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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-nai¨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 12. Bottlender R, Mo¨ller HJ. The impact of the duration of psychosis specific treatment can be implemen- untreated psychosis on short- and long-term outcome in schizophrenia. Curr Opin Psychiatry 2003;16:39-43.
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