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Malaysian Journal of Medical Sciences
School of Medical Sciences, Universiti Sains Malaysia
ISSN: 1394-195X
Vol. 9, Num. 2, 2002, pp. 1-6
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Malaysian Journal of Medical Sciences, Vol. 9, No. 2, July 2002, pp. 1-6
Editorial
Is Pre-Psychotic Intervention of Schizophrenia Realistic?
Mohd. Razali Salleh
Department of Psychiatry
School of Medical Sciences, Universiti Sains Malaysia
16150 Kubang Kerian, Kelantan, Malaysia
Correspondence: Profesor Mohd. Razali Salleh Department
of Psychiatry, School of Medical Sciences, Universiti Sains Malaysia 16150
Kubang Kerian, Kelantan, Malaysia
Code Number: mj02011
Key words : Schizophrenia, prodrome, early intervention,
prevention
Background
Schizophrenia is a serious disorder that often affects young
people in their early twenties. The outcome is often poor, associated costs
and burdens are extensive. Almost 15% of schizophrenics end up with frequent
admission and require long-term residential care (1). Recently, the idea of
early detection and intervention has been launched as a new and promising approach.
The starting point for consideration regarding early intervention
strategies is the observation that most patients who develop schizophrenia
have had a period with non-specific, non-psychotic prodormal symptoms before
the onset of psychosis (2,3). The prodormal period has been reported to last,
on average, 1 - 2 years. Another finding across studies in that the period
from onset of a manifest psychosis to onset of adequate treatment (duration
of untreated psychosis DUP) is long. The mean duration of DUP is 1-2 years
with a median of approximately 26 weeks. The majority of studies show a statistically
significant correlation between long DUP and poor outcome (4,5), although others
have not found the correlation (6,7).
Genes that Contribute to Schizophrenia
Many theories have been offered to explain the genetic mechanisms
that produce schizophrenia. One hypothesis is that schizophrenia has a homogeneous
pathogenic genotype with pleiotropic effects. Individuals with schizophrenia
may present with a variety of symptoms. Yet the preponderance of evidence argues
against the possibility that most cases of schizophrenia are caused by a common
gene
(8). In particular, single major gene models do
not explain familiar pattern of illness accurately, in
either families or twins; multi-factorial polygenic
models explain such data better. In a model version of
this view, the schizophrenia phenotype results from
the additive effect of multiple genes and
environmental factors. Each factors contributes effects until
a critical threshold level is reached and the
critical symptoms are manifested. In this model,
common genes of small effect may be involved, rather
than rare genes of much larger effect, as is more likely
in single major gene models. Although models like these account best for family
patterns of transmission, we will not know their accuracy
with certainly until we identify the actual genes that
are involved in schizophrenia.
The important implication of multi-factorial polygenic models
is that genetic heterogeneity at least partly accounts for phenotypic heterogeneity.
While most cases of schizophrenia are accounted for best by polygenic models,
some may indeed result from the effects of one or several genes of moderate
to large effects. In some cases for example, family transmission patterns are
predicted about as well by oligogenic models (a type of model that points to
relatively small number of aetiological genes that have moderate or larger
effects) as they are by multi-factorial polygenic ones (8)
In contract to the high genetic `loading' apparent in many
familiar cases of schizophrenia, sporadic or non-familiar cases of schizophrenia
may result primarily from factors other than schizophrenia genes. Psychosocial
causes, amphetamine misuse, schizophrenia-like psychosis or epilepsy and other
brain trauma, brain disorders, infection in utero and /or complication of pregnancy
are among the variable likely to contribute to
the development of such cases. Finally, some
isolated cases may be due to gross chromosomal abnormalities (9)
In the light of the high heretability estimates for schizophrenia,
the discovery of genes that cause the disorder has been eagerly anticipated
since the 1980s, spurred in part by the development of polymorphic DNA markers
that can detect multiple forms of a gene (alleles) in chromosomal locations.
