Department of Psychiatry, University of Melbourne and ORYGEN Research Centre, Australia
Yale Psychiatric Unit, Yale University, New Haven, CT, USA
New York High Risk Project to the Hillside Recognition and Prevention (H-RAP) Program
Departments of Psychiatry and Psychotherapy, University of Cologne, Germany
Correspondence: Lisa Phillips, PACE Clinic, Orygen Research Centre, Locked Bag 10, Parkville 8052, Victoria, Australia. E-mail: lisa.phillips{at}mh.org.au
Declaration of interest None. Funding detailed in Acknowledgements.
* Paper presented at the Third International Early Psychosis Conference,
Copenhagen, Denmark, September 2002.
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ABSTRACT |
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Aims To describe the principles, progress and dilemmas associated with the prospective detection, engagement and treatment of young people at risk of developing a psychotic disorder.
Method Strategies to identify young people at heightened risk of a psychotic disorder are described. Preventive interventions and results of their evaluation are provided.
Results Well-validated criteria for identifying young people at heightened risk of psychosis have been developed, evidence of the efficacy of various psychological and pharmacological interventions in preventing progression has accumulated and progress towards the identification of clinical and neurobiological predictors of transition to acute psychosis has been made.
Conclusions The detection, monitoring and treatment of young people in the prepsychotic phase is a growth area in psychiatry. The ethical considerations about treatment options, treatment of minors and provision of information about risk status must be treated with sensitivity if the potential benefit to many young people and their families is to be realised.
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INTRODUCTION |
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This paper describes principles, progress and dilemmas in the prospective detection, engagement and treatment of young people with incipient psychosis. The research programmes conducting this research are also described.
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METHOD |
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The period prior to clear-cut diagnosis of psychosis has traditionally been referred to as the premorbid phase. However, this term is confusing because it suggests that changes in mental state and functioning only occur with the onset of acute illness. Studies of childhood antecedents of schizophrenia, although demonstrating significant but minor differences between controls and those who later developed schizophrenia, highlighted the quiescence of the illness during the early phase of life (Jones et al, 1994). Research by Häfner and colleagues, however, revealed that psychotic illnesses really begin to have clinical and social consequences after puberty, typically during adolescence and early adult life (Häfner et al, 1995). A period of non-specific symptoms and growing functional impairment often occurs prior to the full emergence of the more diagnostically specific positive psychotic symptoms. This phase is referred to as the prodrome.
Prodrome derives from a Greek word meaning the forerunner of an event (Fava et al, 1990). This concept is commonly used in clinical medicine to refer to symptoms and signs of an illness experienced before the full-blown syndrome becomes evident. This implies that symptoms are experienced during the prodrome and that the development of full-blown illness is inevitable.
Within the mental health field, indicated prevention is, according to Mrazek & Haggarty, ... targeted to high-risk individuals who are identified as having minimal but detectable signs or symptoms foreshadowing mental disorder, or biological markers indicating predisposition for mental disorder, but who do not meet... diagnostic levels at the current time (1994, p. 154). Intervention during the prodromal phase of a first psychotic episode with the intention of stopping the onset of the full-blown illness is an example of indicated prevention.
Benefits and obstacles of prepsychotic intervention
The fact that a very substantial amount of the disability that develops in
schizophrenia accumulates prior to the appearance of the full positive
psychotic syndrome and may create a ceiling for eventual recovery in young
people is a key reason for attempting some form of prepsychotic intervention.
Other potential benefits are outlined in Appendix 1. A number of obstacles to
intervention during this phase should also be noted (Appendix 2).
Challenges in identifying the prepsychotic phase
Indicated prevention in the prepsychotic phase relies on the accurate
identification of individuals who are truly experiencing this phase of
illness. This requires the ability to distinguish between the prodrome and the
premorbid phase as well as between the prodrome and frank psychosis.
Defining the beginning of the onset of a potential psychotic disorder is difficult because a specific group of symptoms occurring during this time has not been identified. In fact, retrospective descriptions of the prodromal phase have indicated that the earliest symptoms experienced by an individual who later developed an acute episode are non-specific, such as sleep disturbance, depressed mood, anxiety and irritability (Yung & McGorry, 1996; Møller & Husby, 2000).
Subtle attenuated forms of psychotic symptoms have also been reported during this early stage. Sub-threshold psychotic symptoms deviate from normal phenomena but are not frankly psychotic. They differ from frank psychotic symptoms in either their degree of intensity or frequency. For example, individuals may be concerned that others are laughing at or are hostile towards them, but realise that this is not really true and that he or she is just being a bit paranoid. Perceptual disturbances can also occur below psychotic intensity.
Identifying the onset of the prepsychotic phase requires differentiation of normal experiences from abnormal. This is made more difficult by evidence that attenuated psychotic symptoms and psychotic-like experiences are experienced by the general population, at far higher rates than psychotic disorders (Peters et al, 1999; Peters, 2001; van Os et al, 2000, 2001). This indicates that at least some attenuated psychotic symptoms must either resolve without developing into full-blown psychosis or they can persist without developing into a full-blown psychotic disorder.
