Download The "Close-in" or Ultra High-Risk Model: A Safe and Effective

The "Close-in" or Ultra High-Risk Model:
A Safe and Effective Strategy for Research
and Clinical Intervention in Prepsychotic
Mental Disorder
by Patrick D. hicQorry, Alison R. Yung, and Lisa J. PhiUips
Abstract
In recent years there has been a groundswell of clinical
and research interest in early intervention in psychotic disorders (Edwards and McGorry 2002; Malla and Norman
2002). The early psychosis paradigm, which is centered on
early detection and optimal treatment of first episode psychosis and the subsequent critical years, has become a sustained growth front in both the clinical and research arenas. This is due to the high stakes involved, the strong
commitment to evidence-based medicine, the quality of
the research endeavors, and the close integration of the
research and clinical questions. Further progress is evident
in this special issue of Schizophrenia Bulletin, which
reflects the involvement of an increasingly broad range of
researchers in the new frontier of prepsychotic or prodromal research.
The rise of the early psychosis paradigm has enabled
the prepsychotic phase of schizophrenia and related psychoses to come strongly into focus for the first time.
Reacting to the pessimism intrinsic to the concept of
schizophrenia and also to the damage wrought by a disorder for which effective treatments were lacking, an earlier
generation of psychiatrists were attracted to the notion of
prepsychotic intervention (Sullivan 1927; Meares 1959).
What remained a dream for decades is now starting to
become a reality. This article describes principles and
progress in the prospective detection and engagement of
young people with incipient psychosis.
Urgent public health challenges associated with psychotic disorders (particularly schizophrenia and bipolar
disorder) remain. These include the unacceptable and prolonged delay in accessing treatment even after frank psychosis, well above the diagnostic threshold, has developed
(McGlashan 1999) and the all-too-often poor quality of
treatment and insecure tenure within specialist mental
The development of a new frontier for research and
early intervention in psychotic disorders is highly
dependent on the construction of synergistic clinical
infrastructures. This has catalyzed great progress in
the recognition, enhanced treatment, and study of first
episode psychosis, and the task is even more challenging when the boundaries are extended to include the
earliest clinical phase of illness, the prodromal or
prepsychotic phase. This article describes the conceptual and practical building blocks for the construction
of service models for intervention hi the postonset clinical phase prior to the attainment of current diagnostic
thresholds. This is best regarded as indicated prevention, a form of very early secondary prevention, which
involves a blend of immediate clinical care combined
with research-oriented preventive intervention. The
experience of the Personal Assessment and Crisis
Evaluation (PACE) Clinic hi Melbourne across several
stages of growth is described and contrasted with that
of several emerging centers in Europe and North
America. The progress to date, the lessons learned,
and the unresolved challenges and opportunities are
detailed. It is concluded that service models can be
developed that are acceptable and helpful to young
people and their families, and that create a unique
environment for the study of the transition to frank
psychotic disorder. The ultimate clinical utility and
general safety of this approach and the range of effective treatments remain unclear, and will be determined
by more extensive research. Such research must be
conducted in a logical and rigorous manner with the
best designs possible, sensitive to input from consumers and caregivers and to ethical considerations.
Keywords: Psychosis, prodrome, high risk, prevention.
Schizophrenia Bulletin, 29(4):771-790,2003.
Sendreprintrequests to Patrick D. McGoiry, M.D., Ph.D., ORYGEN
Research Centre, Locked Bag 10, Parkville, Australia 3052; e-mail:
[email protected].
771
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGotry et al.
health services, even when initial entry has been achieved
(Lieberman and Fenton 2000; McGorry 2002; McGorry
and Yung 2003). With the advent (in many countries) of
widespread first episode programs aimed at addressing the
two major weaknesses of current care, the prepsychotic
phase offers a tantalizing additional focus for treatment It
has become possible to detect and engage a subset of
young people who are subthreshold for fully fledged psychotic disorder yet who have demonstrable clinical needs
and other syndromal diagnoses and who appear to be at
incipient risk of frank psychosis (Yung et al. 1996). However, the extension of the early intervention paradigm from
mainstream medicine to psychiatry has generated anxiety
and controversy in some quarters. Concerns about the
risk/benefit balance of early intervention strategies lie at
the heart of this controversy and need to be addressed by
an evidence-based approach.
antecedents of schizophrenia, while demonstrating significant but minor differences between controls and those who
later developed schizophrenia, paradoxically highlighted
the quiescence of the illness during this phase of life
(Jones et al. 1994). However, this study and the findings of
HSfner et al. (1995) revealed that psychotic illnesses really
begin to have clinical and social consequences after
puberty, typically during adolescence and early adult life.
The period of nonspecific symptoms and growing functional impairment prior to the full emergence of the more
diagnostically specific positive psychotic symptoms constitutes the prodromal phase.
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
(HSfher et al. 1995; Agerbo et al. 2003) and may create a
ceiling for eventual recovery in young people is a key reason for attempting some form of prepsychotic intervention
(table 1). Other benefits include the capacity to research
the onset phase of illness and examine the psychobiology
of progression from the subthreshold state to the fully
fledged disorder. More proximal risk factors such as substance use, stress, and the underlying neurobiology can
also be uniquely studied. The delineation of this discrete
phase, the boundaries of which are often difficult to map
precisely, is of great heuristic and practical value. Whether
"prodrome" is the best term for it is, however, debatable
(Yung and McGorry 1996a, 1996fc; Yung et al. 1998;
Phillips et al. 2002a). A number of obstacles to intervention during this phase should also be noted (table 2). These
obstacles are largely generic to all preventive or early
Conceptual Issues
The prepsychotic or prodromal phase needs to be clearly
distinguished from the premorbid phase on the one hand
and the first episode of psychosis on the other. To understand the potential advantages of prepsychotic intervention, it is important to explicate the concept of prodrome, a
concept that has only recently become widely used in
schizophrenia. The period prior to clear-cut diagnosis has
traditionally been referred to as the premorbid phase.
However, this term has led to some confusion because it
actually covers two phases, not one, and has not been useful from a preventive perspective. Studies of the childhood
Table 1. Potential advantages of prepsychotic Intervention
• An avenue for help is provided, irrespective of whether transition ultimately occurs, to tackle the serious problem
of social withdrawal, impaired functioning, and subjective distress that otherwise become entrenched and steadily
worsen prior to the onset of frank psychotic symptoms.
• Engagement and trust are easier to develop, and a foundation is laid for later therapeutic interventions, especially
drug therapy, if and when required. The family can be similarly engaged and provided with emotional support and
information outside of a highly charged crisis situation.
• If psychosis develops, it can be detected rapidly and duration of untreated psychosis minimized, and hospitalizatJon
and other lifestyle disruption rarely occur. A crisis with behavioral disturbance or self-harm is not required to gain
access to treatment.
• Comorbidity, such as depression and substance abuse, can be effectively treated and the patient therefore gets
immediate benefits. If psychosis worsens to the point of transition, the patient enters the first episode in better
shape with less distress and fewer additional problems.
• If treatment is influencing the underlying biological pathophysiology and/or psychosocial contributory causes, then
the onset of psychosis may be either delayed or averted, with substantial health benefits.
• The prospective study of the transition process is enabled, including neurobiological, psychopathological, and environmental aspects. Patients are less impaired cognitively and emotionally and are more likely to be fully competent to give Informed consent for such research endeavors.
772
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
"Close-in" or Ultra High-Risk Model
Table 2. Obstacles to prepsychotic Intervention
The false-positive rate for first episode psychosis remains substantial. Are falsely identified individuals helped or
harmed by involvement in clinical strategies? Receiving treatment at this time may heighten stigma or personal anxiety about developing psychosis or schizophrenia. If patients are exposed to drug therapies, especially antjpsychotic
medications, adverse reactions may occur without benefit in false-positive cases.
If the false-positive rate is improved, then the accurate detection rate may, conversely, decrease. This is a mathematical
feature of the screening process, even when the ultra high-risk based on encouraging help seeking for sacrifice of
sensitivity for specificity group. Even with enrichment or successful screening, most of the '"cases" will still emerge
from the low-risk group. The solution may be two- or three-step sequential screens with a continuous entry mechanism. Even if there is a ceiling for the proportion of cases that can be detected and engaged at this phase, there will
still be some advantages.
False positives cannot be distinguished from false false positives (Yung et al. 2003).
Lessons from earty intervention in cancer, coronary heart disease, and stroke are not yet translated to psychosis and
schizophrenia.
intervention models and have been confronted in cancer
and cardiovascular disease. In psychiatry they are magnified by the tenacious reality of stigma and therapeutic
nihilism.
completion date. This strategy was better suited to clarify
pathophysiological candidates for schizophrenia and other
psychoses and was never really a viable basis for widespread early detection.
The Ultra High-Risk or "Close-in" Strategy. The
Focus on the Ultra High-Risk
Population: The "Close-in" Strategy as
a Key Methodological Advance
development of an alternative high-risk strategy with a
higher rate of transition to psychosis, a lower false-positive rate, and a shorter followup period than in the traditional genetic studies has been central to progress in preventive interventions for psychosis. Bell (1992) proposed
that "multiple-gate screening" and "close-in" followup of
cohorts selected as being at risk of developing a psychosis
would minimize false-positive rates. Multiple-gate screening is a form of sequential screening that involves putting
in place a number of different screening measures to concentrate the level of risk in the selected sample. In otheT
words, an individual must meet a number of conditions to
be included in the high-risk sample rather than just one
condition, as in the traditional studies. Close-in followup
involves shortening the period of followup necessary to
observe the transition to psychosis by commencing the
followup period close to the age of maximum incidence
of psychotic disorders. To improve the accuracy of identifying the high-risk cohort further, Bell also recommended
using signs of behavioral difficulties in adolescence as
selection criteria, such as the inclusion of clinical features.