While several forms of molecular genetic analyses are in use, linkage analyses
provide a particularly versatile procedure that is helping to explain the familial
basis of schizophrenia. Results from linkage studies depend on a variety of
factors, including the presumption of the mode of inheritance, the involvement
of genes whose effects are large enough to be detected and /or the extent to
which family members are diagnosed accurately. Since all these factors (and
others, such as the importance of statistical power) are in some way problematic;
it is not surprising that linkage studied have thus far been less than conclusive,
and have yet to identify the genes that causes schizophrenia.
In the last few years, evidence for the presence of susceptibility
genes have been shown by linkage studies. A study in 1995 provided evidence
of such genes in chromosome 6p and 8p (10). Additional sites have been identified
including chromosome 10 p (11), 13q (12) 15q (13) and 22q (14). However although
these loci have been identified, the actual genes involved in schizophrenia
have yet to be positively.
Early Intervention after the onset of psychosis
Until recently most preventive work in schizophrenia and related
disorders has been of secondary nature, aiming to minimise disability, relapses
and co-morbidity, and to maximise recovery in those with already diagnosed
disorders. The approach means that treatment is given as soon as possible after
the psychosis is detected. This leads to a shortening of DUP (duration of untreated
psychosis) and should reduce the prevalence of the disorder. However, these
measures are too late for most patients, because damage is already extensive.
The onset of psychosis could be defined as related not only
to positive and negative symptoms, but also the onset of a syndrome with specific
criteria of symptoms combination and duration. The onset
of positive symptoms has been reported to be
more reliable than negative symptoms (15), but
through studies of the early course of illness have
shown that about 70% of the patient with
schizophrenia develop negative symptoms before
positive symptoms (16). The literature generally
recommend the use of positive symptoms to define the onset
of psychosis (17), but the possibility of using
other definitions should be recognised.
Early Intervention in the Prodormal Period
Identifying and treating symptoms that are precursors to a
more serious disease in order to prevent outbreak of the disease is called
primary prevention. This should lead to a decrease in the incidence of the
disorder. In this context treatment of prodormal symptoms of schizophrenia
may be labeled as primary prevention. This is because the treatment is targetted
to those who are symptomatic but who do not yet have a fully developed disorder.
The first step in planning indicated prevention is therefore
to acquire accurate knowledge of the various `symptoms foreshadowing mental
disorder'. One example where this model has been applied is the treatment for
individuals with mild depressive symptoms who would be seen as being at risks
for the development of a major depressive episode (18). The same indicated
prevention principle can be applied to the area of psychiatric disorder in
which the prodorme, the period of change from the person's premorbid state
immediately precedes a first psychotic episode.
What are the prodormal features in psychotic disorders which
we should detect in people in order to plan the prevention?. Yung and McGorry
(19) in their literature review found that prodormal psychopathology is extremely
diverse and includes many non-specific symptoms such as depression and anxiety.
The prominence of these non-specific features highlights the fact that the
presence of an apparent prodormal syndrome does not make subsequent development
of disorder inevitable. Prospectively, it is unclear whether or not a person
presenting with a cluster of symptoms characteristic of a psychotic prodrome
will make the transition to psychosis or not.
Uncertainty about whether a particular mental state (the prodrome)
will be followed by diagnosable disorder raises both terminology and practical
issues. The term `prodrome' implies that this syndrome will always be followed
by the disorder. Hence, it can
only be `diagnosed' accurately in
retrospect. Prospectively, a more appropriate term would
be `precursor syndrome (18) or `at risk mental
state' (20), both of which emphasise that the
particular mental state places the individual at risk for
the disorder at that time point but the transition to a
fully developed disorder is not invariable.
Studies of the psychotic prodrome, particularly of the features
which seem to occur just prior to the development of full blown psychosis,
and early symptoms of psychotic disorders have led to suggestion that some
sub-threshold forms of psychotic symptoms and transient isolated psychotic
experiences may precede the development of a psychotic disorder (21). This
has led to another approach to identifying high-risk individuals which involves
defining symptoms which may indicate `psychotic-proneness'. For example `psychotic-like
symptoms' (attenuated form of psychotic symptoms) and isolated psychotic symptoms
(22), or other definitions of prodormal features (23) have all been suggested
as candidate psychopathological indicators of vulnerability to psychosis. Individuals
with these symptoms may or may not have a genetic risk.
