Who needs antipsychotic medication in the earliest stages of psychosis? A
reconsideration of benefits, risks, neurobiology and ethics in the era of
S.M. Franceyb,d, B. Nelsona,b,d, A. Thompsona,b,d, A.G. Parkera,d, M. Kerra,d, C. Macneilb,d, R. Fraserb,d,
F. Hughesb,d, K. Crispb,d, S. Harrigana,d, S.J. Woodd,f, M. Berka,b,c,d,e, P.D. McGorrya,b,d,⁎
aOrygen Youth Health Research Centre, Centre for Youth Mental Health, University of Melbourne, 35 Poplar Road (Locked Bag 10), Parkville, Victoria 3052, Australia
bOrygen Youth Health, 35 Poplar Road (Locked Bag 10), Parkville, Victoria 3052, Australia
cDepartment of Psychiatry, University of Melbourne, Geelong, Australia
dDepartment of Clinical and Biomedical Sciences, Barwon Health, University of Melbourne, Geelong, Australia
eMental Health Research Institute, Parkville, Victoria 3052, Australia
fMelbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Victoria 3052, Australia
a r t i c l ei n f oa b s t r a c t
Received 5 October 2009
Accepted 26 February 2010
Available online 26 March 2010
In recent years, early intervention services have attempted to identify people with a first episode of
psychosis as earlyaspossible,reducingtheduration ofuntreatedpsychosis and changing the timing
of delivery of interventions. The logic of early intervention is based partly on accessing people in a
on remediating a putatively active process of neuroprogression that leads to pathophysiological,
symptomatic and structural changes, hence improving symptomatic and functional outcomes.
However, as in other areas of health care, earlier identification of new patients may mean that
the minimal effective dosage of antipsychotic medication and the content of psychosocial
interventions. With the substantial reductions of DUP now seen in many early psychosis services,
based on clinical staging and stepped care principles, it is even possible that the immediate
introduction of antipsychotic medication may not be necessary for all first episode psychosis cases,
but that potentially safer interventions, which may be more acceptable to many patients, such as
comprehensivepsychosocialintervention,may constituteeffectivetreatmentat leastfor a subgroup
of patients. In this paper, we review this theoretical background and describe a randomised
in Melbourne designed to test outcomes for first episode psychosis patients in response to two
different treatments: intensive psychosocial intervention plus antipsychotic medication versus
in that it will provide evidence as to whether intensive psychosocial intervention alone is sufficient
for a subgroup of first episode psychosis patients in a specialised early intervention service, and
provide a test of the heuristic clinical staging model. By experimentally manipulating duration of
untreated psychosis, the study will also provide a methodologically strong test of the effect of
antipsychotic medicationsand theputativeneurobiological processes associated with brain changes
and symptom profiles in the early phase of psychotic disorders. The study has been carefully crafted
to satisfy critical ethical demands in this challenging research domain.
Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.
Randomised controlled trial
Schizophrenia Research 119 (2010) 1–10
⁎ Corresponding author. Orygen Youth Health, 35 Poplar Road (Locked Bag 10), Parkville, Victoria 3052, Australia. Tel.: +61 3 9342 2800; fax: +61 9342 3706.
E-mail address: firstname.lastname@example.org (P.D. McGorry).
0920-9964/$ – see front matter. Crown Copyright © 2010 Published by Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/schres
During the past 15 years, there has been a growing
worldwide focus on early identification, diagnosis, and staged
treatment for psychotic disorders (Edwards and McGorry,
2002; McGlashan, 1998; McGorry et al., 1996; McGorry and
Yung, 2003). The early intervention paradigm is based on the
view that the earliest possible detection and effective inter-
vention for psychosis will deliver thebest outcome for patients
and result in the least burden and cost over time for the health
care system (Edwards and McGorry, 2002; McGorry et al.,
1996). A key rationale has been the relationship between
prolonged illness duration and poor outcome in psychotic
disorders (Harrigan et al., 2003; Marshall et al., 2005). In a
recent meta-analysis (Perkins et al., 2005) and systematic
review (Marshall et al., 2005), longer duration of untreated
psychosis (DUP) was associated with poorer response to
antipsychotic treatment as measured by severity of global
psychopathology, positive and negative symptoms, demoral-
ization, depression, and functional outcomes. In most of the
literature “untreated” refers to treatment with neuroleptic
medication, in contrast to other forms of intervention, such as
psychosocial treatment. 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).