Difficulties also exist in identifying the transition point between prepsychotic and acute phases of illness. There is some uncertainty about which types of symptoms should be used to define psychosis and when a symptom has become sufficiently deviant to be labelled psychotic. The subjective nature of psychotic symptoms also needs to be considered as observers often date onset of psychotic symptoms well after the individual recalls them as having begun (Häfner et al, 1993; Yung & McGorry, 1996; Norman & Malla, 2001). Psychotic symptoms rarely arise suddenly, but are more likely to gradually evolve and worsen, from an attenuated state to a full-threshold state. Most clinicians have no difficulty in diagnosing a full-blown psychotic syndrome in a patient, but more subtle early psychotic features are more difficult to recognise. Appendix 3 summarises other reasons why recognising the onset of psychosis is frequently challenging.
These issues are yet to be resolved. Indeed, discussions about the definition of psychotic disorder tend to become embroiled in debate about the definition of health, disease and illness in general, a subject which is beyond the scope of this article.
Strategies for identifying the prepsychotic phase
A number of strategies have been developed to identify individuals who are
thought to be experiencing a prepsychotic phase of illness and are at
heightened risk of developing a psychotic disorder. Although differences exist
between the strategies they all aim to minimise the identification of
false-positives and to maximise true-positives
(Yung & McGorry, 1996).
Brief descriptions of these approaches follow.
Close-in strategy and the at-risk mental state
Bell (1982) suggested that a close-in or multiple gate
screening approach should be used to identify a high-risk cohort
(Bell, 1992). Using this
strategy, an individual must meet a number of conditions to be included in the
high-risk group. Bell also recommended using behavioural difficulties in
adolescence as selection criteria to improve the accuracy of identifying the
high-risk group further. Thus, unlike traditional screening paradigms, this
approach is more clinically oriented, focusing on troubled young people, who
are experiencing precursor signs and symptoms
(Eaton, 1995). In line with
this, these state-based criteria are thought to identify an at-risk mental
state.
Studies using this approach have been referred to as ultra-high-risk or clinical high-risk studies to differentiate them from traditional high-risk studies, such as the New York high-risk programme (Erlenmeyer-Kimling et al, 1995) or the Copenhagen high-risk project (Cannon & Mednick, 1993), that rely on family history as the primary inclusion criteria. At-risk mental state/ultra-high risk does not imply that a full-threshold psychotic illness, such as schizophrenia, is inevitable, but suggests that an individual is at risk of developing a psychotic disorder by virtue of their mental state. This terminology is more conservative than the use of the term prodrome, which can only be accurately applied in retrospect if and when the disorder in question fully emerges.
The recommendations made by Bell (1992) were first put into practice at the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne, Australia. The first risk factor used to identify the ultra-high-risk group is age: the strategy focuses on individuals in the peak age range of risk of onset of psychotic disorderadolescents and young adults (Häfner et al, 1994). According to the criteria developed by the PACE Clinic, other potential risk factors must also be met, such as attenuated psychotic symptoms, self-resolving psychotic symptoms, a trait risk factor (a schizotypal personality disorder in the young person or a family history of a psychotic disorder in a first-degree relative) and functional decline (Appendix 4). Criteria for identifying the ultra-high-risk group have been operationalised according to the Comprehensive Assessment of At Risk Mental States (CAARMS) (Appendix 5) and subsequently using the Structured Interview for Prodromal States (SIPS) and related instruments (Miller et al, 1999, 2002) and have been validated. The CAARMS and SIPS are semi-structured interviews that were designed to prospectively assess symptoms and signs suggestive of a psychotic prodrome. It should be noted that all young people meeting these criteria are also seeking support and help and are distressed by their symptoms to some degree.
The validity of the ultra-high-risk criteria has now been well supported in longitudinal studies. Out of 49 young people, 20 (41%) who met ultra-high-risk criteria developed an acute psychotic episode within 12 months of recruitment and were started on appropriate neuroleptic treatment (Yung et al, 1998, 2003). This occurred despite the provision of supportive counselling, case management and antidepressant medication if required. The majority of those who developed a psychotic disorder had a DSMIV diagnosis of schizophrenia (13 out of 20 in the psychosis group, 65%) (Yung et al, 2003). The sensitivity and specificity of the criteria could not been determined as individuals who did not meet intake criteria were not followed-up to determine whether they too developed psychosis.
The criteria have been adopted with minor modifications in other centres in different parts of the world. Comparable rates of transition to acute psychosis have been described at these other centres (Table 1). It should be remembered that the population from which subjects are drawn affects the predictive validity of the intake (ultra-high-risk) criteria. As the prevalence of a disorder decreases, the positive predictive value decreases also (Mojabai et al, 2003). If the ultra-high-risk criteria were applied to a general population or school setting, the transition rate to full-blown psychosis would be much less than 41%, because the prevalence of truly prodromal individuals in that setting is lower than in the population of help-seeking young people who meet these criteria. There might also be variation in the underlying proportions of true- and false-positives who are referred for assistance. This is dependent on the base rate of psychosis in the different referral source samples, which may change over time within one centre and certainly across centres. For example, the rate of ultra-high-risk positive cases in a general psychiatric out-patient group is 15% (Salokangas et al, 2004).