The fact that an at-risk mental state may or may not progress
to psychosis (i.e. the problem of false positives) raises several important
logistic and ethical dilemmas in relation to the indicated prevention model.
There are attempts to minimise the `false positive problem' by adding in further
risk factors to enhance prediction and minimise false positives. This involves
combining other risk factors such as trait-risk factors (family history of
schizophrenia and related disorders) and state-risk factors (prodromal symptoms,
attenuated and transient psychotic symptoms). Other studies are investigating
the predictive power of a number of other putative risk factors for schizophrenia
such as attention and other cognitive deficits (24), neuropsychological soft
signs (25) and structural brain abnormalities (26).
High-risk Studies
A few research groups throughout the world set out to combine
multiple strategies for identifying high-risk individuals, including modification
of the above approaches. Their main objective is to identify a group at high
risk of transition to psychosis within a brief follow-up period, that is a
group at risk of impending psychosis. Identification of those at risk of transition
to psychosis in short term would enable
detailed and frequent prospective assessment of
the at-risk individuals and therefore
psychological mapping of the process of becoming psychotic.
This could enable identification of precursor features which
occur just prior to psychosis. The specificity of these features can be examined
and their utility in predicting psychosis studied. Ultimately they could be
used as `warning signs' indicative of impending psychosis. Thus the underlying
objective is to be able to predict with a reasonable degree of specificity
which high-risk individuals, will in the absence of treatment, become psychotic
in the short term.
The Buckinghams Project
The Buckingham study from 1984 to 1988 (23,27) is a pioneer
study in primary prevention. It is claimed to be the first study to organise
a very early detection of psychosis. The study was carried out in the country
of Buckinghamshire, England.
The project teams established a mental health service system
with close connection to the existing primary health services. 16 general practitioners
in the area (population 35,000) were trained in detecting early cases of psychosis
with the use of a checklist for prodormal symptoms similar to the prodormal
symptoms in DSM-III R (28). Patients with possible prodormal symptoms were
referred immediately to specialist mental health team for assessment and treatment.
During this 4-year period, 16 patients with prodormal symptoms
were detected; only one of these definitely had schizophrenia and she was treated
with low-dose neuroleptics. Epidemiological studies carried out 10 years earlier
indicated that an incidence of 2.5 new cases per year. The investigators draw
the conclusions 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.
Despite several methodological shortcomings and ambiguous
evidence that primary prevention can be achieved through identification of
prodormal states, the Buckingham study could be classified as a prospective
clinical trial according to the APA coding system. The most remarkable finding
in this study is that no first-episode cases with long DUP were identified
had been heavily critised Most other studies of first-episode schizophrenia
that about 50% of the patient have been psychotic for quite a long time at
the time of inclusion.
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. The
focus of PACE is to look for predisposing 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 (29). Three types of
prodormal states are defined : attenuated and transient psychotic symptoms;
and trait plus state risk factors for psychosis (genetic risk).
The PACE service is located at a generalist out-patient services
and health promotion centre for adolescent. 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 prodormal states are followed-up with
monthly ratings of psychopathology in order to detect the transition to psychosis.
During the first 16-month period, 119 referrals were assessed
and 49 patients met the criteria for prodormal syndromes. 20 patients had been
follow-up for at least 6 months, 40% of those developed psychosis; 5% within
the first month of follow-up (30). A comparison between those who develop psychosis
(n=8) and those who did not (n=12) showed that the psychotic group initially
had significantly higher BPRS total scores, more negative symptoms and signs
of depression and poorer quality of life and lower GAF scores. This study also
has several methodological weaknesses. The statement that 40% of the patients
identified in a possible prodormal stage of psychosis developed psychosis within
the first year of follow-up had been heavily critised.
Other Project on Primary Prevention
The `Born Early Recognition' study which was conducted in
Germany found that 81% of 96 patients included in the study had at least one
early or basic symptom (BS) of schizophrenia at baseline (31). At 8-year follow
up, 58% had developed schizophrenia. One-quarter of the patients with early
symptoms of schizophrenia 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.
