1. Staging in Neuropsychiatry: A Heuristic Model
for Understanding, Prevention and Treatment
Patrick D. McGorry
Received: 11 November 2009 / Revised: 22 March 2010 / Accepted: 22 March 2010 / Published online: 3 April 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The main mental disorders which develop and
persist through adult life typically emerge during the crit-
ical developmental phase of adolescence and early adult-
hood, and are frequently associated with considerable
associated distress and functional decline. Our current
diagnostic system lacks validity and therapeutic utility,
particularly for the early stages of these mental disorders,
when symptoms are still evolving and may have not yet
stabilised sufficiently to fit familiar or traditional syndro-
mal criteria. Furthermore, there is often difficulty in dis-
tinguishing transient developmental or normative changes
from the early symptoms of persistent and disabling mental
illness. These factors point to the need for reform of our
current diagnostic systems. The clinical staging model
seeks to define the extent of progression of a disorder at a
particular point in time and aims to differentiate early,
milder clinical phenomena from those that accompany
illness progression and chronicity. The staging framework
allows clinicians to select treatments relevant to earlier
stages of an illness, and to evaluate their effectiveness in
preventing progression and producing remission or return
to milder or earlier stages of disorder. For staging to be a
valid approach, interventions in the early stages need to
shown to be not only more effective but also safer than
treatments delivered later in the course of illness. Staging
may also allow a more efficient integration of our rapidly
expanding knowledge of the biological, social and
psychological vulnerability factors involved in develop-
ment of mental illness into what may ultimately resemble a
clinicopathological staging model.
Keywords Clinical staging Á Pluripotential risk
syndrome Á Psychosis Á Schizophrenia Á Bipolar disorder Á
Mood disorder Á Early intervention Á Youth mental health
I feel certain that many incipient cases might be
arrested before the efficient contact with reality is
completely suspended. (Sullivan 1927)
The majority of the psychiatric morbidity which mani-
fests during adult life emerges for the first time before the
age of 25 years, either evolving from childhood emotional
and behavioural disorder, or appearing de novo from
puberty through to the mid-twenties as a surge of new
incident cases (Kessler et al. 2005). Lifetime risk for
mental disorder can reach as much as 50% (Kessler et al.
2005). There are many biological, psychological and
sociological reasons for this pattern of onset (Arnett 2004;
Eckersley 2008; Paus et al. 2008).
The onset of mental disorder can be difficult to distin-
guish from transitory and normative changes in emotions
and behaviour, especially in young people. This is consis-
tent with the high rate of initial resolution, even with min-
imal or no intervention (Stice et al. 2007), which conversely
underestimates the level of underlying chronicity. There are
no clear criteria at present for defining a threshold for initial
‘caseness’, a status most commonly attained in emerging
adulthood. How symptoms are acquired, intensify and
cohere into syndromes, and how these ebb and flow, has not
been widely considered (Eaton et al. 1995). We also lack
valid definitions for distinguishing between benign and
P. D. McGorry
Centre for Youth Mental Health, University of Melbourne,
Melbourne, Australia
P. D. McGorry (&)
Orygen Youth Health Research Centre, Locked Bag 10,
Parkville, VIC 3052, Australia
e-mail: pmcgorry@unimelb.edu.au
Neurotox Res (2010) 18:19–30
DOI 10.1007/s12640-010-9179-x
Originally published in Neurotoxicity Research, Volume 18, Nos. 3-4

2. self-limiting states and states which represent the early
stages of what will become persistent and disabling condi-
tions (Kessler et al. 2005). While much distress seems,
initially at least, self-limiting (Eaton et al. 1995), it is
important not to trivialise the significance of this since sub-
threshold symptoms strongly predict future disorder (Eaton
et al. 1995; Harrington and Clark 1998; Yung et al. 2004a, b;
Hetrick et al. 2008a, b; Seeley et al. 2009). The concepts and
definitions we have used to date, since they are quasi-syn-
dromal, polythetic and descriptive, tend to lack discriminant
validity and therapeutic utility. Arbitrary strategies to force
discriminant validity such as hierarchies, have merely
obscured the problem and are breaking down; however,
currently popular dimensional adjuncts are just as unlikely
to solve it. There is an overdue impatience with the tradi-
tional ‘purer’ categories and a welcome desire to explore
larger super-ordinate categories with a complementary
dimensional crosscutting matrix (Regier et al. 2009).
However, no practical research strategy has yet been for-
mulated to take us beyond the current impasse. We need a
heuristic strategy that aims to develop ground rules for
clarifying as early as possible which people with emotional
and behavioural disturbance are at specific risk of persistent
and disabling mental illness, and what the sequence of
established and novel therapeutic strategies is which is most
likely to not only successfully achieve remission of current
symptoms and psychosocial recovery, but also to reduce the
risk of persistence and recurrence.