Service reform and restructuring to adopt an early
intervention approach has been effective in reducing the
DUP of patients with first episode psychosis (FEP). This is
shown by the significantly lower median DUP reported by
specialist early psychosis services (e.g., Carbone et al., 1999;
Linszen et al., 1998) compared to the DUP reported for first
episode cases in non-specialised services (e.g., Melle et al.,
2004) and in standard psychiatric services in the early 1990s
(e.g., Loebel et al., 1992; Szymanski et al., 1996). Recent data
indicates that the median DUP in our own early intervention
service, the Early Psychosis Prevention and Intervention
Centre (EPPIC), Orygen Youth Health is as low as 8.7 weeks
(Schimmelmann et al., 2008), while the Norwegian TIPS
study reported a median DUP of 5 weeks in a geographical
region with a specialised early psychosis service compared to
16 weeks in a region without such a service (Melle et al.,
2004). There is accumulating evidence for improved short-
term [e.g., earlier remission (Loebel et al., 1992), fewer
hospital admissions and improved functional outcome (Ber-
telsen et al., 2008)] and longer-term outcome [e.g., fewer
relapses (Crow et al., 1986; Marshall et al., 2005)] as well as
economic benefit for the health care system from the early
intervention model (Killackey and Yung, 2007). Randomised
controlled trials (RCTs) have also suggested that initiation of
atypical antipsychotic medication at the first episode of
psychosis can prevent progression of the structural brain
changes associated with psychotic disorders (Lieberman et
al., 2005b; Nakamura et al., 2007). Widespread antipsychotic
use has also led to the most severe manifestations of
schizophreniasuch ascatatoniaandthe severelydisorganised
phenotypes becoming rare in modern clinical settings, again
suggesting an impact of treatment on limiting the expression
of the most deteriorated forms of the disorder (van der
Heijden et al., 2005). Similarly, in the TIPS study earlier
detection was associated with a reduction in the degree of
bizarreness of psychotic features (Larsen et al., 2006).
2. Revisiting optimal treatment for first episode psychosis
The earlier detection of FEP cases has resulted in young
people receiving treatment for psychotic disorders earlier in
the course of their illness than was previously the case
(Johannessen et al., 2001; Larsen et al., 2006). Based on the
clinical staging model, when patients are treated earlier, the
risk/benefit dynamics change and it is important to consider
whether more benign and less extensive treatment may be
sufficient to achieve the same or ideally superior levels of
remission and recovery. In addition to considering timing
issues, the composition of FEP cohorts may be changing as a
result of early detection programs associated with specialist
early psychosis services. It is well established that psychotic
symptoms occur on a continuum throughout the general
population (Johns and van Os, 2001; van Os et al., 2000), that
there are high rates of psychotic-like experiences in commu-
nity studies (Laurens et al., 2007; Poulton et al., 2000; Yung et
al., 2009) and that many people experience such symptoms
without distress, lowered functioning or any discernable
“need for care” (Yung et al., 2006). It is possible that early
intervention efforts have resulted in some of these indivi-
duals being referred for treatment. It is also possible that
more patients enter early psychosis programs without
psychotic symptoms being their main source of clinical
distress or reason for referral. That is, they are suffering
from some form of psychiatric morbidity, such as depression
or personality disorder, and FEP threshold-level psychotic
symptoms are only detected upon referral to the service. This
trend has been seen in recent years in the prodromal or “ultra
high risk” (UHR) domain of clinical research where samples
entering care may have become more inclusive and contain a
lower level of risk for transition and potential chronicity
(Yung et al., 2007). Positive symptoms may often be regarded
as “incidental” psychotic-like experiences and not have the
same diagnostic or therapeutic significance as earlier, more
enriched and incipient cohorts (Yung et al., 2007). A greater
number of these types of patients may be referred due to the
“broadening” of early psychosis services to encompass the
pre-psychotic period (the putatively prodromal or UHR
population) and the restructuring of some services in