There are a number of ongoing projects on the primary prevention
of psychosis (32) such as a) The PRIME (Prevention through Risk Identification,
Management and Education) Clinic, located at the Yale Medical School in New
Haven, Connecticut, United States; b) The TOPP (early Treatment Of Prepsychosis
Project) which is being carried out at Rogaland Psychiatric Hospital, Stavanger,
Norway as part of an ongoing international multi-site study testing the efficacy
of Early Treatment and Intervention in Psychosis (TIPS) and c) The DEEP (Detection
of Early Psychosis) project is
being carried out in Turku, Finland.
Ethical Issues
Several ethical issues arise when attempting to intervene
in a group who, although defined as high risk, are not psychotic and in whom
transition to psychosis is not inevitable.
Stigma
The use of psychiatric services and labelling a person as
a psychiatric case is stigmatising (33). In addition, the definition of a person
as being `high risk' can result in a change in the way he or she is perceived
by others. Despite rigorous public psychology education campaigns, there is
still a prevailing view that psychotic disorder have poor prognoses with inevitably
deteriorating courses such as gloomy out-looks could result in demoralisation
and even depression in individuals labelled as `high risk'. The situation would
be compounded if such a nihilistic view were reinforced by family members,
general practitioners and others significant persons.
Given all of these ethical pitfalls, should we promote psychiatric
treatment for putatively high risk people?. Experience with PACE patients (29)
have shown that many are aware of their increased risk and often wish to discuss
this with a clinician. Young people presenting with transient psychotic experiences
often want to know if these will occur again and whether they may progress
to something more serious. The discussion must be carried out in a sensitive
manner. It is also important not only to communicate the idea of risk, but
also offer a possible solution. At the end patients and their families will
decide whether to receive treatment or not. We should respect their decisions.
Treatment of High Risk Cases
A further issue of concern is what treatment to provide for
those putatively high risk people. Is use of neuroleptics justified to prevent
later development?. Of course the false positive issue is relevant again as
some cases would then be in danger of receiving the medication unnecessarily,
with all the implications of short and long term side-effects and stigma. The
opposing view point has also been expressed, with suggestions that neuroleptic
treatment should not be withheld from those obviously at the point of imminent
onset of psychosis. However even if such a particular point could be defined,
such as level of symptoms, type of symptoms, number of risk factors, the question
arises of which antipsychotic treatment should begin and how long should medication
continue?
Few would argue with providing treatment for those presenting
with particular symptoms or problem, particularly when symptoms have been long
lasting and unlikely to resolve spontaneously. The problem arises in deciding
whether to start antipsychotics or not for those with prodormal symptoms. Falloon
(23) commented that both psychosocial treatment and low dose of neuroleptics
seemed to be of benefit for people experiencing the possible prodormal symptoms
of schizophrenia. In order to avoid treating a false positive, some center
(29) withhold antipsychotic medication for prodormal symptoms; they just treated
them symptomatically targeting at the specific symptoms. Finally, the cost
/benefit ratio of the treatment needs to considered such as side-effects of
atypical antipsychotics, decreased cost of treatment and increased benefit
of neuroleptics if the cases progress to psychosis.
CONCLUSIONS
Early intervention programmes for schizophrenia are difficult
to organise and expensive to carry out. For the time being, no research projects
have shown beyond reasonable doubt that primary prevention in psychosis in
possible. Several ongoing studies describe characteristic of prodormal states
which indicate increased risk of transition to psychosis. However the issue
of false positive remained unresolved because the conversion rate reported
from the early phases of these studies lie between 33 and 58% (32). Even though
these findings are encouraging, the specificity of prodormal states is still
ambiguous and caution must
be taken to avoid unnecessary
stigmatisation. Despite carrying the risks of somatic
or psychological side-effects due to the use of antipsychotic medications or
labelling such as `early schizophrenia' or `prepsychosis' we believe
that patients who worry over their symptoms and
wish to receive treatment should be treated without
further delay.
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