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Basic symptoms
The German approach to early detection and intervention in schizophrenia
follows the long-standing observation that cognitive, affective and social
disturbances often occur years before the first psychotic episode and are
often recognised by the person affected at this early stage. In the 1960s,
these self-experienced deficits were described as basic symptoms
in great detail by Gerd Huber and colleagues and, based on long-term follow-up
studies, have significantly influenced concepts of schizophrenia in
German-speaking countries. The Bonn Scale for the Assessment of Basic symptoms
(BSABS) was developed to assess the occurrence of these experiences.
In the Bonn long-term study (Huber
et al, 1979), basic symptoms were found prepsychotically
in 37% of patients who later developed schizophrenia. These findings were
confirmed by the retrospective Age-Beginning-Course (ABC) study
(afner
et al, 2002), which revealed even higher rates of
patients with long-lasting prepsychotic deficits. Of this group, 73% reported
the onset of negative and non-specific symptoms, including basic symptoms, an
average of 5 years before the first positive symptom of schizophrenia.
Furthermore, social deficits appeared as early as 24 years before the
first hospital admission and, thus, in the prodromal phase about a year before
the onset of the first psychotic symptom
(Häfner et al,
1999).
In the prospective Cologne Early Recognition study (CER; Klosterkötter et al, 2001), 160 individuals who were suspected of being in the onset phase of schizophrenia were assessed with the BSABS (Gross et al, 1987): 79 patients developed schizophrenia over the follow-up period, which averaged 9.6 years, on average, 1.9 (s.d.=2.5) years after the first examination, and 77 of these 79 participants and 33 who did not develop schizophrenia had reported at least one basic symptom at first examination, indicating reasonably good prognostic accuracy of symptoms (Table 2).
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Although the German basic symptom approach is more theoretically guided than the ultra-high-risk approach, the transition rate to schizophrenia among the 110 individuals included in the CER study who reported at least one basic symptom at baseline interview was 70%. This is obviously higher than any transition rates to psychosis reported from studies utilising the ultra-high-risk approach (Table 1). It should be noted that the mean follow-up period of the CER study of 9.6 years was much longer than the 12 months reported for the ultra-high-risk samples hitherto. A new instrument to assess basic symptoms was recently developedthe Schizophrenia Prediction Instrument, Adult version (SPIA). Preliminary results have indicated that 25 of 147 individuals (17%) who have reported experiencing at least one basic symptom have developed schizophrenia within an average of 12 months of assessment (s.d.=7.6; range 233). Although preliminary, this result reveals that the basic symptom approach to early detection is not inevitably associated with the strategic and practical disadvantage of necessarily long follow-up periods.
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There is a growing consensus in the field that the ultra-high-risk and the basic symptom approach are complementary, providing criteria to detect different prodromal stages, a concept already realised in the German Research Network on Schizophrenia (GRNS) (Fig. 1).
Clinical high risk
The Hillside Recognition and Prevention (H-RAP) Program in New York further
elaborated the Melbourne ultra-high-risk criteria for identifying young people
thought to be at high risk of psychosis. The H-RAP researchers refer to their
criteria as identifying a clinical high-risk group to distinguish it from the
genetic high-risk studies. Adolescents are recruited to this programme if they
experience attenuated positive psychotic symptoms (referred to as the clinical
high riskpositive group) or if they display specific combinations of
cognitive, academic and social impairments and disorganisation/odd behaviour
(referred to as CASID features). This second cohort is referred to as the
clinical high risknegative group and the programme specifically focuses
on cognitive impairments which may precede the onset of acute psychosis
(Cornblatt, 2002).
Operationalised criteria for identifying the clinical high risknegative
group are not yet available. The researchers in this group hypothesise that
the developmental course of schizophrenia follows a progression from clinical
high risknegative to positive to schizophrenia-like
psychosis (essentially schizophreniform/brief psychotic disorder) to
schizophrenia. The transition rate from clinical high riskpositive
status to psychotic disorder, using both the PACE and Prevention through Risk
Identification, Management and Education (PRIME) clinics definitions of
psychosis, was 26.5% (9 of 34 patients) within 6 months
(Lencz et al, 2003),
a rate similar to the 6-month transition rate in the PACE Clinic
(Yung et al, 2003)
(Table 1). The transition rate
to schizophrenia in the schizophrenia-like psychosis group was 33%
(Cornblatt et al,
2002). The key difference between the clinical high-risk and the
ultra-high-risk approach is that first-episode schizophrenia rather than
first-episode psychosis is the indicated prevention target here, hence the
extra category of schizophrenia-like psychosis. This is a key distinction that
allows the investigators to regard frankly psychotic patients as
sub-threshold for schizophrenia and hence contributes to
different terminology, strategies and interpretations of results.