This also allows the approach to become more clinical, to
move away from traditional screening paradigms, and to
focus on help-seeking troubled young people, who are
therefore highly "incipient" and frankly symptomatic. To
maximize the predictive power as well as enable the
engagement of the patient to be well justified on immediate clinical grounds, the timing is critical. Patients should
be as "incipient" as possible, yet this is difficult to measure and consistently sustain. Transition rates in samples
may therefore vary on this basis and also because of differences in the underlying proportions of true and false
The model that underpins this new wave of studies is a
significant departure from earlier endeavors at identifying
high-risk cohorts. The new approach reflects the adage
"timing is everything," aiming to maximize the accuracy
of prediction and the need for clinical care as well as preventive intervention. This means focusing on patients who
have manifest symptoms and impaired functioning and
demonstrate a substantially increased risk of psychosis
onset
Traditional or Genetic High-Risk Model. A range of
studies recruited individuals with a family history of psychotic disorder (usually schizophrenia) during early childhood and monitored them over time—in some studies for
up to 35 years (Nagler 1985; Fish et al. 1992; Cannon and
Mednick 1993; Erlenmeyer-Kimling et al. 1995, 1997;
Ingraham et al. 1995; Hodges et al. 1999; Johnstone et al.
2001). Selection of subjects for these studies on the basis
of a crude measure of genetic risk (family history)
restricts the generalizability of any findings to the early
detection of schizophrenia, as most cases do not in fact
have a first degree relative with the disorder (McGuffin et
al. 1984; Kendler 1986; Asamow 1988). Conversely, only
a low proportion of cases in these studies eventually
develop schizophrenia or psychosis, and the latent period
is long. These studies have been characterized by low
positive predictive values and high rates of false positives,
and they tend to become obsolete before their eventual
773
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
positives of those who enter the sample. It should be
emphasized that young people involved in this strategy
have clinical problems, and help is being sought either
directly by them or on their behalf by concerned relatives.
The ideas expressed by Bell (1992) were first translated into practice in Melbourne, Australia, in 1994 at the
Personal Assessment and Crisis Evaluation (PACE) Clinic
(McGorry and Singh 1995; Yung et al. 1995) in parallel
with the development of the Early Psychosis Prevention
and Intervention Centre (EPPIC) program (McGorry
1993; Edwards et al. 1994; McGorry et al. 1996). This
approach has now been adopted in a number of other clinical research programs across the world (e.g., Cornblatt
2002; Miller et al. 2002; Morrison et al. 2002). These studies have been referred to as ultra high-risk (UHR) studies
to differentiate them from the traditional high-risk studies
that rely on family history as the primary inclusion criteria. Intake criteria for such studies were initially developed
from information gleaned from literature reviews and clinical experience with first episode psychosis patients and
have been evaluated and reviewed in the PACE Clinic
over the past 8 years. Although UHR studies ostensibly
seek to identify individuals experiencing an initial psychotic prodrome, infallible criteria have not yet been
developed toward this end. In addition, prodrome is a retrospective concept that can only be diagnosed once.
Therefore, criteria used in these studies are referred to as
at-risk mental state criteria (ARMS; McGorry and Singh
1995; Yung and McGorry 1997) or precursor signs and
symptoms (Eaton 1995). This terminology does not imply
that a full-threshold psychotic illness such as schizophrenia is inevitable but suggests that individuals are at risk of
developing a psychotic disorder by virtue of their current
mental state. This terminology is more conservative than
prodrome. Additionally, the ARMS concept acknowledges
current limitations in our knowledge and understanding of
psychosis. It also has ethical advantages in underlining the
reality of false-positive "cases." It should be noted again
that participants in the UHR model are seeking help on a
voluntary basis; they are concerned about changes in their
mental state and functioning and are requesting some
assistance to address these changes. Therefore, while some
turn out to be false positives for subsequent psychotic disorder, they are all "cases" in the sense of a need for care.
The young people are often overtly concerned about the
possibility that they may be developing a psychotic disorder.
UHR criteria currently in operation at the PACE
Clinic require that the person fall into one or more of the
following groups: (1) attenuated psychotic symptoms
group: patients who have experienced subthreshold, attenuated positive psychotic symptoms during the past year;
(2) brief, limited or intermittent psychotic symptoms
group (BLIPS): patients who have experienced episodes of
frank psychotic symptoms that have not lasted longer than
a week and have spontaneously abated; or (3) trait and
state risk factors group: patients who have a first degree
relative with a psychotic disorder or who have a schizotypal personality disorder, and have experienced a significant decrease in functioning during the previous year.
Operationalized criteria are shown in table 3. As well as
meeting the criteria for at least one of these groups, subjects are between 14 and 30 years old, have not experienced a previous psychotic episode, and live in the Melbourne metropolitan area. Thus, the UHR criteria identify
young people who are in the age range for peak incidence
of onset of a psychotic disorder (late adolescence/early
adulthood) who additionally describe mental state changes
that are suggestive of an emerging psychotic process or
who may have a strong family history of psychosis. This
represents an initial effort to translate the multiple-gate
screening and close-in strategies recommended by Bell
(1992) into practice. Exclusion criteria are intellectual disability, lack of fluency in English, presence of a known
organic brain disorder and a history of a prior psychotic
episode (lasting longer than 1 week)—either treated or
untreated. It is recognized that some subthreshold cases, in
particular those meeting BLIPS criteria, might meet criteria for DSM-IV brief psychotic disorder.
Criteria have also been developed to define the onset
of psychosis in the UHR group (table 3). These are not
identical to DSM-FV criteria but are designed to define the
minimal point at which neuroleptic treatment is indicated.
This definition might be viewed as somewhat arbitrary but
does at least have clear treatment implications and applies
equally well to substance-related symptoms, symptoms
that have a mood component (either depression or mania),
and schizophrenia spectrum disorders. The predictive target is first episode psychosis that is judged to require
antipsychotic medication, arbitrarily defined as the persistence of frank psychotic symptoms for over 1 week. Schizophrenia is a subset or subsidiary target, because although
the majority of progressions from the ARMS fall within
the schizophrenia spectrum (schizophreniform or schizophrenia), a significant minority do not. In fact, the broader
first episode psychosis target is a more proximal and therapeutically salient one than schizophrenia, which can be
considered a subtype to which additional patients can
graduate distal to the first episode psychosis (as well as
being one of the proximal categories). This logic applies to
the early intervention field generally, where first episode
psychosis is a more practical and safer concept than first
episode schizophrenia (again best considered as a subtype)
(McGorry 1995).
This strategy derived subsequent support from a landmark publication addressing contemporary conceptualiza-
774
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
Table 3. PACE Clinic Inclusion criteria according to CAARMS* scores
Group 1: Attenuated Psychosis Group This criterion identifies young people at risk of psychosis due to a subthreshold
psychotic syndrome. That is, they have symptoms which do not reach threshold levels for psychosis due to subthreshold
intensity (the symptoms are not severe enough) or they have psychotic symptoms but at a subthreshold frequency (the
symptoms do not occur often enough)
2a) Subthreshold Intensity:
• Severity Scale Score of 3-5 on Disorders of Thought Content subscale, 3-4 on Perceptual Abnormalities subscale
and/or 4-5 on Disorganized Speech subscales of the CAARMS; plus
• Frequency Scale Score of 3-6 on Disorders of Thought Content, Perceptual Abnormalities and/or Disorganized Speech
subscales of the CAARMS* for at least a week, or
• Frequency Scale Score of 2 on Disorders of Thought Content, Perceptual Abnormalities and Disorganized Speech subscales of the CAARMS on more than two occasions
2b) Subthreshold frequency:
• Severity Scale Score of 6 on Disorders of Thought Content subscale, 5-6 on Perceptual Abnormalities subscale and/or
6 on Disorganized Speech subscales of the CAARMS*; plus
• Frequency Scale Score of 3 on Disorders of Thought Content, Perceptual Abnormalities and/or Disorganized Speech
subscales of the CAARMS
PLUS (for both categories)
• Symptoms present in past year and for not longer than five years
Group 2: Brief Limited Intermittent Psychotic Symptoms (BLIPS) Group This criterion identifies young people at risk
of psychosis due to a recent history of frank psychotic symptoms which resolved spontaneously (without antipsychotic
medication) within one week
• Severity Scale Score of 6 on Disorders of Thought Content subscale, 5 or 6 on Perceptual Abnormalities subscale
and/or 6 on Disorganized Speech subscales of the CAARMS; plus
• Frequency Scale Score of 4-6 on Disorders of Thought Content, Perceptual Abnormalities and/or Disorganized Speech
subscales; plus
• Each episode of symptoms is present for less than one week and symptoms spontaneously remit on every occasion;
plus
• Symptoms occurred during last year and for not longer than five years
Group 3: Vulnerability Group 77J/S criterion identifies young people at risk of psychosis due to the combination of a trail
risk factor and a significant deterioration in mental state and/or functioning
• First degree relative with a psychotic disorder or schizotypal personality disorder in the identified patient (as defined by
DSM-IV); plus
• Significant decrease in mental state or functioning maintained for at least a month and not longer than 5 years
(reduction in GAF Scale of 30 percent from pre-morbid level); plus
• The decrease in functioning occurred within the past year and has been maintained for at least a month.
Full threshold psychosis criteria
• Severity Scale Score of 6 on Disorders of Thought Content subscale, 5 or 6 on Perceptual Abnormalities subscale,
and/or 6 on Disorganized Speech subscales of the CAARMS; plus
• Frequency Scale Score of greater than or equal to 4 on Disorders of Thought Content, Perceptual Abnormalities, and/or
Disorganized Speech subscales; plus
• Symptoms present for longer than one week.
Note.—CAARMS = Comprehensive Assessment of At-Risk Mental States; GAF = Global Assessment of Functioning.
tions of preventive approaches to mental illness. Mrazek
and Haggerty (1994) wrote that the current lack of definitive knowledge about the etiology and risk factors for psychotic disorders, particularly schizophrenia, meant that
developing universal (targeting the entire population) and
selective (targeting groups whose risk of developing psychosis is significantly higher than average) preventive
interventions is not currently possible. Rather, they suggested that indicated prevention—targeting individuals
who exhibit subthreshold signs and symptoms of psy-
775
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
chosis—was the most appropriate approach. They further
suggested that combining known risk factors provides the
best chance for identifying high-risk individuals—that is,
the multiple-gate screening approach. The theoretical
basis for this drew on the work of Eaton (1995), who was
looking at subthreshold clinical features as a form of proximal risk factor for full clinical disorder, in this case
depression, and opened up the whole notion of how disorders actually "onset" and what constitutes an initial
"case." Acquisition, intensification, and coherence of
symptoms and syndromes are necessary but perhaps insufficient dimensions for "caseness" (Eaton 1995). Other
variables such as distress, additional comorbidity (van Os
et al. 1994), functional impairment, and perceived and
objective "need for care" also need to be considered as
necessary features or alternatively as "risk factors for caseness." Clearly, greater precision is necessary for defining
die onset of mental disorders generally, not only schizophrenia and psychotic illnesses.
