduce
DUP. It has been shown that this is possiblethrough early detection programmes (77).
Magnetic resonance imaging. Manifold structural
Therefore, Ôthe prime focus for the moment
changes of the brain have also been described in
ﬁrst episode schizophrenia and in individuals at
speciﬁc management of patients from the
risk (56, 57, 70–74). In a very important study,
Pantelis et al. (75) recently scanned 75 individuals
psychotic illnessÕ [cited from (7)].
at risk, 23 of whom developed psychosis within
ii) Second, differential diagnosis. Thus, for exam-
12 months. Those who developed psychosis had
ple, in our Early Detection Clinic we detected
already at baseline shown less grey matter in
certain brain areas when compared with those
presented psychopathology such as epilepsy,
who did not develop psychosis. Furthermore,
encephalitis and even chronic subdural hae-
those with progression to frank psychosis also
showed progressive grey matter reduction within
iii) Third, early detection clinics should also
contribute to a more reliable assessment ofthe risk for schizophrenia in individuals suf-
Multidomain approach. Some projects now combine
fering from still unclear clinical conditions and
diﬀerent assessment methods, respectively domains
suspected beginning schizophrenia. In these
of investigation. Thus, McGorry et al. (76) found
individuals we should, however, not talk about
not only psychopathology but also neuroradiology
early ÔdiagnosisÕ but rather about early Ôrisk
to be relevant for the prediction of transition to
assessmentÕ. Ethically, in these patients speciﬁc
psychosis. In a sample of 49 individuals at risk the
neuroleptic treatment usually is not yet justi-
best predictors were: duration of symptoms longer
ﬁed in our opinion, as the criteria for inter-
than 100 days, global assessment of functioning
vention are not clear enough until now. For
score <51, Brief Psychiatric Rating Scale (BPRS)
the moment these individuals should be very
total score >15, BPRS psychotic subscale >2,
cautiously informed about their potential risk,
Scale for the Assessment of Negative Symptoms
should be cared for and receive unspeciﬁc
(SANS) attention score >1, Hamilton depression
treatment, if they suﬀer from unspeciﬁc symp-
score >18, cannabis dependency, high maternal
toms, which some of them already do to quite
age at birth and a normal left hippocampus size (in
some extent. And they should carefully be
contrast to the group without progression to
observed so that in case of transition to
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