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RESULTS |
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Brief descriptions of these programmes are described below.
The PACE Clinic
This clinic was established in Melbourne, Australia in 1994. It is one arm
of a comprehensive early psychosis research programme affiliated with the
Early Psychosis Prevention and Intervention Centre
(McGorry, 1993;
McGorry et al, 1996).
PACE began on a small scale with only a part-time consultant psychiatrist and
one research psychologist and a necessarily limited research agenda of mapping
the onset of psychosis and establishing valid criteria for identifying the
ultra-high-risk cohort. There is now a team of 12 clinicians and research
staff at PACE and a more sophisticated clinical research structure. This
growth has also mirrored an increased focus on youth mental health in
Melbourne over the past few years and the establishment of a youth mental
health service (ORYGEN), which contrasts with the usual child and adolescent
v. adult mental health divide, reflects the epidemiology of onset of
disorders and recognises the special needs of the youth population.
The development and growth of the PACE Clinic has been previously documented (Yung et al, 1995, 1996, 1999, 2004; Phillips et al, 1999, 2002b; McGorry et al, 2001a). Many of the strategies adopted in the establishment of PACE, such as distinguishing the ultra-high-risk service from mainstream mental health services, have ensured that community education is a key feature of the work of the clinic and the provision of clinical assistance to young people referred to the serviceindependently of their involvement in research projectshas been adopted by other centres.
Prevention through Risk Identification, Management and Education Clinic
The ultra-high-risk concept and close-in strategy have been adopted at the
Prevention through Risk Identification, Management and Education (PRIME)
Clinic at Yale University, headed by Professor Thomas McGlashan. Young people
aged between 12 and 45 years who are thought to be experiencing the onset
phase of a first psychotic episode are recruited to the clinic. The PRIME
group has coined the term Criteria of Prodromal Syndromes, or COPS, to
describe their intake criteria, which are very similar to the ultra-high-risk
criteria developed earlier at PACE. The PRIME group have also developed a
semi-structured interview originally influenced by the CAARMS and the Positive
and Negative Symptom Scale (PANSS; Kay
et al, 1987) called the Structured Interview for
Prodromal syndromes (SIPS). The SIPS is utilised to rate presenting
symptomatology and to determine if COPS criteria are met
(Miller et al, 2002).
Ratings are made on the Scale of Prodromal Symptoms (SOPS), also developed by
the PRIME group. Although the PRIME investigators based their definition of
the psychosis threshold on that developed at PACE, they did make some changes.
For example, PRIME patients are considered to meet the criteria for psychosis
if they have attenuated psychotic symptoms and are markedly suicidal or
dangerous. The transition rate to acute psychosis in a cohort of young people
attending PRIME was 54% (Miller et
al, 2002). The PRIME clinic has expanded to involve other
North American centres (Toronto, Calgary and North Carolina) as part of a
multicentre clinical trial network.
H-RAP Program
As indicated earlier the H-RAP Program is based in New York. This programme
drew from experience with the New York High Risk Projectone of the
longest running traditional high-risk projects
(Erlenmeyer-Kimling et al,
1997). Although the RAP programme has not yet conducted a
randomised clinical trial with the clinical high-risk population, a
naturalistic study of the range of clinical treatment provided
to this group of young people has been conducted.
Psychological Assistance Service
In 1997 the Psychological Assistance Service (PAS) opened in Newcastle,
Australia as a clinical service for the assessment and treatment of young
people at high risk of psychosis and those experiencing a first psychotic
episode. The high-risk criteria are based on those of PACE but also allow
inclusion if a young person has a second-degree relative with a history of
psychotic disorder in conjunction with a significant decline in functioning
(Carr et al, 2000).
The transition rate to psychosis within a 12-month period was 50%
(Mason et al,
2004).
TOPP Clinic
The TOPP Clinic in Norway is an off-shoot of the TIPS programmea
comprehensive community development programme addressing first-episode
psychosis (Johannessen et al,
2001). Larsen
(2002) has used the
questionnaire and criteria developed by the PRIME group to identify and
follow-up an ultra-high-risk cohort and 84 patients have been assessed with 14
recruited to the study over a 2-year period. Within 12 months of recruitment,
6 out of the 14 (43%) had developed acute psychosis
(Larsen, 2002).
Early Identification and Intervention Evaluation trial
The Early Identification and Intervention Evaluation (EDIE) trial, based in
Manchester, UK, reported a 22% transition rate to acute psychosis in 23 young
people recruited based on the PACE Clinic criteria who have been followed-up
for 612 months (Morrison et
al, 2002). This service is slightly different from the others
described in that it is largely a mobile service that utilises other
facilities to see patients, such as general practitioner surgeries, schools
and so forth and promotes psychological treatment (cognitivebehavioural
therapy, CBT) for young people over and above medical approaches
(French & Morrison, 2004). Results indicate that cognitively oriented psychological treatment is more
effective than monitoring alone in reducing transition rates to acute
psychosis in patients at ultra-high risk
(Morrison et al,
2004).