The criteria described above were evaluated in a
series of studies at the PACE Clinic between 1994 and
1996. Young people meeting the ARMS criteria were
recruited and their mental state was monitored over a 12month period. Forty-one percent of the cohort had developed an acute psychosis and had been started on appropriate neuroleptic treatment at the end of the followup (Yung
et al. 1998, 2003). This occurred despite the provision of
minimal supportive counseling, case management, and
selective serotonin reuptake inhibitor medication if
required. The primary diagnostic outcome of the group
who developed an acute psychosis was schizophrenia
(65%) (Yung et al. 2003).
The high transition rate to psychosis indicates that the
PACE criteria accurately identify young people with an
extremely high risk of developing a psychotic disorder
within a short followup period. These results cannot be
easily generalized to the wider population or even to individuals who have a family history of psychosis but are
asymptomatic. Participants recruited to research at the
PACE Clinic are a selected sample, characterized perhaps
by high help-seeking characteristics or other nonspecific
factors. It undoubtedly includes only a minority of those
who proceed to a first episode of psychosis, and a possibly
unstable proportion of false positives, depending on sampling and detection factors, which in turn are difficult to
define and measure but can affect the base rate of true positives in the sample. Hence, the transition rate may vary
and needs to be validated and monitored because the UHR
criteria are not the only variable involved. However, these
criteria are now being utilized in a number of other settings around the world, with preliminary results indicating
that diey predict as well in the United States, the United
Kingdom, and Norway as they do in Melbourne, Australia
776
(Larsen 2002; Miller et al. 2002; Morrison et al. 2002).
Undoubtedly, there are other clinical features and nonclinical variables that need to be identified and incorporated
into future definitions of the UHR state. In our view, the
UHR concept better lends itself to this task than does the
concept of prodrome.
Establishing a Prepsychotic Clinical
Research Environment
Aims and Principles. There are several key, interdependent aims of such clinical research programs:
1. To improve the understanding of die neurobiological
and psychosocial processes that occur during the
prepsychotic phase and contribute to the onset of acute
and persistent psychosis. Conversely, processes that
protect against progression and promote recovery and
resolution of symptoms and impairment may be clarified.
2. To improve the predictive power for identification of
individuals at risk for psychosis (or schizophrenia vs.
affective psychosis) to better target treatment interventions.
3. To develop and evaluate a range of psychosocial and
biological interventions to treat current syndromes and
prevent future disorders from fully expressing themselves. Effectiveness and safety issues, including
stigma, need to be evaluated hand in hand.
4. To establish a clinical service that is not only highly
accessible but also acceptable to young people at ultra
high risk of developing psychosis.
5. To educate the community about early signs of mental
illness in general and psychosis in particular.
The PACE Clinic: An Example of an Integrated UHR
Clinical/Research Program. The PACE Clinic was
established in Melbourne, Australia, in 1994 (Yung et al.
1995). It is one arm of a comprehensive early psychosis
research program affiliated with EPPIC (McGorry 1993;
McGorry et al. 1996). Although the clinic initially operated on a limited basis with a part-time consultant psychiatrist and one research psychologist, its team now comprises 12 clinicial/research staff. The modest beginnings
with a necessarily limited research agenda of mapping the
onset of psychosis and establishing valid criteria for identifying the UHR cohort have blossomed into 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 Youth
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
Health) that now incorporates PACE and EPPIC and contrasts with the usual child and adolescent versus adult
mental health divide, reflects the epidemiology of onset of
disorders, and recognizes the special needs of the youth
population.
The PACE Clinic, EPPIC, and ORYGEN Youth
Health have always sought to distinguish themselves from
mainstream mental health services, which are typically
viewed in an extremely negative light, particularly by
young people. PACE'S name is deliberately generic in
order to avoid stigma and labeling. This reduces disincentives to help-seeking and engagement. Furthermore, PACE
has always been located within nontraditional mental
health settings such as generic youth health or community
health settings or, more recently, within a large metropolitan shopping center. Where possible, clinicians and
researchers do not limit themselves to working within the
office but initially aim to engage with young people in
their own environment (e.g., at home, at school, or in primary care settings). These methods seem to largely overcome the effects of stigma, with 72 percent of all accepted
referrals coming for three or more visits and 55 percent
agreeing to involvement in research.
A much more flexible approach is required when
working with young people, who typically are naive users
of mental health services. An initial willingness to go to
them—to meet them "on their own turf"—helps minimize
initial nonattendance. This flexibility is now expected
within the service system, and clinicians tend to self-select
to embrace this model of care. Similarly, the multidisciplinary PACE team, reflecting changes within the local mental health scene, undertake a broad range of case management and therapy tasks. Clinical case management in
Australia is handled by professionals in a range of disciplines, including psychologists. Cognitive therapy tends to
remain the province of psychologists and, within PACE,
psychologists provide both types of intervention. PACE
services are free and offered as part of the public mental
health system, even though the bulk of the funding derives
from research grants.
Although PACE seeks to distinguish itself from traditional mental health services, which tend to focus on those
who already have diagnosable levels of disorder, it also
benefits from close relationships with such services, especially EPPIC. Many referrals to PACE come from other
mental health services. Such patients experience less
stigma through diversion from traditional psychiatric settings into the low-stigma PACE environment. Additionally, if members of the UHR cohort do develop acute psychosis, then referral to another service (preferably an early
psychosis—specific service) for treatment is necessary.
Other referrals to the PACE Clinic come from the
educational sector, primary health services, drug and alco-
hol services, and other youth-oriented services (Phillips et
al. 1999, 2002a). A key challenge facing the clinic, therefore, has been to educate potential referrers about psychotic disorders and the signs of an emerging psychotic
disorder, and also about the PACE Clinic itself. Given the
specificity of the intake criteria, a widespread saturation
campaign about these issues is normally considered too
expensive and time-consuming (although such a comparison is now underway in our region, with the broader
objective of early intervention in youth mental health). A
more strategic approach is usually necessary.
Incidence rates of first episode psychosis indicate that
within the Northwestern Melbourne region there are
potentially 500 UHR cases per year (Krstev et al., submitted). Referrals to PACE in previous years clearly indicate
that many of these young people seek some assistance or
explanation for the mental state changes they are experiencing. Most commonly, they go first to someone already
known to them (e.g., a general practitioner or schoolbased counselor, rather than a mental health service).
Therefore, community education at PACE has targeted
these potential referrers: general practitioners, psychiatric
services, school and university counseling services, and
other support agencies working with young people, such
as drug and alcohol services (Phillips et al. 1999). Support
groups for siblings and children of individuals with psychotic disorders are also provided with information about
PACE as an available clinical service. The clinic works
closely with other mental health services, as previous
experience shows that these services tend to refer most
accurately to PACE. Formal professional development
and training forums as well as informal case discussions
and secondary consultation are used to inform potential
referrers about the clinic. Close working relationships are
established with the most relevant services in an attempt
to address some of the usual barriers to referral. These
activities are described in detail elsewhere (Phillips et al.
1999, 2002a).
Additionally, brochures, newsletters, a promotional
video, and various other materials about the research and
clinical program at PACE and the profile of young people
attending the service are regularly produced and distributed. Staff members with a clinical background carry out
these tasks as well as provide secondary consultation. The
same clinicians provide the triage component for the clinic
as a whole. This allows for continuity between the professional development/training activities and the referral triaging process—making referrals smoother. Community education strategies have ensured that PACE is recognized as a
potential referral point for professionals who may have
concerns about a young person they are working with. The
capacity to offer a clinical service to patients from their
early teens to their late twenties has been a critical factor
777
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
behind the growth of PACE, EPPIC, and the ORYGEN
Youth Health concept The creation of a third tier, one positioned between child psychiatry and adult psychiatry, is a
challenging long-term objective that has attracted strong
support from many clinicians, consumers, and families but
considerable resistance from health bureaucrats and professional groups within psychiatry. The partial breaking of the
mould achieved by the PACE/EPPIC models has been
based upon local opportunities, a strong theoretically and
clinically oriented model, and the capacity to attract substantial research funding to underpin the clinical reform
agenda. From the PACE standpoint, the link with a very
substantial first episode psychosis program has been critical. In Australia, the creation of this third tier is inhibited by
the global undersourcing of mental health services,
although the new approach may not be intrinsically more
expensive (McGorry and Yung 2003). The public mental
health service system is not fundamentally insurance-based
but derived from historical reallocations of the resources of
the former asylum model. With funding growth, a wider
adoption, as in the United Kingdom, of early intervention
models will be quite feasible.
changes such as the subjective sense of cognitive impairment, which can be rated on the Conceptual
Disorganization scale on a continuum with other objectively observed formal thought disorder, as well as subjective emotional changes. The CAARMS has been found to
have good to excellent interrater reliability and predictive
validity (Yung et al., submitted). More recently, the UHR
criteria have been operationalized using CAARMS rather
than BPRS scores (table 3). A copy of the CAARMS is
available from Dr. Yung on request
A similar instrument, now well validated, has also
been developed by the PRIME group (the Structured
Interview for Prodromal Symptoms [Miller et al. 1999,
2002]). While there was initial close correspondence
between the two assessment procedures because of their
common ancestor, the ARMS criteria, the process of separate local evolution may have introduced some variation.
The further development of reliable and valid methods for
assessing prepsychotic symptomatology across multiple
centers is a crucial step for research progress in this area.
In addition to establishing the validity of the intake
criteria for the clinic, early work at PACE increased familiarity with the profile of clients meeting ARMS or UHR
criteria and their clinical needs. Young people attending
the clinic were offered clinical care and treatment, as it
was felt that offering monitoring alone was unethical in
view of the patients' clinical status and help-seeking
nature. Treatment with neuroleptics at this early stage was
clearly premature, as the high-risk nature of the client
group had not yet been established, and the risk/benefit
balance of such treatment had not been researched. Thus,
clients attending PACE at this stage received supportive
counseling and more specific psychotherapeutic strategies
(particularly cognitive-behavioral) where appropriate.