accordance with the youth mental health model to encom-
pass non-psychotic disorders (McGorry, 2007b). This trend
may have spilled over to affect the composition of first
In summary, with earlier detection and shorter DUP, the
possible inclusion of a broader composition of patients, and
the considerable diagnostic heterogeneity that occurs in first
episode samples (Rosen et al., 2006; Subramaniam et al.,
2007; Whitty et al., 2005), it is timely to reevaluate the mix
and sequence of drug and psychosocial treatments in first
3. The clinical staging model in psychiatry
We have previously argued that simpler and more benign
treatments (i.e., treatments with fewer risks or side effects)
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
may be the most appropriate first line intervention for the
earliest stages of the onset of psychiatric symptoms
(McGorry, 2007a; McGorry et al., 2006; McGorry et al.,
2007b), provided they can be shown to be efficacious. This
concept is central to the clinical staging model of psychiatric
disorders. The clinical staging model is a heuristic framework
for developing more refined forms of diagnosis, developing
and evaluating intervention strategies, and for studying the
variables and processes underlying the evolution of psychi-
atric disorder (McGorry, 2007a; McGorry et al., 2006;
McGorry et al., 2008). The concept of clinical staging is
widely used in mainstream medicine, particularly in the
treatment of malignancies, where the earliest possible
delivery of effective interventions is vital to increase the
chances of remission and survival. The potential cost of this
approach as with all early diagnosis is unnecessary risks and
anxieties resulting from the “overtreatment” of phenotypi-
cally similar benign conditions. The staging concept actually
applies to a diverse range of diseases, including potentially
many psychiatric disorders. Clinical staging differs from
conventional diagnostic practice in that it defines the extent
of progression of disease at a particular point in time, and
where a person currently lies along the continuum of the
course of illness (McGorry et al., 2008). The differentiation of
early and milder clinical phenomena from phenomena that
accompany illness extension, progression and chronicity lies
at the heart of the concept. It enables the clinician to select
treatments relevant to earlier stages, and assumes that such
interventions will be both more effective and less harmful
than treatments delivered later in the course (McGorry,
2007a; McGorry et al., 2006; McGorry et al., 2007b; Singh
et al., 2004). While staging links treatment selection and
prediction, its role in the former is more crucial than in the
latter, particularly since early successful treatment may
change the prognosis and thus prevent progression to
subsequent stages. Staged treatment models for psychotic
disorders (McGorry et al., 2007a), depressive disorders (Fava
and Kellner, 1993; Hetrick et al., 2008), eating disorders (Le
Grange and Loeb, 2007), and bipolar disorders (Berk et al.,
2007) have recently been described.
4. Clinical staging for psychotic disorders
4.1. Drawing the boundaries in the right place; stepped care as a
We have assumed that the timing of introduction of
antipsychotic medication should be closely linked to the
onset of threshold and sustained positive symptoms of a
certain level of severity and persistence. However, this may
be aninexactguide.Somepatientswithsubthreshold positive
symptoms but other clinical features may need antipsychotic
medications to get better, while some who cross the positive
symptom threshold for psychosis and attract a DSM diagnosis
within the schizophrenia spectrum may respond to simpler
non-biological interventions. Defining the boundary is com-
plex, and probably depends on both symptomatic, functional
and cognitive measures. For example, one feature of the
research literature in UHR individuals is that cognitive
impairment is fairly minimal prior to transition to psychosis
(Brewer et al., 2006), with poorer performance being limited
to tasks involving rapid processing and organization of
information, such as recall of prose passages (Brewer et al.,
2005) or Go/NoGo false alarms (Riecher-Rossler et al., 2009).
The implication of these findings is that cognitive function
should decline with the onset of full-threshold psychotic
disorder, and while there is some evidence for this (Wood
et al., 2007) it is not consistently identified (Becker et al.,).