We have been very patient with the traditional diag-
nostic system, which, for the psychotic and mood disor-
ders, is over a century old. Having struggled with
Procrustean diagnostic concepts that receive little valida-
tion until the illness has fully evolved, we are now
beginning to see how a more flexible system linking the
course, extension and pattern of illness over time might be
more strategically useful not only in clinical practice but
also in basic research. Our current diagnostic systems are
characterised by artificial divisions based on cross-sec-
tional symptom sets, propped up with course and outcome
variables. Early clinical features are not differentiated from
those that become apparent as a disorder persists, and no
consideration is given to the definition of the onset of a
disorder. The traditional diagnostic concepts in the mood
and psychotic disorders have been derived from the more
prevalent subsamples of chronic patients, thereby enhanc-
ing the impression of stability and validity. However, in
everyday clinical practice these operationally defined
diagnostic criteria have unfortunately done little more than
create a spurious precision which does not extend far
beyond the research setting, and questions of validity and
utility remain unresolved (Jansson and Parnas 2007). They
may be alternately viewed as stable outcome variables,
rather than useful tools for guiding early intervention or
treatment of people with less severe illness, or uncovering
underlying pathological mechanisms.
The ubiquity of comorbidity and polypharmacy provides
evidence of the practical weakness of our current diag-
nostic concepts. Drug therapies lack specificity for indi-
vidual diagnoses as reflected in high levels of off-label use
and ever-widening indications. Psychosocial treatments
appropriately focus on broader personal and social needs
and hence range freely across the diagnostic landscape.
How can we reform and refine diagnosis so that treatments
can be selected in a safer, more effective manner, prognosis
can be more accurately assessed, and the confusing array of
biological disturbances rearranged into something resem-
bling a clinicopathological framework? Clinical staging, a
deceptively simple and practical tool found useful in other
areas of medicine, may provide a way forward (McGorry
et al. 2006, 2007a, b). In a pre-emptive psychiatry (Insel
2007) based on the clinical staging paradigm, end-stage
syndromes such as deficit schizophrenia may fade into the
background as destinations to be avoided. This is a wel-
come departure from the deterministic thinking that has
plagued psychiatry for so long, and opens the door for
better understanding of gene–environment interactions in
the onset and course of psychiatric illness (Insel 2007).
What is Clinical Staging?
Clinical staging is, simply, a more refined form of diag-
nosis. Its value is recognised in the treatment of malig-
nancies and many other potentially serious medical
illnesses, such as diabetes and arthritis, where limiting the
extension and secondary impacts of the disease, and
improving quality of life and survival, all rely on the ear-
liest possible delivery of effective interventions. Clinical
staging differs from conventional diagnostic practice in
that it not only defines the extent of progression of a dis-
order at a particular point in time, but also where a person
lies currently along the continuum of the course of an ill-
ness. The differentiation of early and milder clinical phe-
nomena, from those that accompany illness extension,
progression and chronicity, lies at the heart of the concept,
which therefore makes it especially useful in adolescence
and early adulthood, when most adult-type disorders
emerge for the first time. A staging framework enables
clinicians to select treatments relevant to earlier stages of
an illness, and generally assumes that such interventions
will be both more effective and less harmful than treat-
ments delivered later in the course.
Early successful treatment may change the original
prognosis and thus prevent progression to subsequent
stages, optimally resulting in remission and cure. Our
current diagnostic categories are disconnected from the
20 Neurotox Res (2010) 18:19–30

3. underlying substrates of the disorders and impose artificial
boundaries without utility. In addition to guiding treatment
selection, a staging framework, which cuts across the
current ‘diagnostic silos’ to encompass a broader range of
clinical phenotypes, yet which introduces subtypes along a
longitudinal dimension, has the potential to organise
endophenotypic and biomarker data in a more coherent and
mutually validating fashion.
How do We Define the Stages of a Disorder?
In other medical conditions, clinical stages are defined by the
extent and progression of the illness and its biological impact
on the patient, which in turn must correlate with prognosis.
This approach usually depends on a capacity to define
pathologically, as well as clinically, the limits or extent of the
disease process. In clinical psychiatry, this could involve not
only a cross-sectional clinical definition, but a wider bio-
psychosocial definition of extent or progression. Therefore,
in addition to the severity, persistence and recurrence of
symptoms, biological changes (e.g. hippocampal volume
loss, neurocognitive deficits and dysregulation of the HPA)
and the social impact of a disorder (e.g. the effect on social
relationships and employment) could also be drawn into the
definition. Ultimately, something approaching a clinico-
pathological model could emerge.
What are the Potential Benefits of Staging?
On the clinical side, defining discrete stages according to
progression of disease creates a framework for the evalu-
ation of interventions oriented towards prevention and
cure. The aim is to prevent progression to more advanced
stages, or to promote regression to an earlier stage,
including full and sustained remission. In order to achieve
this, an accurate understanding of the social, biological,
and personal risk and protective factors that influence
progression from one stage to the next will be essential.