Antidepressant and anxiolytic medication was also provided if deemed necessary. Treatment was therefore
focused on the presenting clinical problems and was
offered for a period of 1 year, after which time clients
were referred elsewhere if appropriate. Those who developed acute psychosis were commenced promptly on lowdose atypical neuroleptic medication and transferred to a
more appropriate service for continuing care—in most
cases the EPPIC program. This careful and relatively standardized approach minimized confounding factors that
might have masked the transition to psychosis. In our
view, naturalistic studies that permit treatment that is not
standardized by protocol and carefully monitored, particularly if the use of "doctor's choice" neuroleptic medication is allowed, will not provide useful information in
terms of prediction or treatment efficacy. Open trials of
particular types of medication or psychotherapy may still
have a place, but unregulated, non-protocol-driven intervention is unlikely to add clarity. This will probably
Measurement Early in the establishment of the PACE
Clinic and the associated research program, it became
obvious that existing psychopathology measures were
inadequate for assessing prepsychotic symptomatology.
Although scales such as the Brief Psychiatric Rating Scale
(BPRS: Overall and Gorham 1962; McGorry et al. 1988),
the Scale for the Assessment of Negative Symptoms
(Andreasen 1982), and the Positive and Negative
Syndrome Scale (Kay et al. 1987) are commonly used in
research with psychotic patients—including those with
first episode psychosis—it was felt that they did not allow
for a sufficiently fine-grained assessment of the subthreshold positive symptoms or the full range of precursor
symptoms required at this earlier phase (Yung and
McGorry 19966). For this reason, in 1994, a semistructured interview aimed at assessing prepsychotic (prodromal) symptomatology began to be developed in serial
fashion: the Comprehensive Assessment of At-Risk
Mental States (CAARMS). Unlike other symptom assessment tools, which collapse the intensity, frequency, and
duration of symptoms into one score, the CAARMS
teases out each of these individual aspects. Therefore, it
can track small changes in the symptoms and individual
experiences, such as an increase in the frequency of hearing voices from weekly to daily with no change in the
intensity of the experiences. A cruder instrument such as
the BPRS may not pick up such subtle changes. Drawing
on the work of the Bonn-Cologne group of Huber and
Klosterkatter (KlosterkStter et al. 1997), the CAARMS
also enables assessment of subjectively experienced
778
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
become an area of controversy as data from a range of
centers accumulate.
Studies of Prediction and Neurobiology of Transition.
The development and validation of criteria that identify
young people at very high risk of developing a psychotic
disorder within a short followup period have created a
novel channel for further research evaluating putative risk
factors for psychosis onset. These include mental state
changes such as presence of mood and anxiety features,
Huber's basic symptoms (Koehler and Sauer 1984; Gross
1989; Klosterkotter et al. 2001), drug and alcohol usage,
neurocognitive impairment, obstetric complications,
delayed childhood milestone achievement, and possible
trait markers, including neurological abnormalities and
poor premorbid adjustment (Olin and Mednick 1996;
Buckley 1998; Ismail et al. 1998). The investigation of the
presence of viral antibodies (Torrey 1988; O'Reilly 1994;
Yolken et al. 2000) as a risk factor for future psychosis
has also recently commenced within the clinic.
Some factors have been found to be associated with
increased risk of transition to psychosis within the UHR
group. Clinical variables include long duration of nonspecific symptoms, poor psychosocial functioning, comorbid
depression, and disorganization (Yung et al. 2003).
Preliminary results examining central nervous system
structure indicate that within the UHR group those who
subsequently developed psychosis had reduced grey matter in right medial and lateral temporal areas, in the right
inferior frontal cortex, and in the cingulate gyms at baseline compared with those who did not develop psychosis
(Pantelis et al. 2003). Thus far, no clear neuropsychological or developmental risk factors have emerged.
Many studies have suggested that the hippocampal volumes of individuals with established schizophrenia or first
episode psychosis are smaller than those of controls
(reviewed by Velakoulis et al. 2000). Magnetic resonance
imaging (MRI) scans of the brains of UHR patients are
obtained to determine whether volume changes in this
region precede the development of acute psychosis or
emerge as mental state deteriorates. Consistent with the neurodevelopmental hypothesis, hippocampal volumes of
PACE UHR patients at intake he midway between those of
normal controls and patients with chronic schizophrenia or
first episode psychosis (Phillips et al. 20026). More puzzling
and challenging to the original neurodevelopmental model
are the results of survival analysis, which revealed that UHR
patients 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. 20026). Consistent with this finding, a comparison of PACE UHR patients' MRI scans taken prior to
the onset of psychosis and again after an acute disorder
779
developed has revealed reduction of gray matter volumes in
the left insular cortex and the left posterior medial temporal
structures, including the hippocampus and posterior hippocampal gyms, during the transition to psychosis (Pantelis
et al. 2003). This finding suggests that brain changes occur
during the process of transition to psychosis and opens up the
possibility that with sufficiently early treatment such changes
could be minimized or aborted, although the basis of this latter possibility remains uncertain. These MRI and more recent
magnetic resonance spectroscopy (MRS) studies are ongoing, and other brain regions are also being investigated
The possible role of stress and the hypothalamic-pituitary-adrenal axis (HPA axis) in the development of psychosis is also being studied (Corcoran et al. 2001, this
issue). Cortisol levels and other indexes of HPA function are
being monitored in UHR patients to assess whether there is
a relationship between stressful life events, coping strategies, HPA axis functional change, neurocognitive variables,
hippocampal volume change, and development of acute
psychosis. These studies are examining the validity of the
time-honored stress-vulnerability model of psychosis.
Intervention Studies. The aim of treatment provided at
PACE is to reduce a young person's symptoms and, if
possible, to prevent these symptoms from worsening and
developing into acute psychosis. Hence, there are two
clinical foci, one immediate and linked to presenting syndromes and problems, and the second preventive and
aimed at reducing the risk of a future syndrome developing. The more proximal syndrome or target to be prevented is acute psychosis (more than 1 week of sustained
and severe psychosis), with a subsidiary and often more
distal target of schizophrenia itself also in the clinician's
sights. A stress-vulnerability model of the development of
psychosis underpins the treatment approach, incorporating
medical and psychological strategies. Treatment options
are discussed with patients and their families and are
reviewed regularly as mental state changes unfold over
the course of treatment Young people attending the clinic
are allocated to a treatment team consisting of a psychiatrist and a psychologist/case manager.
The medical staff at PACE undertake a range of
assessments, including blood tests and neurological and
physical examinations. The medical staff are also responsible for managing and monitoring medication that may
be prescribed. Furthermore, general physical conditions
are taken into consideration and treated accordingly, with
considerable attention being paid to the way general
health status (e.g., sleep, diet, substance use) may be
affecting mental health.
The psychological treatment provided at the clinic is
primarily based on cognitive-behavioral therapy principles and draws not only on mainstream cognitive-behav-
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
ioral therapy 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. The clinical psychologist working
with the young person also functions as a case manager
and helps connect the young person with housing, education, employment, or other services, as difficulties in these
areas may contribute to the increased risk status through
increasing stress levels. In the Australian setting, such a
blend of case management and psychological intervention
is now commonplace. In addition to providing treatment
for the young person, family members are actively invited
to be involved in both individual sessions and family education sessions. The principle of family involvement is as
central as it is in established schizophrenia, but the focus
and content are obviously different.
The first randomized controlled trial specifically
developed around the needs of the UHR population with
the aim of preventing or delaying the onset of psychosis,
or at least ameliorating presenting symptoms, was conducted at PACE between 1996 and 1999. This was felt to
be required because of the high transition rate in the earlier study, which occurred despite comprehensive psychosocial intervention and active treatment of presenting
syndromes (e.g., depression) and problems. In the randomized controlled trial, the impact of a combined intensive and specific psychological (cognitive) treatment plus
very low dose atypical antipsychotic (risperidone) medication (specific preventive intervention [SPI]; n = 31)
was compared with the effect of supportive therapy
(needs-based intervention [NBI]; n = 28) on the development of acute illness in the high-risk group. At the end of
die 6-month treatment phase, significantly more subjects
in the NBI group had developed an acute psychosis than
had subjects in die SPI group (p = 0.026). This difference
was no longer significant at die end of a posttreatment 6month followup period (p = 0.16), although it did remain
significant for die risperidone-adherent subgroup of cases.
This result suggests that it is possible to delay die onset of
acute psychosis in die SPI group compared with the NBI
group. Both groups experienced a reduction in global psychopathology and improved functioning over die treatment and followup phases compared with entry levels
(McGorry et al. 2002). Longer term followup of die participants in this study is now taking place. A second randomized trial commenced in 2000. This is a more sophisticated study with three treatment groups and blind
randomization to these groups. The three groups are (1)
risperidone (antipsychotic medication—up to 2 mg) and
cognitive-behavioral dierapy, (2) placebo and cognitive-
behavioral dierapy, and (3) placebo and befriending. All
treatments are offered for 12 months. Participants are
interviewed monthly to assess side effects and die impact
of die treatments and are men interviewed for a further 12
months to determine die long-term impact of the treatment.
Young people who attend PACE but who do not wish
to be involved in a clinical trial are still provided with
comprehensive treatment (but not antipsychotic medication) for dieir presenting clinical problems, as it is felt (as
noted above) diat it is unediical to witiihold treatment for
current problems—particularly from mose who are seeking it. This treatment is governed by a specified clinical
padiway (figure 1). All clients are assigned a case manager who provides practical assistance, supportive counseling, and more specific interventions (e.g., antidepressants and cognitive-behavioral therapy if necessary).
Ethics. Obviously, mere are many ediical questions surrounding this clinical research endeavor. They have been
at the forefront of me planning and development of PACE
(Yung and McGorry 1997). We have consulted extensively widi our local institutional review board (TRB) and
family and consumer organizations at each stage of the
evolution of our clinical research strategy. This has
enabled us to be sensitive to and address the risks of
stigma and labeling and has increased our confidence that
we are appropriately responding to a significant clinical
need. The IRB members (some of whom are caregivers
for people with serious mental illness) appreciated die
efforts to provide low-stigma access to young people and
to examine the risks as well as die benefits of intervention
but clearly saw mese as second order issues; die primary
goal remained providing much more timely access to
help. Their confidence in our strategy was enhanced by
tiieir firsthand knowledge of our local commitment and
track record in providing and improving mental healdi
services for young people over more man a decade—
efforts independent of our research agenda. This has led to
a high degree of trust and mutual understanding between
the IRB, consumer organizations, and our clinical
research endeavor, but the IRB's independence of view
has never been compromised. Ediical considerations have
been addressed at a number of forums and in recent journal articles (DeGrazia 2001; Heinssen et al. 2001;
McGlashan 2001; McGorry et al. 2001; Schaffner and
McGorry 2001; Wyatt and Henter 2001; Bentall and
Morrison 2002). These questions include the following:
1. Should antipsychotic medication be used in such a heterogeneous group of individuals who do not fulfill
diagnostic criteria for psychosis at the time of treatment?