Early Recognition and Intervention Centre
This centre was established in 2000. As described earlier, criteria have
been developed to identify individuals with prepsychosis based on the
experience of basic symptoms. Young people are referred to the Early
Recognition and Intervention Centre (FETZ) from a broad network of more than
500 primary and mental healthcare professionals, psychiatric hospitals,
counselling services, carer associations, schools and health insurance
companies. In addition to intensive and continuous public education and
awareness campaigns about schizophrenia and psychosis, FETZ provides a
thorough psychopathological and neurobiological diagnostic and a wide
psychological and biological range of interventions that can be tailored to
individual needs. Research conducted by the centre continues the German
tradition of early detection, early intervention and investigation of the
biological, genetic and neuropsychological basis of schizophrenia. A trial of
psychological treatment is currently underway for the early prodromal phase at
FETZ, and the late prodromal phase is the focus of a psychopharmacological
study utilising amisulpride (Bechdolf
et al, 2002).
OASIS
The OASIS service has recently commenced in south London, UK to detect,
assess and intervene in young people at ultra-high risk of psychosis. The PACE
Clinic criteria are used and links with the established early psychosis unit
(Lambeth Early Onset; LEO) are utilised to identify those individuals who do
not meet full criteria for a psychotic disorder but who do meet
ultra-high-risk criteria. OASIS is soon to begin a randomised controlled trial
using quetiapine and CBT (Johns et
al, 2002).
Portland Identification and Early Referral service
The Portland Identification and Early Referral (PIER) service is a
population-wide system of early detection that utilises a broad-ranging
community education and development programme to identify individuals with the
early stages of a psychotic disorder based on the COPS/ultra-high-risk
criteria (McFarlane et al,
2002). Detection and engagement rates from this important study
are very encouraging. Clinical intervention is multimodal and includes the use
of antipsychotic medication where indicated. The design of this
study is in fact similar to the original Buckingham, UK study of Falloon
et al (1990), the
findings of which were heuristically very useful, although inconclusive.
Cognitive Assessment and Risk Evaluation programme
The Cognitive Assessment and Risk Evaluation (CARE) programme at the
University of California, San Diego is conducting a longitudinal research
project to identify psychophysiological, neurocognitive and
information-processing measures that are vulnerability markers for
schizophrenia-spectrum disorders. Participants in this programme are
experiencing low-grade psychotic features, have a schizotypal personality
disorder or have a family history of schizophrenia in conjunction with a
recent deterioration in functioning. The participants are assessed monthly for
a period of 25 years (Cadenhead,
2002).
Center for the Assessment and Prevention of Prodromal States
This centre was established at the University of California, Los Angeles in
2000. This programme aims to investigate the predictive validity for
schizophrenia and other psychotic disorders of a range of behavioural,
diagnostic, neurocognitive, psychophysiological and neuroimaging measures.
Interventions aimed at preventing the onset of psychosis in individuals at
high risk are also developed and evaluated.
Commonalities among centres
The International Prodromal Research Network (IPRN), which includes many clinicians and researchers working within the services described above, has been created. Meetings are held on a regular basis to discuss progress, implications of research findings and future directions. It is hoped that the creation of such a network will lead to a collaborative research approach.
Prediction of transition to acute psychosis
Clinical predictors
The development and validation of criteria that identify young people at
very high risk of developing a psychotic disorder within a short follow-up
period has opened the way for further research evaluating putative risk
factors for psychosis. Research is currently underway at various centres
investigating the role of mood and anxiety, drug and alcohol usage, obstetric
complications, delayed childhood milestone achievement, neurological
abnormalities, poor premorbid adjustment and other factors in the prediction
of psychosis.
Clinical variables including long duration of non-specific symptoms, poor psychosocial functioning, comorbid depression and disorganisation have been associated with increased risk of transition to psychosis within the ultra-high-risk group (Yung et al, 2003). Obstetric complications have not been associated with a higher risk of transition to psychosis in the ultra-high-risk cohort. Results of other investigations are anticipated.