Furthermore, we need to know the relative potency of these
risk factors and which of them may be responsive to cur-
rent interventions. While some factors may operate across
several or all stage transitions, others may be stage-spe-
cific; for example, substance misuse or stress may be
especially harmful in triggering the onset of the first epi-
sode of an illness, yet be less toxic subsequently (or vice
versa). Gene–environment interactions probably underpin
and mediate these transitions and recent advances in the
understanding of epigenetics and brain plasticity offer new
pathways to study this process.
A clinicopathological staging model that spans the
current diagnostic categories and allows the mapping of the
relationships between biological markers and the stages of
disorder will allow us to define and validate more mean-
ingful boundaries for clinical entities, and distinguish core
biological processes from epiphenomena and sequelae,
enabling existing knowledge to be better represented and
understood (McGorry et al. 2006). It is likely that by
focusing earlier on what appear to be pluripotential syn-
dromes, and testing broader psychosocial and more generic
neuroprotective interventions, we may learn more about the
subtle pathophysiology of the onset and persistence of
disorder and distinguish this better from vulnerability on
the one hand, and sequelae on the other.
The Pluripotential Risk Syndrome Versus the Specific
Prodrome
The above discussion points to several questions regarding
the specificity of the earliest stages of psychiatric disorders.
First, if we define target syndromes such as deficit
schizophrenia, persistent or recurrent major depression or
fully developed mania, how soon can specific indicators of
progress towards such defined syndromes or disorders be
recognised? A second, related question is whether earlier
stages of disorders, which tend to be phenotypically very
similar, are in fact ‘pluripotential’ (i.e. may develop into
one of a range of disorders) or whether they contain a
‘mixed bag’ of people on the way to a fixed destination,
a particular target or outcome, such as schizophrenia (i.e.,
a ‘predetermined’ outcome). If we follow prospective
cohorts, we may see a gradual separation and intensifica-
tion over time within individual patients of symptom
clusters and syndromes, often in a kaleidoscopic fashion.
An apparently pluripotential prodrome may exit into psy-
chotic disorders, non-psychotic mood and anxiety disor-
ders, substance use disorders or comorbid combinations of
these disorders.
Can these alternative models, pluripotentiality versus
predetermination, of the evolution of psychiatric disorders
be distinguished? The question can be addressed by natu-
ralistic studies to some extent, but ultimately randomised
trials of different interventions and measurement of
potentially predictive biomarkers and risk factors may be
more informative in revealing to what extent the clinical
pathways are fluid or fixed.
Staging and Psychosis: A Framework for Preventively
Oriented Care
Over the past 15 years or so, an international collaborative
endeavour has sought to modify and apply the principles
and practice of early diagnosis and staged treatment to the
21Neurotox Res (2010) 18:19–30

4. field of psychotic disorders (McGorry et al. 1996;
McGlashan 1998; Edwards and McGorry 2002; McGorry
and Yung 2003). One pillar of the early intervention par-
adigm has been the relationship between prolonged illness
duration and poor outcome in the psychotic disorders
(Harrigan et al. 2003). In a recent metaanalysis (Marshall
et al. 2005) and systematic review (Perkins et al. 2005),
longer duration of untreated psychosis (DUP) was associ-
ated with poorer response to antipsychotic treatment as
measured by severity of global psychopathology, positive
and negative symptoms, demoralisation, depression and
functional outcomes. Neuroimaging studies have also
indicated that prolonged untreated illness is associated with
more pronounced structural brain abnormalities, while this
is less prominent earlier in the course of the disorder
(Keshavan and Amirsadri 2007). Treatment delay may be
reduced by early detection and intervention, resulting in
improved short-term and longer-term outcome (Johannes-
sen et al. 2001, 2005; Larsen et al. 2001, 2006). Ran-
domised trials have also suggested that initiation of
atypical antipsychotic therapy at the first episode may
prevent progression of the structural changes seen in the
disorder (Lieberman et al. 2005).
The Prodromal or Ultra-High Risk Stage
Initially, the early psychosis focus was on the timely rec-
ognition and phase specific treatment of first-episode psy-
chosis (FEP; see below). However, it was also recognised
that for most patients a prolonged period of attenuated
symptoms and impaired functioning precedes the first
psychotic episode (Hafner et al. 1993; Yung and McGorry
1996a, b). Much of the disability associated with the psy-
chotic disorders, particularly schizophrenia, develops long
before the onset of frank psychosis and is difficult to
reverse even if the first psychotic episode is successfully
treated (Hafner et al. 2003). This pre-onset period of illness
has been termed the prodromal phase (Huber et al. 1979;
Yung 2003). Intervening during this phase may ameliorate,
delay or even prevent onset of fully fledged disorder,
thereby reducing the burden of disability, prevalence and
possibly even the incidence of psychotic disorders
(McGorry et al. 2001).