780
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
"Close-in" or Ultra High-Risk Model
Figure 1. Clinical pathway for ultra high-risk or subthreshold patients in PACE clinic
1
Referral Sources
Triage & Assessment
/
Failed to
attend/engage
Meets UHR criteria?
I
Yes
Referral to other
clinical service
Offered clinical care
7
Offer accepted
Offer rejected
Clinical trial
participation
offered
referred back to
referral agent or
elsewhere
""Rejected
Accepted
/
Needs Based Intervention (NBI) & regular monitoring
for at least 12 months.
• 2-4 weekly visits with psychiatrist & case manager
• supportive psychotherapy & problem solving
• family psychoeducation & support
• specific treatment of clinical syndromes esp. anxiety,
depression & substance abuse
• careful monitoring of level of positive psychotic mood
symptoms, risk of self harm & functional status
• if meets criteria for acute psychosis - antipsychotic
medications offered/commenced with referral to EPPIC
or other specialist mental health agency
781
Enter RCT
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
2. Should treatment studies with this cohort be naturalistic, blinded, or randomized?
chotic illnesses, including schizophrenia, but this reassuring experience cannot necessarily be generalized and
needs to be demonstrated empirically.
3. Should minors (the definition varies across cultures) be
included in this research?
International Experience With the UHR
Paradigm
4. Will individuals who meet UHR criteria but turn out to
have been incorrectly labeled—at least in the short
term—(false positives) be harmed by the treatment
approaches offered?
Since the late 1990s, several other international centers
have established clinical research programs focusing on
the prepsychotic or prodromal phase of illness. While
many of them have been influenced by the PACE
model, others (e.g., the FETZ centre in Cologne) derive
from a different tradition and have developed different
criteria. Centers or clinics have been established in the
United States (6), Canada (2), Germany (1), the United
Kingdom (2), Australia (2), and Norway (1) (Cornblatt
et al. 1998, 2002; Carr et al. 2000; Bechdolf et al. 2002;
Cadenhead 2002; Cannon, personal communication,
2002; Johns et al. 2002; Larsen 2002; McFarlane et al.
2002; Miller et al. 2002; Morrison et al. 2002;
McGlashan et al. 2003). Some of these have been
described in this issue of the journal; a more detailed
description of each initiative is beyond the scope of this
article. There has been good communication and cooperation between all of these centers through a network
structure during recent years, and consequently the
research approach has remained relatively homogeneous across centers during this period. The main
lessons learned are summarized in table 4. Nevertheless, important local variables and valid differences of
opinion have created variation in the clinical criteria,
research strategy, and treatment approach in different
settings. These commonalities and differences are summarized below.
5. Should the level of risk a patient has for the development of psychosis be made explicit to that patient, and
how should this be done?
6. Do the potential benefits of proposed preventive interventions outweigh the potential side effects?
7. Does this form of early intervention stigmatize and
unnecessarily label the young person?
8. Can the patient give "informed consent" to a prophylactic treatment given the unknown degree of risk being
faced?
Obviously, these are all legitimate areas of concern.
We are currently in a state of "equipoise" in relation to the
issue of medication, particularly neuroleptics, in the UHR
group (McGlashan 2001). That is, it is not clear whether
such treatment will be of benefit, but there is sufficient
evidence to suggest that further clinical trials are warranted. Hence, those affiliated with the PACE Clinic
believe that psychopharmacological 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 are highest) at present However, the widespread use of antipsychotic medication outside the protection and close monitoring
afforded by a clinical trial, such as in naturalistic studies
where clinician's choice prevails, is not recommended.
Our experience in the PACE Clinic is 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.
We believe that such treatment is not currently sufficiently
evidence-based and should be rigorously evaluated. The
effects of stigma also need to be investigated. In some settings, if there is an inappropriately pessimistic mindset
linked to the diagnosis of schizophrenia or psychotic disorder (a widespread phenomenon still) and the treatment
is provided in a traditional mental health service, there
may indeed be iatrogenic effects of this type in the newly
identified UHR patient. We have not seen such impact in
the PACE Clinic, where an optimistic attitude is consistently projected about prospects for patients with psy-
Commonalities Among Centers
1. All centers attempt to identify young people in their
teens and twenties suspected to be at high risk of psychosis in the near future; that is, they are trying to pick
up those in the prodromal phase of illness. This
involves community-based educational and recruitment
strategies.
2. All services utilize criteria that involve mental state
changes, and in most, family history and functional
decline also contribute to the entry criteria.
3. Help-seeking by the young people in their own right or
on their behalf by relatives or friends is a requirement
for entry. Those who do not wish to receive assistance
cannot be compelled to attend. Screening for asymptomatic, non-help-seeking, nondistressed young people
does not occur.
782
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
Table 4. The prepsychotic phase: The lessons so far
It is possible to provide access for and engage in clinical care a subset of young people at substantially increased risk
for first episode psychosis.
The provision of a quality clinical service to both participants and nonpartidpants in research studies is essential.
Capacity and expertise in treating nonpsychotic disorders in young people must be available.
Reliable and valid operational criteria for ultra high risk of early transition to psychosis can be developed. Clinical
research interview schedules to rate these features can be developed and utilized in treatment settings.
Clinical criteria seem to be the best immediate predictors of transition so far.
Stigma and sequelae of labeling can be minimized by creating a youth-friendly environment combined with a realistically optimistic attitude to the treatment of psychotic disorders.
It is possible to openly discuss current problems and the risk of future disorders, namely psychosis and schizophrenia,
with patients and families, provided the clinician does not have a pessimistic or therapeutically nihilistic attitude
regarding these disorders.
This clinical phase is dynamic, and progression to psychosis seems not to be predetermined. It also seems possible to
at least delay progression to psychosis in a proportion of cases.
The terms ultra high risk or at-risk mental states better reflect the clinical focus of this work than the term prodrome,
which runs the risk of becoming reified as a quasi-disorder in itself. The term chosen needs to make clear that we are
dealing with a clinical state that indicates risk.
A broad range of biological and psychosocial interventions are likely to be effective.
Good communication with all stakeholders, especially patients, families, funding agencies, other clinicians, and institutional review boards, is essential. Judicious and cautious use of the media can also be helpful.
Providing access to a proportion of patients in this incipient or subthreshoid phase enables unique studies of the onset
process from clinical, biological, and epidemiological perspectives to be conducted. These studies, including imaging,
are acceptable to many patients, and valid informed consent to participation in research is more readily obtained than
in established psychotic disorder.
The base rate for transition has been relatively reproducible across the various centers, but despite the criteria for ultra
high risk and for transition being carefully operationalized, base rates may still fluctuate. This is probably because of
differing base rates according to referral source (variable "enrichment" of sample) and differing thresholds and interpretations for the criteria themselves between individual raters and across centers.
The lessons from screening and early detection strategies for subciinicai disorder in general medicine have been poorly
understood and applied in psychiatry. Examples include screening for cancer, especially breast and cervical cancer,
and the detection and treatment of transient ischemic attacks to prevent stroke.
The concept of staging could be better developed in psychiatry.
4. Funding is usually provided through research grants,
and the center is therefore rarely a stable element of the
local service system.
8. Transition rates are comparable across centers,
ranging from 22 percent to 54 percent within 12
months.
5. All centers provide a clinical service as well as conducting research and evaluation of interventions. It
appears that no programs offer clinical services without
research occurring.
Differences Between Centers
1. Criteria for entry and transition to psychosis are
similar but not identical across centers. The greatest
difference lies between the Cologne model and the
others, but there are increasing differences between
the transition criteria for the PRIME group
(McGlashan et al. 2003), the recognition and prevention (RAP) group (Cornblatt et al. 2002), and the
PACE group.
6. There are two discrete but overlapping clinical foci: management of current difficulties, and monitoring and possible prevention or attenuation of emerging psychosis.
7. Where antipsychotic medications are offered, low
doses of atypical agents are the norm.
783
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGony et al.
2. Some centers have pursued an approach based on the
need for randomized controlled trial data to evaluate
the differential efficacy of alternative treatments. Others have preferred to conduct naturalistic follow-along
studies in which treatment has been deregulated. This
has been largely driven by local research funding policies. In practice, the latter approach has had the effect
of allowing liberal use of antipsychotic medications to
occur in this population.
or from the side effects of treatment. So far, there is
some evidence from trials of mild/moderate side effects
where atypical antipsychotic agents have been used.
Mild sedation and modest weight gain have been
reported. However, patients have been free to withdraw
from the research and cease medication if these effects
concern them, and indeed the withdrawal rate in these
studies has been appreciable, although for a variety of
reasons, not merely adverse events. No ill-effect of psychosocial intervention has so far been recorded. Indeed,
when 6- and 12-month ratings of psychopathology and
functioning are contrasted with baseline scores, all
patients entering the PACE Clinic improve substantially—including those who progressed to first episode
psychosis and were promptly treated (McGorry et al.
2002). Engagement and retention rates in the clinic are
high (over 70%), and the acceptability of the model as a
whole to young people, their families, and local IRBs
has been very high as well. These features need to be
more systematically measured to reassure those who are
concerned about these issues.
Another obvious limitation is related to the population-attributable risk of the UHR criteria and hence the
generalizability and clinical utility of this early intervention approach. Although transition rates are high
within this group, most cases of first episode psychosis
are not currently identified as UHR prior to detection of
the full-blown syndrome (although the Portland
Identification and Early Referral [PIER] program suggests this may be possible) (McFarlane et al. 2002).
This low yield is a structural consequence of any
screening process, even though here the "screening" is
relatively reactive, nonsystematic, and clinically based.