Neurobiological predictors
Many studies have suggested that the hippocampal volumes of individuals
with established schizophrenia or first-episode psychosis are smaller than
controls (Velakoulis et al,
2000). Magnetic resonance imaging (MRI) scans of the brains of
patients at ultra-high risk are obtained to determine if volume changes in the
hippocampal region precede the development of acute psychosis or emerge as
mental state deteriorates. Consistent with the neurodevelopmental hypothesis,
hippocampal volumes of PACE patients at ultra-high risk at intake lie midway
between those of normal controls and patients with chronic schizophrenia or
first-episode psychosis (Phillips et
al, 2002a). More puzzling are the results of a
survival analysis, which revealed that those patients at ultra-high risk with
larger (although in the normal range) left hippocampal volumes at intake were
more likely to develop a psychotic episode in the subsequent 12-month period
(Phillips et al,
2002a). A comparison of MRI scans of PACE patients at
ultra-high risk taken prior to the onset of psychosis, and again once frank
psychotic disorder had developed, revealed reduction of grey matter volumes in
the left insula cortex and the left posterior medial temporal structures,
including the hippocampus and posterior hippocampal gyrus, during the
transition to psychosis (Pantelis et
al, 2003). This suggests that brain changes occur during the
process of transition to psychosis, and although the basis of this remains
uncertain it opens up the exciting possibility that with sufficiently early
and effective treatment such changes, and their consequences, could be
minimised or aborted. Other imaging techniques, such as magnetic resonance
spectroscopy (MRS) and functional MRI are currently being investigated.
Assessment of olfactory (smell) identification provides an indication of circuitry involving the orbitofrontal cortex. Deficits in olfactory identification are consistently found in patients with chronic schizophrenia (Brewer et al, 1996) and first-episode psychosis (Moberg et al, 1997; Seidman et al, 1997; Brewer et al, 2001). The olfactory identification ability of 81 PACE individuals at ultra-high risk was compared with 31 healthy controls. Those individuals at ultra-high risk who later developed a schizophrenia-spectrum disorder (12 members of the cohort) displayed a significant impairment in olfactory identification ability compared with the individuals at ultra-high risk who did not develop psychosis, the individuals at ultra-high risk who developed a non-schizophrenia-spectrum disorder and the healthy comparison group (Brewer et al, 2003).
Neuropsychological impairment has been consistently associated with psychotic disorders. It is reasonable to speculate that cognitive functioning might be impaired in individuals who are in the early phases of developing a psychosis and that these changes might also be predictive of future psychosis or whether they come on-line once acute psychosis has developed (Cadenhead, 2002). With this in mind, neuropsychological assessment of individuals at high risk is undertaken as a focus of research at some of the centres described earlier.
Individuals with schizophrenia often display impairments in attention (Heinrichs & Zakzanis, 1998). Particular interest has been paid to performance of individuals with prepsychosis on the Continuous Performance Task (CPT; Cornblatt et al, 1988), which assesses attention. The performance of PACE individuals at ultra-high risk on the CPT lies between healthy controls and patients with first-episode psychosis but was closer to the performance of the first-episode group. However, no differences have been found between individuals at ultra-high risk who later developed acute psychosis and those who did not on CPT performance (Francey, 2002).
The performance of individuals at ultra-high risk on a range of other neurocognitive tests has been compared with individuals with established or first-episode psychosis as well as healthy age-matched controls at the PACE Clinic. Individuals at ultra-high risk have shown marked impairments in performance on tests of spatial working memory and delayed matching to sample compared with a healthy comparison group (Wood et al, 2003a). Further investigation is required to assess the validity of working memory as a predictive tool for psychosis (Wood et al, 2003b).
PACE patients at ultra-high risk have also been found to show significantly worse performance on the Performance and Full (short-form) IQ scales of the WAISR (Ward, 1990) compared with controls. Specifically, individuals at ultra-high risk who developed psychosis performed significantly more poorly than those who did not on tests of logical memory and the Visual Reproduction test (Brewer et al, 2005). This finding is suggestive of prefrontal impairments and is in line with findings of impaired spatial working memory (Wood et al, 2003b), poorer olfactory identification (Brewer et al, 2003) and lower frontal grey matter volumes (Pantelis et al, 2003).
The performance of young people attending the PRIME Clinic on a range of neurocognitive tests assessing intellectual functioning, memory, executive functioning and attention was also intermediate to normal controls and those with schizophrenia (Hawkins et al, 2004). Those participants who developed psychosis tended to perform worse on tasks assessing control and tasks of visual memory (Hawkins et al, 2004). Those who developed psychosis early (within 28 days of assessment) performed worse at entry on tasks of working memory and visual memory than those who became psychotic later (Hawkins et al, 2004).
The group at ultra-high risk with basic symptoms seen at FETZ performed worse than healthy controls on tests of verbal fluency, attention and memory function (Hambrecht et al, 2002). The relationship between neurocognitive performance and transition to acute psychosis in the FETZ group has not yet been reported.
Intervening in the prepsychotic phase
The aim of treatment provided during the prepsychotic phase is to reduce
distressing symptoms experienced by young people who meet high-risk criteria,
and, if possible, to prevent these symptoms from worsening and developing into
acute psychosis. A stressvulnerability model of the development of
psychosis underpins the treatment approach, incorporating medical and
psychological strategies.
Psychological treatment
The psychological treatment provided at the PACE Clinic is primarily based
on CBT principles and draws not only on mainstream CBT techniques, but also on
the treatment approaches that have been developed and evaluated for use in
established psychotic disorders. The therapist and client work together to
develop a personal formulation or model for understanding the symptoms the
young person is experiencing and strategies for coping with, and reducing
these symptoms. Assistance is often provided in liaising with housing,
education, employment or other services as difficulties in these areas may
contribute to the young persons increased risk status through
increasing stress levels.