However, this goal presented the major challenge of
prospectively identifying the prodromal phase, a task
complicated by the non-specific nature of prodromal
symptoms (Yung et al. 1998). Criteria were introduced for
the prospective identification of individuals at heightened
risk of developing FEP within a brief time period—that is,
as possibly being in the prodromal phase of illness. These
criteria are based on a combination of known trait and state
risk factors for psychosis, including attenuated positive
psychotic symptoms, brief self-limited psychotic symp-
toms and family history of psychotic disorder. They have
been termed the ‘ultra-high risk’ (UHR) criteria (Yung
et al. 2004a, b). The first published study using the UHR
criteria found a transition rate of 40% to threshold psy-
chotic disorder within 1 year (Yung et al. 2003), despite
the provision of needs-based psychosocial intervention and
antidepressant treatment where indicated. This finding has
subsequently been replicated by several groups interna-
tionally (Miller et al. 2002; Mason et al. 2004; Riecher-
Rossler et al. 2007), including the recent multi-centre
North American Prodromal Longitudinal Study (NAPLS)
(Addington et al. 2007; Cannon et al. 2008). Using a
combination of studies, Ruhrmann et al. (2003) reported an
average 1 year transition rate of 36.7% in UHR subjects
who did not receive antipsychotic treatment. These results
indicated that the UHR criteria are valid and reliable cri-
teria for predicting psychosis onset in this population.
Intervention Studies in Ultra-High Risk Groups
The successful identification of the ‘at-risk’ population
facilitated two important advances in the early psychosis
field: (i) research into processes associated with the onset
of psychosis, including psychopathological, neurocognitive
and neurobiological variables; and (ii) the implementation
of intervention trials aimed at treating existing symptom-
atic and functional impairment in the UHR population and
determining whether specific interventions are able to
ameliorate, delay or prevent onset of fully fledged psy-
chotic disorder in this population.
The intervention studies to date are summarised briefly
below (see McGorry et al. (2009) for review). The first
such intervention trial, conducted by our group in Mel-
bourne, Australia, compared combined cognitive behaviour
therapy (CBT) and low dose atypical antipsychotic medi-
cation (risperidone) (n = 31) with usual case management
(n = 28) (McGorry et al. 2002). Subjects were randomised,
but neither patients nor investigators were blind to the
intervention received. The rate of psychosis onset in the
treatment group was significantly lower than in the control
group at the end of the 6 month treatment phase (9.7 vs.
35%, P = 0.026). However, after a further 6 months of
follow up this finding was no longer statistically significant
due to patients who were not fully adherent to their anti-
psychotic medication developing a psychotic disorder over
the second 6 month period. Those who were fully adherent
to risperidone during the initial 6 month treatment phase all
remained non-psychotic over the follow up period even
though they had ceased drug treatment. This study dem-
onstrated that the onset of psychosis can at least be
delayed, if not prevented, by specific intervention.
22 Neurotox Res (2010) 18:19–30

5. However, the active component of the treatment regime
could not be identified since medication and CBT were
combined. The results also suggested that further benefit
may be obtained with a longer treatment time, an outcome
reinforced by a longer-term follow up of the sample which
failed to show any persisting benefit over 3–4 years in the
experimental group (Phillips et al. 2007).
A randomised double-blind placebo-controlled trial was
then conducted by researchers from Yale University, USA
(McGlashan et al. 2004). Low dose olanzapine (n = 31)
was compared to placebo (n = 29) for 12 months followed
by a 12-month monitoring period. Although there was a
trend towards the olanzapine-treated group having a
reduced rate of transition to psychosis, this finding was not
significant. There were also some adverse effects associ-
ated with olanzapine treatment, leading to a more conser-
vative interpretation of the results (McGlashan et al. 2006).
The risk–benefit ratio for olanzapine thus appears to be less
favourable than risperidone at this stage of illness.
A third treatment trial in UHR patients was conducted in
Manchester, UK (Morrison et al. 2004). Subjects (n = 58)
were randomised to receive cognitive therapy for 6 months
or monitoring of mental state only. The group that received
cognitive therapy had a significantly lower rate of transi-
tion to full-threshold disorder (6 vs. 26%, P 0.05) and a
significantly greater reduction in psychiatric symptoms
(P 0.02) at 12 months. At 3 year follow up, cognitive
therapy was associated with a significantly lower rate of
transition to psychosis when baseline cognitive factors
were controlled for and a significantly reduced likelihood
of being prescribed antipsychotic medication (Morrison
et al. 2007). Consistent with this, Bechdolf et al. (2007)
reported that for patients in the early initial prodromal
state, as identified by the presence of basic symptoms, CBT
was superior to supportive counselling in reducing pro-
gression to sub-threshold psychotic symptoms and to full-
threshold psychosis over 24 months. The OPUS trial
(Nordentoft et al. 2006) also indicated that transition rates
could be reduced in a group of patients with schizotypal
disorder by intervening with the OPUS package, which
consisted of intensive clinical case management, family
involvement and a psychoeducational approach within a
cognitive behavioural framework.
Recently, there has been interest in the possibility of
using antidepressants to reduce risk of psychosis in high-
risk samples. Cornblatt et al. reported a naturalistic study of
young people with prodromal symptoms treated either with
antidepressants or antipsychotics (Cornblatt et al. 2007).