Although the risk is substantially higher in the UHR
group and the false-positive problem can be greatly
minimized, most cases of first episode psychosis still
come from the low-risk and undetected groups. This
places a ceiling on the utility of the strategy, as pointed
out by Warner (2001), and is a fact of life for any form
of screening, even a clinically grounded variant like
this. However, we contend that the strategy still has
substantial value and that the ceiling may be able to be
raised using broader enrichment strategies via a youth
mental health model (see below).
3. Some centers have close relationships with first episode
psychosis programs, while others are stand-alone "prodromal" clinics.
4. Neurobiological research is central to several research
programs but has not been part of the focus of others.
Unsolved Problems
Despite a number of publications and a prominent presence at recent psychiatry conferences, especially schizophrenia conferences, the aims of this field of clinically oriented research remain unclear to many. Similar issues
have also been faced in early intervention in serious medical disorders, and experience there could be usefully
applied in psychiatry. This lack of understanding has
resulted in potentially inappropriate impediments being
placed in the way of further progress in this field. There
is also concern that this approach to identifying individuals and providing treatment prior to the onset of acute
phases of disorder is an attempt to medicalize distress in
adolescence rather than an effort to identify the early
stages of serious mental illness in the context of a broad,
flexible approach to youth mental health issues. These
misunderstandings appear to have had a greater impact
in some countries than they have in others and have
influenced research funding policies. In Australia, such
concerns have so far been assuaged through close dialogue and consultation with, and subsequent support of,
consumer and caregiver groups; an open relationship
with ethics committees that oversee psychiatric
research; and cautious use of the media to inform the
community about progress. A positive reputation and
demonstrated commitment to comprehensive services
for young people in general have also helped this
endeavor to move forward in a broader context than the
treatment of schizophrenia per se.
Nevertheless, for progress to occur, a genuine effort
to address obvious and legitimate concerns is not only
appropriate but necessary. The most pressing of these
concerns relates to fears concerning possible harm to
the false-positive group, which represents one-half to
two-thirds of the UHR population currently identified.
Harm could flow from the effects of stigma and labeling
It could be argued that one possible contributing
factor is that health and educational professionals do not
yet apply the UHR criteria widely enough and that if
they were publicized more broadly, perhaps more UHR
young people could be encouraged to seek help. This
belief has led some to suggest that large-scale active
screening may be justified (e.g., in schools) to identify
students with high levels of attenuated psychotic symptoms and promote them into a clinical service. However,
784
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
recent community surveys (Eaton 1995; van Os et al.
2000, 2001) have suggested that attenuated and even
frank psychotic symptoms are not uncommon in the
general population, with lifetime prevalence estimates
of 12 percent (Tien et al. 1992) to 17.5 percent (van Os
et al. 2000) for some positive "psychotic-like" symptoms. Many people experiencing these phenomena
were not distressed by them and did not seek help, in
contrast to those who request treatment from high-risk
services such as PACE. It is not fully clear what degree
risk of psychosis is associated with these nondistressing attenuated symptoms, although it could be greater
than estimated by van Os et al. (2001) because a lack
of awareness of impairment is commonly associated
with psychotic experience. It is readily conceded, however, that it may be unwise to embark on such a screening strategy now, unless its focus includes a broad
range of mental disorders, because the accuracy of prediction of true clinical disorder will probably be low
and there may be significant risks associated. More
research is needed into community samples to investigate stability and outcome of attenuated and frank psychotic symptoms that do not come to the attention of
clinical services.
have been critical of the use of antipsychotic medications
in randomized controlled trials with prepsychotic patients.
However, unless naturalistic studies are tightly protocol
limited, the use of antipsychotics, driven by clinician's
choice or consumer pressure, is likely to be very widespread. While it will be possible to measure adverse
effects of such use, any benefits will be difficult to determine.
Second, open trials of specific agents or of specific
psychosocial interventions have a place because they
would involve adherence to a specific protocol with measurement of benefits and harm.
Third, both open and double-blind placebo-controlled
randomized trials are clearly justified in a field where the
value of all interventions remains in equipoise. Such trials
are more demanding to perform and generally require a
multicenter approach, yet they yield higher quality data
and evidence and involve better measurement of adverse
events and a higher standard of informed consent for consumers and families.
Future Progress
The Youth Model. Because of the low annual incidence
rates, trying to detect young people at risk of psychosis
has been likened to searching for a needle in a haystack
(Jones 2000). However, one approach to making this
task feasible could be the development of a comprehensive youth mental health service with the capacity to
manage young people with established and emerging
nonpsychotic as well as psychotic disorders. This service
would therefore aim to find not just needles but all sharp
metallic objects, which could be attracted via a "magnetic" clinical strategy (an attractive youth-friendly
environment) and sorted out later. Enriched samples of
this type would give predictive measures a much better
chance of accuracy. Community links and secondary
consultation with primary care, education, and other
youth services would increase the ability of the program
to provide assistance to young people with a range of
problems and turn the ubiquitous comorbidity seen in
young people from a diagnostic problem into an opportunity. Many young people may move in and out of
ARMS, and the ability to monitor them and provide
timely intervention as appropriate may aid our understanding of the process of onset not only for psychosis
but for other syndromes, and also our ability to provide
preventive treatment. Perhaps this is one type of "naturalistic" approach that should be supported.
Intervention Research: What
Methodologies Are Relevant?
The growth of the UHR or prodromal field was catalyzed
by naturalistic follow-along studies that demonstrated that
relatively simple clinical criteria were capable of predicting rapid transition to first episode psychosis under certain
conditions, despite the availability of need-based clinical
care (Yung et al. 1998, 2003). The replication of this finding in several centers demonstrated that a highly incipient
group of cases could be reliably recognized and safely
engaged in clinical care. What methodologies are available to further clarify the appropriate range of interventions in such cases?
First, further naturalistic follow-along studies could
be considered. The advantages of these are that further
data can be collected with the same or different criteria
sets to enlarge and refine the evidence base for prediction
of outcome. This approach will have maximum value if
the treatment options are restricted to interventions that
target major presenting problems (e.g., depression, interpersonal problems) rather than those that may more powerfully influence the process of transition to first episode
psychosis (e.g., antipsychotic medications, potential neuroprotective agents such as lithium and eicosapentaenoic
acid). A minimalistic or safety net approach to intervention is probably ideal. Supporters of this methodology
Neuroprotection. It is becoming more likely that the
onset phase of illness during which clinical features and
functional impairment emerge for the first time is associ-
785
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
ated with active yet subtle neurobiological changes in
the patient (Pantelis et al. 2003a). In contrast to the original neurodevelopmental model of schizophrenia
(Weinberger 1995), which proposed a dormant lesion
that becomes activated around the time of adolescence,
it seems that complex neuronal dysfunction may develop
as a new process around the time of psychosis onset
(Pantelis et al. 20036). Thus early treatment, before fullblown psychotic disorder occurs, may prevent some
brain changes and thus alter the neurobiological pattern
of illness (Wolkin and Rusinek 2002). Earlier crude
models of neurotransmitter imbalance, derived in reverse
from the mechanism of action of psychotropic medications, may ultimately give way to models based on intracellular disturbances and influences via gene expression
upon neuronal integrity and connectivity (Berger et al.
2003). The therapeutic paradigm linked to such models
is neuroprotection. If neuroprotective agents, such as
lithium (Manji et al. 1999) and eicosapentaenoic acid
(Berger et al. 2002, 2003), which have been shown in
laboratory models to have specific neuroprotective
effects, could be shown to reduce the risk of progression
from early to more severe forms of disorder, then early
intervention would receive even stronger support as a
strategy.
References
Agerbo, E.; Byrne, M.; Eaton, W.W.; and Mortensen, P.B.
Schizophrenia, marital status, and employment: A fortyyear study. [Abstract]. Schizophrenia Research, 60(l):32,
2003.
Andreasen, N. Negative symptoms in schizophrenia:
Definition and reality. Archives of General Psychiatry,
39:784-788, 1982.
Asarnow, J.R. Children at risk for schizophrenia:
Converging lines of evidence. Schizophrenia Bulletin,
14(4):613-631, 1988.
Bechdolf, A.; Wagner, M.; and Hambrecht, M.
Psychological intervention in the pre-psychotic phase:
Preliminary results of a multicentre trial. Acta
Psychiatrica Scandinavica, 106:41, 2002.
Bell, R.Q. Multiple-risk cohorts and segmenting risk as
solutions to the problem of false positives in risk for the
major psychoses. Psychiatry, 55(4):370-381, 1992.
Bentall, R.P., and Morrison, A.P. More harm than good:
The case against using antipsychotic drugs to prevent
severe mental illness. Journal of Mental Health,
11:351-356,2002.
Berger, G.E.; Wood, S.; and McGorry, P.D. Incipient neurovulnerability and neuroprotection in early psychosis.
Psychopharmacology Bulletin, 37(2):79-101, 2003.
Conclusion
Berger, G.E.; Wood, S.J.; Pantelis, C ; Velakoulis, D.;
Wellard, RM:, and McGorry, P.D. Implications of lipid biology for the pathogenesis of schizophrenia. Australian and
New Zealand Journal of Psychiatry, 36(3):355-366, 2002.
This article has explored the development and expansion
of services specifically designed for the detection, monitoring, and treatment of the prepsychotic or UHR phase
of illness and the study of the psychobiological processes
contributing to onset. The conceptual underpinnings,
practical issues, and ethical issues related to UHR
research and clinical intervention have been described.
This is truly a growth area with the potential to benefit
such symptomatic UHR young people and their families.
Our ability to identify those at particularly high risk is
being refined and the biological basis for psychosis onset
investigated. Caution must be exercised, however, and
each step evaluated in an evidence-based manner. Continued modification of UHR criteria and a better understanding of the process of screening and sample enrichment may be needed. Randomized clinical 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.
Buckley, PR The clinical stigmata of aberrant neurodevelopment in schizophrenia. Journal of Nervous and
Mental Disease, 186:79-86, 1998.
Cadenhead, K.S. Vulnerability markers in the schizophrenia spectrum: Implications for phenomenology, genetics,
and the identification of the schizophrenia prodrome.
Psychiatric Clinics of North America, 25:837-853, 2002.
Cannon, T.D., and Mednick, S.A. The schizophrenia highrisk project in Copenhagen: Three decades of progress.
Acta Psychiatrica Scandinavica, 87(Suppl 370):33-47,
1993.