Clinicians at EDIE in Manchester, UK have described cognitive therapy aimed at assisting young people meeting ultra-high-risk criteria to cope with their symptoms and possibly to prevent the onset of acute psychosis (French & Morrison, 2004). This psychological therapy is targeted towards symptoms that are causing distress and disability with little or no side-effects and is based around a formulation of the affected individuals life experiences, environment, self and social knowledge, intrusions and their interpretations of intrusions, and their emotional, behavioural, cognitive and physiological responses. Change strategies, such as normalisation, and generating and evaluation of alternative explanations are then employed to assist the individual to deal with the symptoms and to alter their interpretation of events.
Biological treatment
More controversy surrounds the proposal of providing pharmacological
treatment for individuals in the prepsychotic phase of illness. The optimal
approach remains to be clarified by research. The risk/benefit ratio of
offering pharmacological therapy prior to psychosis onset is a big
consideration.
One treatment that has been proposed is antipsychotic medication. The rationale behind this proposal is straightforward: antipsychotic medication has demonstrated efficacy with individuals with established psychotic illnesses and this efficacy might translate to the prepsychotic phase. It has been argued that transition rates to psychosis in the ultra-high-risk and basic symptoms groups are not sufficiently high to warrant provision of neuroleptic treatment with known side-effects, as the false-positive rate is too great (Bentall & Morrison, 2002). However, the number-needed-to-treat for early clinical trials is not supportive of this argument (Yung & McGorry, 2003). One strategy for reconciling this impasse is to provide antipsychotic medication within a well-monitored clinical trial environment. Results of two such trials have been released (see below).
Neuroprotective agents might also benefit young people in the prepsychotic phase. The rationale behind such an approach is that dysregulation of neuronal cell production and degeneration in some brain areas might explain neurodevelopmental abnormalities seen in early psychosis (Berger et al, 2003). Neuroprotective substances promoting the regulation of these processes, such as lithium (Manji et al, 1999), eicosapentanoic acid (EPA; Fenton et al, 2000) and glycine (Javitt et al, 2001), might be potent therapeutic avenues to explore. Open-labelled studies using lithium, glycine and EPA are now underway in Melbourne and Yale (Woods, personal communication, Colorado Springs, 2003).
Other treatment options have yet to be tested in the population at ultra-high risk. One candidate treatment is corticotrophin-releasing hormone receptor agonists (Corcoran et al, 2003). Furthermore, a recent study has suggested that oestrogen may be effective as an adjunct to atypical antipsychotic medications in reducing the psychotic symptoms experienced by women with established psychosis (Kulkarni et al, 2001, 2002). Oestrogen might therefore have a neuroprotective role in the treatment of women at ultra-high risk.
Investigators at the H-RAP Clinic in New York believe that the development of specific preventive interventions is premature at present. Instead, they have chosen a naturalistic approach to study the appropriateness and efficacy of various potential treatments for young people at ultra-high risk. Thus, the treatment provided by psychiatrists to young people meeting RAP criteria is surveyed but RAP do not seek to direct the type of treatment provided. The mental state of over 80% of the patients recruited to RAP has either improved or stabilised over time (Cornblatt, 2002). Over 80% of patients received a pharmacological treatment, either antipsychotic medication or an anti-depressant, with both demonstrating clinical improvements (Cornblatt, 2002). The authors of this study suggest that this indicates that antidepressants may be effective in treating the underlying vulnerability to schizophrenia and should be considered when developing preventive interventions. It should be noted that many of these young peopleparticularly the group labelled as schizophrenia-like psychosis or SLPwould be seen as already psychotic within the PACE framework and clearly requiring antipsychotic medication in other clinical settings.
Intervention trials
The first randomised controlled trial with a high-risk cohort was conducted
at the PACE Clinic between 1996 and 1999. In this trial a combined intensive
psychological (cognitive) treatment plus very low-dose atypical antipsychotic
(risperidone) medication (specific preventive intervention or SPI:
n=31) was compared with the effect of supportive therapy (needs-based
intervention or NBI: n=28) on the development of acute illness in the
high-risk group. At the end of the 6-month treatment phase, significantly more
subjects in the NBI group had developed an acute psychosis than in the SPI
group (P=0.026). This difference was no longer significant at the end
of a post-treatment 6-month follow-up period (P=0.16), although it
did remain significant for the risperidone-adherent subgroup of cases. This
result suggests that it is possible to delay the onset of acute psychosis in
the SPI group compared with the NBI group. Both groups experienced a reduction
in global psychopathology and improved functioning over the treatment and
follow-up phases compared with entry levels
(McGorry et al,
2002). Longer-term follow-up of the participants in this study is
now taking place. A second randomised trial commenced in 2000. This is a more
sophisticated study with three treatment groups and blind randomisation to
these groups. The three groups are: (a) risperidone (antipsychotic medication
up to 2 mg daily) and CBT; (b) placebo and CBT; and (c) placebo and
befriending. All treatments are offered for 12 months and participants are
then monitored for a further 12 months to determine the long-term impact of
the treatment.