Twelve of the 28 patients (43%) who had been prescribed
antipsychotics progressed to full-threshold psychosis in the
following 2 years, whereas none of the 20 patients treated
with antidepressants subsequently developed psychosis.
Similar results are reported by Fusar-Poli et al. (2007) on
the basis of a file audit. However, these results need to be
interpreted with caution due to the uncontrolled nature of
the studies: there may have been differences in baseline
symptom, functioning or other variables between treatment
groups and non-adherence was far more prominent
amongst patients prescribed antipsychotics than patients
prescribed antidepressants. Our initial trial (McGorry et al.
2002) found that antidepressants, again prescribed
according to clinical need, had no influence on the transi-
tion rate.
Open-label trials of aripiprazole and the amino acid
glycine have also recently been conducted in the UHR
population. In the aripiprazole trial (Woods et al. 2007), 15
UHR patients were treated with a flexible dose regime of
5–30 mg/day for 8 weeks. Improvements on clinical mea-
sures were evident by the first week and no participants
transitioned to psychosis. Adverse events were minimal.
These findings indicate a promising efficacy and safety
profile for aripiprazole for UHR patients. In the glycine
pilot trial (Woods et al. 2006), 10 UHR patients were
treated with glycine over an 8-week period. No participants
transitioned to full-threshold psychosis and significant
improvements in different psychopathological domains
were reported, with minimal side effects.
In a recent, more sophisticated double-blind placebo-
controlled intervention trial, we have compared the com-
binations of risperidone and CBT with placebo and CBT or
placebo and supportive therapy in a group of 115 UHR
patients (Phillips et al. 2009). The 6-month transition rates
were low in all three treatment groups, suggesting that
antipsychotics may not be necessary in UHR cases who are
detected early, or that recent UHR cohorts are derived from
less ‘enriched’ samples in terms of the true positive rate
(McGorry et al. 2007a b; Yung et al. 2007a, b, c). Early
detection and treatment may mean that more benign
interventions are sufficient at this stage of illness. These
should certainly be offered first; only when symptoms and
impairment persist or worsen should other options such
as drug therapies be considered. Furthermore, the high
rates of psychotic-like experiences in community cohorts
(Laurens et al. 2007; Yung et al. 2007a, b, c) is consistent
with the notion that a staged approach to treatment may be
indicated, with antipsychotic agents not being necessary for
all individuals with sub-threshold psychotic symptoms.
Another recent study lends further support to this staged
approach to intervention in the UHR group. This was a
12-week placebo-controlled randomised trial of the omega-3
fatty acid eicosapentanoic acid (EPA) in a group of 80
UHR adolescents. At the end of the 12-week intervention
phase, 8 of 38 (21.1%) individuals in the placebo group and
1 of 38 (2.6%) in the EPA group had progressed to FEP, a
statistically significant difference (P = 0.028). No clini-
cally significant adverse effects were reported, and EPA
23Neurotox Res (2010) 18:19–30

6. was well accepted by this patient group. Most notably, the
treatment effect was maintained at 12 month follow up
(Amminger et al. 2010).
Previous treatment studies of EPA supplementation in
different samples of psychotic patients indicate that the
effect of EPA is dependent on stage of illness. EPA has
been found to be partially effective in samples with recent
onset psychosis (Emsley et al. 2002; Berger et al. 2007a, b)
but has no effect in chronic schizophrenia (Fenton et al.
2001). These findings support the clinical staging model in
that the effect of the intervention seems dependent on the
stage of illness progression. There is also good evidence
that EPA has a generalised positive effect on mental health
complaints (Peet and Stokes 2005; Freeman et al. 2006).
This generalised effect is appropriate for the UHR group,
who have been found to have a wide variety of general
psychiatric symptoms, not only attenuated psychotic
symptoms, and which are a target in their own right
(Phillips et al. 2009).
Applying the clinical staging model to treatment of the
UHR population, the evidence reviewed above indicates
that ‘gentler’ therapies such as EPA or psychosocial
interventions, including CBT or supportive therapy, may
be suitable as a first line treatment in UHR patients.
However, the clinical staging model does not necessarily
mean eschewing study of the role of antipsychotic medi-
cation in this population. Broad spectrum antipsychotics
may also have a neuroprotective effect, reduce anxiety and
depression, and may possess minimal side effects. They
may still have a place in delaying or preventing psychosis
onset and should be further studied especially in those who
present late with UHR symptoms or fail to respond to
initial intervention with ‘gentler’ therapies. The best can-
didates are those with a more favourable metabolic and
neurological safety profile such as quetiapine and aripip-
razole (Kahn et al. 2008).