Carr, V.; Halpin, S.; Lau, N.; O'Brien, S.; Beckmann, J.;
and Lewin, T. A risk factor screening and assessment protocol for schizophrenia and related psychosis. Australian
and
New
Zealand
Journal
of
Psychiatry,
34(Suppl):S170-S180,2000.
Corcoran, C ; Gallitano, A.; Leitman, D.; and Malaspina,
D. The neurobiology of the stress cascade and its potential
relevance for schizophrenia. Journal of Psychiatric
Practice, 7:3-14,2001.
786
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
Corcoran, C ; Walker, E.; Huot, R.; Mittal, V.; Tessner, K.;
and Kestler, L. The stress cascade and schizophrenia:
Etiology
and
onset.
Schizophrenia
Hafner, H.; Maurer, W.; Loffler, B.; Bustamante, S.; an
der Heiden, W.; and Nowotny, B. Onset and early course
of schizophrenia. In: Hafner, H., and Gattaz, W.F., eds.
Search for the Causes of Schizophrenia. Vol. 3. New York,
NY: Springer, 1995. pp. 43-66.
Bulletin,
29(4):671-692, 2003.
Cornblatt, B.A. The New York High Risk Project to the
Hillside Recognition and Prevention (RAP) Program.
American Journal of Medical Genetics (Neuropsychiatric
Genetics), 114:956-966, 2002.
Heinssen, R.K.; Perkins, D.O.; Appelbaum, P.S.; and
Fenton, W.S. Informed Consent in Early Psychosis
Research: National Institute of Mental Health workshop,
November
Cornblatt, B.; Lencz, T.; Correll, C ; Authour, A.; and
Smith, C. Treating the prodrome: Naturalistic findings
from the RAP Program. Acta Psychiatrica Scandinavica,
106(Suppl):44, 2002.
15, 2000. Schizophrenia
Bulletin,
27(4):571-583, 2001.
Hodges, A.; Byrne, M.; Grant, E.; and Johnstone, E.
People at risk of schizophrenia: Sample characteristics of
the first 100 cases in the Edinburgh high-risk study.
British Journal of Psychiatry, 174:547-553, 1999.
Cornblatt, B.; Obuchowski, M ; Schnur, D.; and O'Brien,
J.D. Hillside study of risk and early detection in schizophrenia. British Journal of Psychiatry, 172(33):S26-S32,
1998.
Ingraham, L.J.; Kugelmass, S.; Frenkel, E.; Nathan, M.;
and Mirsky, A.F. Twenty-five-year followup of the Israeli
High-Risk Study: Current and lifetime psychopathology.
Schizophrenia Bulletin, 21(2):183-192, 1995.
DeGrazia, D. Ethical issues in early-intervention clinical
trials involving minors at risk for schizophrenia.
Schizophrenia Research, 51:77-86, 2001.
Ismail, B.; Cantor-Graae, E.; and McNeil, T.F. Neurological
abnormalities in schizophrenic patients and their siblings.
American Journal of Psychiatry, 155:84-89,1998.
Eaton, W.W. Prodromes and precursors: Epidemiologic
data for primary prevention of disorders with slow onset.
American Journal of Psychiatry, 152:967-972, 1995.
Johns, L.; Broome, M.; Matthiasson, P.; Power, P.; and
McGuire, P.K. OASIS: A new service for people with prodromal signs of psychosis. Acta
Psychiatrica
Scandinavica, 106:73, 2002.
Edwards, J.; Francey, S.M.; McGorry, P.D.; and Jackson,
H.J. Early psychosis prevention and intervention:
Evolution of a comprehensive community-based specialised service. Behaviour Change, ll(4):223-233,
1994.
Johnstone, E.C.; Abukmeil, S.S.; Byrne, M.; Clafferty, R.;
Grant, E.; Hodges, A.; Lawrie, S.M.; and Owens, D.G.C.
Edinburgh high risk study—findings after four years:
Demographic, attainment and psychopathological issues.
Schizophrenia Research, 46:1-15, 2001.
Jones, P. 'The Epidemiology of Psychotic Disorder."
Keynote address at "Future Possible" 2nd International
Conference on Early Psychosis, New York, NY, March
and April 2000.
Edwards, J., and McGorry, P.D. Implementing Early
Intervention in Psychosis: A Guide to Establishing Early
Psychosis Services. London, U.K.: Martin Dunitz, 2002.
Erlenmeyer-Kimling, L.; Adamo, U.H.; Rock, D.;
Roberts, S.A.; Bassett, A.S.; Squirres-Wheeler, E.;
Cornblatt, B.A.; Endicott, J.; Pape, S.; and Gottesman, I.I.
The New York High-Risk Project: Prevalence and comorbidity of Axis I disorders in offspring of schizophrenic
parents at 25-year follow-up. Archives of General
Psychiatry, 54:1096-1102, 1997.
Jones, P.; Rodgers, B.; Murray, R.; and Marmot, M. Child
development risk factors for adult schizophrenia in the
British 1946 birth cohort. Lancet, 344:1398-1402, 1994.
Erlenmeyer-Kimling, L.; Squires-Wheeler, E.; Adamo,
U.H.; Bassett, A.S.; Cornblatt, B.A.; Kestenbaum, C.J.;
Rock, D.; Roberts, S.A.; and Gottesman, I.I. The New
York High-Risk Project: Psychoses and cluster A personality disorders in offspring of schizophrenic parents at 23
years of follow-up. Archives of General Psychiatry,
52:857-865, 1995.
Kay, S.R.; Fiszbein, A.; and Opler, L.A. The Positive and
Negative Syndrome Scale (PANSS) for schizophrenia.
Schizophrenia Bulletin, 13(2):261-276, 1987.
Kendler, K.S. Genetics of schizophrenia. In: Frances, A.J.,
and Hales, R.E., eds. American Psychiatric Association
Annual Review. Washington, DC: American Psychiatric
Press, 1986.
Fish, B.; Marcus, J.; Hans, S.L.; Auerbach, J.G.; and
Perdue, S. Infants at risk for schizophrenia: Sequelae of a
genetic neurointegrative defect. Archives of General
Psychiatry, 49:221-235, 1992.
KlosterkGtter, J.; Gross, G.; Wieneke, A.; Steinmeyer,
E.M.; and Schultze-Lutter, F. Evaluation of the 'Bonn
Scale for the Assessment of Basic Symptoms—BSABS'
as an instrument for the assessment of schizophrenia
proneness: A review of recent findings. Neurology,
Psychiatry, and Brain Research, 5:137-150, 1997.
Gross, G. The 'basic' symptoms of schizophrenia. British
Journal of Psychiatry, 155(Suppl 7):21-25, 1989.
787
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
Klosterkatter, J.; Hellmich, M.; Steinmeyer, E.M.; and
Schultze-Lutter, F. Diagnosing schizophrenia in the initial
prodromal phase. Archives of General
Psychiatry,
58:158-164,2001.
McGorry, P.D.; Edwards, J.; Mihalopoulos, C ; Harrigan,
S.M.; and Jackson, H.J. EPPIC: An evolving system of
early detection and optimal management. Schizophrenia
Bulletin, 22(2):305-326, 1996.
Koehler, K., and Sauer, H. Huber's basic symptoms:
Another approach to negative psychopathology in schizophrenia. Comprehensive Psychiatry, 25:174-182, 1984.
McGorry, P.D.; Goodwin, R.J.; and Stuart, G.W. The
development, use and reliability of the Brief Psychiatric
Rating Scale (Nursing Modification)—an assessment procedure for the nursing team in clinical and research settings. Comprehensive Psychiatry, 29:575-587, 1988.
Krstev, H.; Carbone, S.; Harrigan, S.M.; McGorry, P.D.;
Curry, C ; and Elkins, K. Early intervention in first
episode psychosis: The impact of a community development campaign. Submitted for publication.
McGorry, P.D., and Singh, B.S. Schizophrenia: Risk and
possibility. In: Raphael, B., and Burrows, G.D., eds.
Handbook of Studies on Preventive
Psychiatry.
Amsterdam: Elsevier, 1995. pp. 491-514.
Larsen, T.K. The transition from the premorbid period to
psychosis: How can it be described? Ada Psychiatrica
Scandinavica, 106(Suppl): 10-11, 2002.
McGorry, P.D., and Yung, A.R. Early intervention in psychosis: An overdue reform. Australian and New Zealand
Journal of Psychiatry, 37:393-398, 2003.
Lieberman, J.A., and Fenton, W.S. Delayed detection of
psychosis: Causes, consequences, and effect on public
health. American Journal of Psychiatry, 157:1727-1730,
2000.
McGorry, P.D.; Yung, A.R.; and Phillips, L.J. Ethics and
early intervention in psychosis: Keeping up the pace and
staying in step. Schizophrenia Research, 51:17-29,
2001.
Malla, A.K., and Norman, R.M.G. Early intervention in
schizophrenia and related disorders: Advantages and pitfalls. Current Opinion in Psychiatry, 15:17-23, 2002.
Manji, H.K.; McNamara, R.; Chen, G.; and Lenox, R.H.
Signalling pathways in the brain: Cellular transduction of
mood stabilisation in the treatment of manic-depressive
illness. Australian and New Zealand Journal of
Psychiatry, 33(Suppl):S65-S83, 1999.
McFarlane, W.R.; Cook, W.L.; Robbins, D.; and
Downing, D. Portland identification and early referral.
Acta Psychiatrica Scandinavica, 413:20, 2002.
McGorry, P.D.; Yung, A.R.; Phillips, L.J.; Yuen, H.P.;
Francey, S.; Cosgrave, E.M.; Germano D.; Bravin, J.;
Adlard, S.; McDonald, A.; Blair, A.; and Jackson, H.J. A
randomized controlled trial of interventions designed to
reduce the risk of progression to first episode psychosis in
a clinical sample with subthreshold symptoms. Archives
of General Psychiatry, 59:921-928, 2002.
McGuffin, P.; Farmer, A.E.; Gottesman, M.; Murray,
R.M.; and Reveley, A.M. Twin concordance for operationally defined schizophrenia. Archives of General
Psychiatry, 49:541-545, 1984.
McGlashan, T.H. Duration of untreated psychosis in firstepisode schizophrenia: Marker or determinant of course?
Biological Psychiatry, 47A73, 1999.
Meares, A. The diagnosis of prepsychotic schizophrenia.
Lancet, 1:55-59, 1959.