The first double-blind, placebo-controlled clinical trial using antipsychotic medication has been completed at the PRIME Clinic. This study randomly allocated participants who met Criteria of Prodromal Symptoms (COPS) to receive either olanzapine or placebo for 12 months followed by a 12-month monitoring period. Three reports have been published to date which detail the study rationale and design (McGlashan et al, 2003), baseline characteristics of the prodromal sample (Miller et al, 2003) and effects of olanzapine v. placebo in the first 8 weeks of the double-blind phase (Woods et al, 2003).
Meanwhile, in the UK, the Manchester EDIE trial has compared the impact of cognitively oriented psychotherapy with monitoring alone, i.e. no psychological treatment, on the rate of transition to psychosis in 23 young people meeting ultra-high-risk criteria (French, 2002; Morrison et al, 2002). After 26 sessions of CBT only 1 of the 13 participants (8%) in this group had developed acute psychosis compared with 4 of the 11 in the monitoring group (36%) (French, 2002). These results are encouraging as they suggest that pharmacological treatment might not be necessary to assist all young people in the prepsychotic phase of illness.
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DISCUSSION |
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These are all legitimate areas of concern. Currently, it remains unclear whether the risk/benefit profile of neuroleptic treatments means that they should be prescribed and for how long, but there is sufficient evidence to suggest that clinical trials are warranted. The clinical treatment of young people identified as being at high risk of developing a psychotic disorder, particularly the use of neuroleptics, should be provided only in the context of a research trial, where standards of informed consent and monitoring are highest. Experience at the PACE Clinic has shown that sometimes young people are prescribed antipsychotic medication by psychiatrists and even general practitioners in the absence of a clear-cut psychotic disorder when the prescribing physician suspects that a psychotic disorder is emerging. It is imperative that such treatment be first investigated in an evidence-based manner. The effects of stigma also need to be examined. In some settings, if there is an inappropriately pessimistic mindset linked to the diagnosis of schizophrenia or psychotic disorder (a widespread phenomenon still), or the treatment setting is of poor quality or stigmatising, there may possibly be iatrogenic effects of this type. Such impact has not been seen in the PACE Clinic but this reassuring experience cannot necessarily be generalised and, indeed, needs to be demonstrated empirically.
Until recently, some major grant-giving bodies baulked at funding intervention research in the prepsychotic phase because of perceived ethical problems. In fact, not supporting the collection of vital evidence to guide clinical decision-making in such clinical samples can be viewed as perpetuating ethical dilemmas and confusion, as well as allowing non-evidence-based practice to flourish. This policy suggests that a double standard might exist for psychiatric disorders, since it clearly does not operate for early diagnosis in potentially serious medical illnesses. Similarly, the notion of funding naturalistic studies where the use of antipsychotic medication in particular is freely permitted seems flawed and ethically inferior to conducting randomised controlled trials examining the use of anti-psychotics and other biological and psychosocial treatments in this phase. Naturalistic studies of this type (other kinds could be considered more useful) are inevitably going to produce confusing or inclusive results and have all the problems which were some years ago attributed to more rigorous research in this field (specially drug side-effects and potential stigma). Future support is required from the large independent research funding bodies, since this would enable necessary non-industry-funded studies to be conducted.
In conclusion, this paper reviews the development of an approach specifically designed for the detection, monitoring and treatment of the prepsychotic or prodromal phase of illness and the study of the psychobiological processes contributing to onset of psychosis in schizophrenia and related disorders. This is truly a growth area with the potential to benefit such symptomatic young people and their families. Increasingly, our ability to identify those at particularly high risk is being refined and a biological basis for psychosis onset investigated. Caution must be exercised, however, and each step evaluated in an evidence-based manner. Continued modification of ultra-high-risk criteria and better understanding of the process of screening and sample enrichment may be needed. Randomised controlled trials of medication and other interventions must be ongoing and rigorously evaluated. Large-scale screening of population samples in order to expand the scope of prepsychotic treatment is probably not justified merely for this purpose at this stage of knowledge. As an alternative, either enriching strategies could be developed to enable interventions to be evaluated, or a broader screening strategy for the full range of emergent mental disorders in young people could be explored. We expect this area of psychiatry to progress steadily over the next few years.
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APPENDICES |
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Appendix 2: Obstacles to prepsychotic intervention
Appendix 3: Defining the onset of psychosis prospectively
Situations that complicate the definition:
Appendix 4: PACE Clinic criteria for the ultra-high-risk group
Aged between 14 and 29 years Referred to a specialised service for help
Meets criteria for one or more of the following three groups:
Appendix 5: PACE Clinic inclusion criteria according to Comprehensive Assessment of At Risk Mental States (CAARMS) scores
Acute psychosis criteria
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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