It is also possible that optimal treatment is not deter-
mined solely by stage of illness factors (i.e., whether the
patient is high risk, the ‘degree’ of high risk, or whether
he/she is suffering from a first episode or in a chronic
stage of illness). In other words, symptom severity alone,
as we have defined it in the definition of ‘transition’, may
not be a perfect guide for the need for antipsychotic
medication. There may be other factors, such as symptom
type and other clinical phenomena, comorbid substance
use, triggers and stressors, genetic and other biomarkers,
etc. that could determine optimal treatment for a given
patient. Therefore, some UHR patients may in fact benefit
from treatment with antipsychotics, while some FEP
patients, especially those with a very short DUP may not
and may remit with intensive psychosocial interventions.
Further intervention research is required in order to shed
light on these issues.
Falling Transition Rates: What does this Mean?
Another critical finding in the UHR group is that the
transition rate to full-threshold psychosis has been drop-
ping in recent cohorts. At the PACE Clinic in Melbourne
the transition rate has dropped from about 50% in 1995 to
about 12% in 2000, with each successive year showing a
transition rate of 0.80 times that of the preceding year
(Yung et al. 2007a, b, c). There has also been a shorter
duration of symptoms prior to entering the clinic for more
recent cohorts. A similarly reducing transition rate has been
observed in some other UHR clinics. The reasons for the
reducing transition rate are unclear. It may be due to earlier
detection and treatment of UHR samples, allowing psy-
chosocial intervention to be more effective in delaying or
reducing transition, in line with the staging model. It may
also be due to identifying more ‘false positives’ in UHR
samples (i.e., a ‘diluted’ sample with less inherent risk),
due to different referral patterns. Against this notion is the
fact that the functional level of the patients presenting to
the clinic remains reduced to the same level as previously.
Alternatively, since patients now have a much shorter
duration of prodromal symptoms, it may be an example of
lead time bias where the patients need to be followed for a
longer period before we can say that the transition rate and
level of risk has truly been reduced. If the staging model is
valid then the ability to offer simpler interventions earlier
may be responsible for a sustained reduction in transition.
Even longer-term follow up, however, will not help to
distinguish between these possibilities, since both greater
effectiveness of the same treatment delivered earlier in the
UHR stage and a more dilute level of true risk in the
sample would both result in a sustained reduction in tran-
sition rates over time. The only way to distinguish would
be to compare monitoring alone with the existing psycho-
social interventions Either way the lower transition rates
and consequently higher false positive rates (at least in
short-term follow up) mean that safer interventions must be
offered as the first line treatment for people who never-
theless have a clear-cut need for care of some kind.
Interventions for First-Episode Psychosis (FEP)
We can divide first-episode psychosis (FEP) into the period
before psychosis is detected and the period after detection.
All too commonly the undetected/untreated phase can be
prolonged, even in developed countries (McGlashan 1999).
Even when psychosis is detected, the initiation of effec-
tive treatment may still be delayed. Post-detection, the
intervention goals are engagement and the initiation of
pharmaceutical and psychosocial treatments. Intensive
interventions aimed at maximal symptomatic and functional
24 Neurotox Res (2010) 18:19–30

7. recovery and the prevention of relapse are ideally delivered
during the early weeks and months of treatment.
The controversy surrounding the importance of DUP
and treatment delay in first-episode psychosis seems to
have been largely resolved following the publication of
some key systematic reviews (Marshall et al. 2005; Perkins
et al. 2005) and recent influential longitudinal research.
These studies have now established that longer DUP is
both a marker and independent risk factor for poor out-
come. The TIPS study in Scandinavia has shown, through
an innovative study design, that reducing DUP leads to
early benefits in reducing suicide risk and severity of ill-
ness at initial treatment, and sustained benefits in terms of
negative symptoms and social functioning (Melle et al.
2009). The relationship between DUP and outcome is
robust, being sustained over many years of follow up
(Bottlender et al. 2002; Harris et al. 2005) and is also found
in low and middle income countries (Farooq et al. 2009).
However, these studies do show that, though it is a mal-
leable risk factor, DUP accounts for a relatively modest
amount of outcome variance, underlining the importance of
treatment access, retention and quality during the early
years of illness, known as the critical period.
There is an extensive literature attesting to the benefits
of comprehensive care of the first psychotic episode, which
has been summarised in the International Clinical Practice
Guidelines for Early Psychosis published in 2005 (Inter-
national Early Psychosis Writing Group 2005). Since then,
the large multicentre EUFEST study has shown that in the
treatment of first-episode schizophreniform and schizo-
phrenic disorders, second generation antipsychotics
(SGAs) have some clear-cut advantages over first genera-
tion agents (FGAs) (Kahn et al. 2008). While most patients
who were able to tolerate the particular medication
responded well to both FGA and SGA medications, with no
significant differences in efficacy, the all-cause discontin-
uation rate and tolerability were clearly superior for the
SGAs. This was true even when compared with very low
dose haloperidol. While the authors’ conclusions and rec-
ommendations highlighted the equivalent efficacy of both
drug classes (a secondary outcome measure), the EUFEST
findings contrast markedly with those of the CATIE study
in chronic schizophrenia where no dramatic advantages
were found for SGAs using similar primary outcome
measures. The EUFEST data support the recommendations
in the International Clinical Practice Guidelines for Early
Psychosis, which favours the use of the SGAs as first line
therapy due to their better tolerability (a crucial issue in
drug-naı¨ve first-episode patients) and the reduced risk of
tardive dyskinesia (International Early Psychosis Writing
Group 2005; Kahn et al. 2008). However, certain SGAs are
associated with a particularly high risk of significant
weight gain and metabolic problems, and these risks need
to be carefully managed and prevented wherever possible,
particularly in view of the increased levels of medical
comorbidity and premature death in people with psychotic
illness (Parsons et al. 2009).