McGlashan, T.H. Psychosis treatment prior to psychosis
onset: Ethical issues. Schizophrenia Research, 51:47-54,
2001.
McGlashan, T.H.; Zipursky, R.B.; Perkins, D.; Addington,
J.; Miller, T.J.; Woods, S.W.; Hawkins, K.O.A.; Hoffman,
R.; Lindborg, S.; Tohen, M.; and Breier, A. The PRIME
North America randomized double-blind clinical trial of
olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis: I. Study rationale
and design. Schizophrenia Research, 61(1): 7—18, 2003.
Miller, T.J.; McGlashan, T.H.; Rosen, J.L.; Somjee, L.;
Markovich, P.J.; Stein, K.; and Woods, S.W. Prospective
diagnosis of the initial prodrome for schizophrenia based
on the Structured Interview for Prodromal Symptoms:
Preliminary evidence of interrater and predictive validity.
American Journal of Psychiatry, 159:863-865, 2002.
Miller, T.J.; McGlashan, T.H.; Woods, S.W.; Stein, K.;
Briesen, N.; Corcoran, CM.; Hoffman, R.; and Davidson,
L. Symptom assessment in schizophrenic prodromal
states. Psychiatric Quarterly, 70:273-287, 1999.
McGorry, P.D. Early Psychosis Prevention and
Intervention Centre. Australian Psychiatry, 1:32-34, 1993.
McGorry, P.D. A treatment-relevant classification of psychotic disorders. Australian and New Zealand Journal of
Psychiatry, 29(4):555-558, 1995.
Morrison, A.P.; Bentall, R.P.; French, P.; Walford, L.;
Kilcommons, A.; Knight, A.; Kreutz, M.; and Lewis, S.W.
Randomised controlled trial of early detection and cognitive therapy for preventing transition to psychosis in highrisk individuals. Study design and interim analysis of
transition rate and psychological risk factors. British
Journal of Psychiatry, 43(Suppl):S78-S84, 2002.
McGorry, P.D. Early psychosis reform: Too fast or too
slow? Acta Psychiatrica Scandinavica, 106:249-251,
2002.
788
"Close-in" or Ultra High-Risk Model
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
Mrazek, P.J., and Haggarty, R.J. Reducing Risks for
Mental Disorders: Frontiers for Preventive Intervention
Research. Washington, DC: National Academy Press,
1994.
Van Os, J.; Fahy, P.; Bebbington, P.; Jones, P.; Wilkins, S.;
Sham, P.; Russell, A.; Gilvarry, K.; Lewis, S.; Toone, B.;
and Murray, R. The influence of life events on the subsequent course of psychotic illness: A prospective follow-up
of the Camberwell Collaborative Psychosis Study.
Psychological Medicine, 24:503-513, 1994.
Nagler, S. Overall design and methodology of the Israeli
high-risk study. Schizophrenia Bulletin, 11(1):31—37,
1985.
Van Os, J.; Hanssen, M.; Bijl, R.V.; and Ravelli, A.
Strauss (1969) revisited: A psychosis continuum in the
general population? Schizophrenia Research, 45:11-20,
2000.
Olin, S.C., and Mednick, S.A. Risk factors of psychosis:
Identifying vulnerable populations premorbidly.
Schizophrenia Bulletin, 22(2):223-240, 1996.
Van Os, J.; Hanssen, M.; Bijl, R.V.; and Vollebergh, W.
Prevalence of psychotic disorder and community level of
psychotic symptoms. Archives of General Psychiatry,
58:663-668, 2001.
O'Reilly, R.L. Viruses and schizophrenia. Australian and
New Zealand Journal of Psychiatry, 28:222-228, 1994.
Overall, J.E., and Gorham, D.R. The Brief Psychiatric
Rating Scale. Psychological Reports, 10:799-812, 1962.
Velakoulis, D.; Wood, SJ.; McGorry, P.D.; and Pantelis,
C. Evidence for progression of brain structural abnormalities in schizophrenia: Beyond the neurodevelopmental
Pantelis, C ; Velakoulis, D.; McGorry, P.D.; Wood, S.J.;
Suckling, J.; Phillips, L.J.; Yung, A.R.; Bullmore, E.T.;
Brewer, W.; Soulsby, B.; Desmond, P.; and McGuire, P.K.
Neuroanatomical abnormalities before and after onset of
psychosis: A cross-sectional and longitudinal MRI comparison. Lancet, 361(9354):281-288, 2003*.
model. Australian and New Zealand Journal of
Psychiatry, 34(Suppl):S113-S126, 2000.
Warner, R. The prevention of schizophrenia: What interventions are safe and effective? Schizophrenia Bulletin,
27(4):551-562, 2001.
Pantelis, C ; Yucel, M.; and Wood, S.J. Early and late
neurodevelopmental disturbances in schizophrenia and
their functional consequences. Australian and New
Zealand Journal of Psychiatry, 37:399-406, 2003a.
Weinberger, D.R. From neuropathology to neurodevelopment. Lancet, 346:552-557, 1995.
Wolkin, A., and Rusinek, H. A neuropathology of psychosis? Lancet, 361(9354):270-271, 2003.
Wyatt, R.J., and Henter, I. Rationale for the study of
early intervention. Schizophrenia Research, 51:69-76,
2001.
Phillips, L.J.; Leicester, S.B.; O'Dwyer, L.E.; Francey,
S.M.; Koutsogiannis, J.; Abdel-Baki, A.; Kelly, D.; Jones,
S.; Vay, C ; Yung, A.R.; and McGorry, P.D. The PACE
Clinic: Identification and management of young people at
'ultra' high risk of psychosis. Journal of Psychiatric
Practice, 8:255-269, 2002a.
Yolken, R.H.; Karlsson, H.; Yee, F.; Johnston-Wilson,
N.L.; and Torrey, E.F. Endogenous retroviruses and
schizophrenia. Brain Research Reviews, 31:193-199,
2000.
Phillips, L.J.; Velakoulis, D.; Pantelis, C ; Yuen, H.P.;
Yung, A.R.; Desmond, P.; Brewer, W.; and McGorry, P.D.
Non-reduction in hippocampal volume is associated with
higher risk of psychosis. Schizophrenia
Research,
58:145-158,2002*.
Yung, A.R., and McGorry, P.D. The initial prodrome in
psychosis: Descriptive and qualitative aspects.
Australian and New Zealand Journal of Psychiatry,
30:587-599,1996a.
Phillips, L.J.; Yung, A.R.; Hearn, N.; McFarlane, C.A.;
Hallgren, M.; and McGorry, P.D. Preventive mental health
care: Accessing the target population. Australian and New
Zealand Journal of Psychiatry, 33:912-917, 1999.
Yung, A.R., and McGorry, P.D. The prodromal phase of
first-episode psychosis: Past and current conceptualizations. Schizophrenia Bulletin, 22(2):353-370, 1996*.
Schaffner, K.F., and McGorry, P.D. Preventing severe
mental illnesses: New prospects and ethical challenges.
Schizophrenia Research, 51:3-15, 2001.
Yung, A.R., and McGorry, P.D. Is pre-psychotic intervention realistic in schizophrenia and related disorders?
Australian and New Zealand Journal of Psychiatry,
31:799-805, 1997.
Sullivan, H.S. The onset of schizophrenia. American
Journal of Psychiatry, 6:105-134, 1927.
Yung, A.R.; McGorry, P.D.; McFarlane, C.A.; Jackson,
H.J.; Patton, G.C.; and Rakkar, A. Monitoring and care
of young people at incipient risk of psychosis.
Schizophrenia Bulletin, 22(2):283-303, 1996.
Tien, A.Y.; Costa, P.T.; and Eaton, W.W. Covariance of
personality, neurocognition, and schizophrenia spectrum
traits in the community. Schizophrenia
Research,
7:149-158, 1992.
Torrey, E.F. Stalking the schizovirus.
Bulletin, 14{2):223-229, 1988.
Yung, A.R.; McGorry, P.D.; McFarlane, C.A.; and
Patton, G.C. The PACE Clinic: Development of a clini-
Schizophrenia
789
Schizophrenia Bulletin, Vol. 29, No. 4, 2003
P.D. McGorry et al.
cal service for young people at high risk of psychosis.
Australian Psychiatry, 3:345-349, 1995.
Yung, A.R.; Phillips, L.J.; McGorry, P.D.; Hallgren,
M.A.; McFarlane, C.A.; Jackson, H.J.; Francey, S.; and
Patton, G.C. Can we predict onset of first episode psychosis in a high risk group? International
Clinical
Psychopharmacology, 13(Suppl l):S23-S30, 1998.
Yung, A.R.; Phillips, L.J.; Yuen, H.P.; Francey, S.M.;
McFarlane, C ; Hallgren, M.; and McGorry, P.D.
Psychosis prediction: 12 month follow-up of a high risk
('prodromal') group. Schizophrenia Research,
60:21-32, 2003.
Alliance for Research on Schizophrenia and Depression,
the Theodore and Vada Stanley Foundation, the Colonial
Foundation, the National Health and Medical Research
Council, and Janssen-Cilag Pty. Ltd. The authors gratefully acknowledge the helpful comments offered on earlier drafts of this manuscript by Dr. Kristin Cadenhead,
CARE program, University of California, San Diego; and
the contributions of the staff and clients of the PACE
Clinic.
The Authors
Patrick D. McGorry, M.D., Ph.D., is Professor and Director of ORYGEN Youth Health and ORYGEN Research
Centre (incorporating EPPIC and PACE), Parkville, Victoria, Australia. Alison R. Yung, M.D., FRANZCP is Associate Professor and Principal Research Fellow, ORYGEN
Research Centre (incorporating EPPIC and PACE),
Parkville, Victoria, Australia. Lisa J. Phillips, B.Sc, is
Research Coordinator of the PACE Clinic, and Research
Fellow ORYGEN Research Centre (incorporating EPPIC
and PACE), Parkville, Victoria, Australia.
Yung, A.R.; Yuen, H.P.; McGorry, P.D.; Phillips, L.; Kelly,
D.; Dell-Olioi, M.; and Francey, S. Mapping the onset of
psychosis—the Comprehensive Assessment of At Risk
Mental States (CAARMS). Submitted for publication.
Acknowledgments
This work was supported by research grants from the Victorian Health Promotion Foundation, the National
790