Psychosocial treatments in early psychosis have been
extensively studied, with positive findings pointing to the
value of cognitive therapies in accelerating and maximising
symptomatic and functional recovery (Jackson et al. 2008).
Increasingly, there has been attention to the fact that medi-
cations, while assisting in symptomatic recovery, do not
contribute to a return to functioning. This has led to an
increased focus on the need to enhance social recovery
(Fowler et al. 2009) especially educational and vocational
aspects (Fraser et al. 2006; Killackey et al. 2006; Killackey
et al. 2008) through the combination of effective psychoso-
cial interventions with well-managed medication. There is
also an increasing focus on targeted cognitive remedia-
tion and to limit the degree of cognitive decline that is often
found as illness progresses (Wykes et al. 2007; Eack et al.
2009).
Future Progress in FEP Intervention
The place of the new SGA long-acting injectables and
clozapine needs to be clarified as well as adjunctive neu-
roprotective agents such as omega-3, lithium and N-acetyl
cysteine (Berger et al. 2007a, b; Berk et al. 2008; Amm-
inger et al. 2010). With the advent of very short DUP for
many patients, there may be a subset of FEP patients for
whom intensive psychosocial intervention may be suffi-
cient as a first line treatment approach without initial
antipsychotic medication. We are currently conducting an
intervention study to examine this possibility. CBT, family
intervention, targeting of substance abuse, suicide risk and
vocational rehabilitation are the key psychosocial inter-
ventions in early psychosis and need to be much more
intensively and widely deployed (McGlashan 1998; Yung
et al. 2007a, b, c; McGorry et al. 2008a, b; Killackey and
McGorry 2008; Mihalopoulos et al. 2009). Assertive
community treatment for the subset of poorly engaged
patients is vital. Family interventions are also an essential
element of care. They have been shown to lead to shorter
periods of hospitalisations in FEP patients, assisting par-
ents in supporting their children within the community
(Lenior et al. 2001). A family psychosocial module was
also an essential component in a relapse prevention inter-
vention, which was more effective than standard care at
preventing the occurrence of a second episode of psychosis
(Gleeson et al. 2009). In patients with schizophrenia, the
evidence indicates that the relapse rate can be reduced by
20% if relatives are included in treatment (Addington and
Addington 2008).
25Neurotox Res (2010) 18:19–30

8. The Critical Period in Early Psychosis
The initial few years beyond the first psychotic episode
have been referred to as the ‘critical period’ (Birchwood
2000). Treatment goals in this phase are sustained
engagement and tenure in specialised care, continuing
effective medication management and the use of effective
psychosocial interventions to minimise the risk of relapse,
the development of disability and to maximise social and
functional recovery. Proof of concept is now established
for these strategies at least in the short term (Craig et al.
2004; Power et al. 2007; Bertelsen et al. 2008; Gleeson
et al. 2009). However, there remains a large gap in most
communities between what works and what is available,
even in high income countries and certainly in the low and
middle income countries (McGorry et al. 2008a, b).
Beyond the first episode, we know that the first 2–5 years
post-diagnosis is crucial in setting the scene for longer-term
recovery and outcome. This is the period of maximum risk
for disengagement, relapse and suicide, as well as coinciding
with the major developmental challenges of forming a stable
identity, peer network, vocational training and intimate
relationships. It makes sense that a stream of care specially
focused on young people and on this stage of illness is
required to maximise the chances of engagement, continuity
of care, appropriate lifestyle changes, adherence to treat-
ment, family support and vocational recovery and progress.
Indeed, the available evidence from naturalistic and ran-
domised studies strongly supports the value of specialised
early psychosis programs in improving outcome in the short
term. If these programs are only provided for 1–2 years,
there is also evidence that some of the gains are eroded,
suggesting that for a substantial subset at least, specialised
early psychosis care needs to be provided for a longer period,
probably up to 5 years in many cases (Harris et al. 2005;
Bertelsen et al. 2008; Killackey and McGorry 2008). At this
point persisting illness and disability may be present in a
much smaller percentage of people whose needs may sub-
sequently be well met by more traditional mental health
services for older adults. This may be a much better point to
transfer care.
Risk Syndromes, Staging and Early Intervention
for Mood Disorders
With the target for early intervention in psychotic disorders
extending forward to the prepsychotic or ultra-high risk
stage, a key question to now ask is: can we treat even
earlier (Egeland et al. 2000; Angst et al. 2003; Lewinsohn
et al. 2003; Thompson et al. 2003; Kessing et al. 2004;
Correll et al. 2007; Duffy et al. 2010)? Furthermore, the
UHR criteria described above which were defined with the
prediction of non-affective psychosis in mind lead to a
heterogeneous range of diagnoses across the spectrum of
psychosis, including psychotic depression and mania
(Mason et al. 2004). Prior to the onset of attenuated psy-
chotic features, in the early prodrome of schizophrenia,
general symptoms such as irritability, anxiety and depres-
sion are known to occur, which could evolve into a number
of different clinical outcomes (as well as resolve or remit)
(Yung and McGorry 1996a b). Ha¨fner et al. failed to dis-
tinguish the prodromal stage of schizophrenia from that of
depression in a retrospective study (Hafner et al. 2005).
Thus, the challenge here is to determine if different end-
stage syndromes (such as schizophrenia, bipolar disorder
and unipolar depression) have a common ‘pluripotential’
early onset phase, or whether there is any early specificity
of the clinical phenotype, perhaps enhanced through bio-
markers. More work is required to clarify whether there is a
specific prodromal stage for mood disorders that can be
reliably differentiated from the prodrome of psychotic dis-
orders. This would justify specific early identification and
intervention strategies for mood disorders. The alternative
approach is to have a broader risk identification and inter-
vention approach, consistent with the pluripotential model.
Fava and Tossani reviewed the literature for identifying a
prodrome for depressive disorders (Fava and Tossani 2007).
They concluded that anxiety and irritability are commonly
observed in the prodromal phase of depression; that sub-
threshold or minor depression is implicated as a risk factor
for the development of major depression, reinforcing the
notion that depressive symptoms occur on a continuum
rather than in discrete categories; and that prodromal
symptoms can persist after full-threshold episodes as
residual symptoms, which may inform efforts towards
relapse prevention (Clarke et al. 2001). Subsyndromal
depression is significant not only as a risk factor for
depressive disorders but also because of its high prevalence
and the impact of symptoms on functioning (Hetrick et al.
2008b). Eaton highlighted the greatly increased risk of
major depression conferred by subthreshold depressive
symptoms (Eaton et al. 1995) thus laying the foundations for
intervention studies to reduce this risk (Harrington and
Clark 1998). Few have taken up this challenge to date.
However, although including some mixed results, studies by
Jaycox et al. (1994), Clarke et al. (2001), Stice et al. (2008)
and Garber et al. (2009) all indicate that the risk of major
depression can be reduced in adolescents with subthreshold
depression, particularly in the context of a family history of
depression. In the case of bipolar disorder, a small number
of retrospective and prospective studies have shown that
while there are some hints of early specificity, these are
weak and it is not possible to differentiate symptomatic
young people with emerging bipolar disorder from those
who remit or progress to other syndromal outcomes.
26 Neurotox Res (2010) 18:19–30

9. In a recent presentation of the clinical staging model for
intervention in depressive disorders, Hetrick et al. (2008a, b)
suggest that simple and effective treatment approaches such
as psychoeducation, self-help and e-health, physical activity
and exercise therapies, and related behavioural approaches
may be appropriate for the earlier stages of depressive dis-
orders. Further intervention studies informed by the clinical
staging model are required to test whether such interventions
prevent individuals progressing to later stages of depressive
disorders.
Conclusion
The current diagnostic categories in psychiatry impede
progress in understanding illness progression and identifying
the most effective intervention strategies. Our nosology was
createdduringthe age of steam and one suspects that even the
best attempts to tinker with it can do little more than produce
a better steam engine. Our current nosology is manifestly
invalid yet we are struggling to move beyond it through lack
of a more valid alternative. Clinical staging may not neces-
sarily be the solution to this paralysis, however, it may be
able to deliver greater utility in the targeting and evaluation
of intervention strategies, and provide a framework for
understanding illness progression, including organising the
explosion of biological research findings, thus lighting the
path to a more valid nosology.
The staging model suggests the possibility of ‘lumping’
at the macro level, for example merging psychoses and
mood disorders at the earliest phase, and then ‘splitting’ or
sub-typing at later stages. Mania, deficit schizophrenia and
‘tenacious’ (persistent or chronically relapsing) depression
and may be among the more distal target syndromes that
emerge from this undifferentiated early stage of disorder.
There may be a range of other outcomes, including, very
commonly, remission and recovery. The challenge remains
to map clinical and biological markers across the stages, to
define points at which diagnostic specificity and specific
predictive factors can be identified, and to refine the most
effective intervention strategies for each stage.
Acknowledgements Professor McGorry receives funding from the
Colonial Foundation, and from a Program Grant and a Clinical Centre
Research Excellence Grant from the National Health and Medical
Research Council of Australia. He has also received research grant
support from Janssen Cilag Eli Lilly, Pfizer, Novartis and Astra
Zeneca.
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