Clearly, the utility of such measures for defining stages
A staged approach to treatment choice for the earliest
stages of psychotic symptoms could consist of psychosocial
effects and would avoid the early introduction of antipsy-
chotic medication, assuming the efficacy of psychosocial
treatments at this stage of illness is proven (we note,
however, that psychosocial interventions are not without
side effects, e.g. increasing emotional arousal, andthat further
research into the possible negative impact of psychosocial
interventions is required (see Berk and Parker, 2009)).
Antipsychotic medications would then only be introduced
as a second line treatment when more benign treatments
have failed, or when a more aggressive course of disorder is
evident, within a stepped care algorithm. Similar stepped
treatment approaches have been trialed in the treatment of
depression (e.g., the Sequenced Treatment Alternatives to
Relieve Depression [STAR*D] study (Warden et al., 2007))
and bipolar disorder (e.g., the Systematic Treatment En-
hancement Program for Bipolar Disorder [STEP-BD] (Sachs
et al., 2003)). It should be noted that the standard stepped
care logic does not incorporate the possibility of preventive
interventions where therapies are prescribed to preempt
what might be rather than resolve what is already apparent.
4.2. Risks and benefits of antipsychotic medications
The evidence to date with regards to pharmacological and
psychological intervention for psychosis suggests that the
staging model proposed above may be viable treatment
approach. While antipsychotic medications have been shown
to be effective for the treatment of acute psychosis, especially
in first episode cases (Kahn et al., 2008), there are well-
documented and sometimes serious side effects associated
with these medications (Allison and Casey, 2001; Muench
and Carey, 2001; Stahl et al., 2009; Tschoner et al., 2007). This
is underscored by evidence of the iatrogenic risks of atypical
antipsychotic medications in the short-term (Allison and
Casey, 2001; Muench and Carey, 2001), possible morpholog-
ical changes in the brain over the intermediate term (Corson
et al., 1999; DeLisi, 2008; Konopaske et al., 2007), and the
poorly understood longer-term effects that may include
weight gain (Alvarez-Jimenez et al., 2008), altered glucose
metabolism (Tschoner et al., 2007) and tardive dyskinesia
(Llorca et al., 2002). Agents that increase the risk of
developing the metabolic syndrome also contribute to a
marked increase in long-term cardiovascular risk, and
contribute to the increased mortality that is documented in
the disorder (Lambert and Chapman, 2004). These risks
indicate the necessity for a cautious and individualised risk–
benefit analysis when prescribing antipsychotics. Conversely,
research studies have also indicated that antipsychotics and
other medications, notably lithium, valproate and SSRIs, and
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
some experimental options such as N-acetyl cysteine and
omega 3 fatty acids may have neuroprotective properties
(Amminger et al., 2010; Berger et al., 2008; Berk et al., 2008a;
Lieberman et al., 2005b) and therefore may be important in
protecting against putative “neurotoxic” effects of underlying
illness or psychosis itself. These superficially diverse agents
share common effects on a number of the biochemical
pathways which may underpin neurovulnerability and
neuroprogresssion, such as the L-HPA system (Takahashi
et al., 2009), oxidative stress mechanisms (Berk et al., 2008b),
inflammatory cytokines (Miller et al., 2009) and lipid
metabolism (Berger et al., 2002, 2003) that seem to be
disorder and schizophrenia share alterations in inflammatory
cytokines, oxidative stress and neurotrophins such as BDNF
(Berk, 2009). Furthermore, lithium, antidepressants, atypical
antipsychotics and anticonvulsants all share effects on
oxidative stress defences (Berk et al., 2008b).
4.3. Antipsychotic medications may not be immediately popular
with the treatment-naive
There is also substantial evidence that adherence with
antipsychotic medications (as with most medications) is
problematic. Many patients who will engage and accept
supportive care are reluctant initially at least to accept
particularly antipsychotic drug therapy. Coldham et al. (2002)
found that approximately 60% of FEP patients at a specialised
with antipsychotic medication, consistent with other reports in
the field (Oehl et al., 2000; Perkins, 1999). Moreover, the
introduction of second-generation antipsychotics does not
appear to have improved adherence to medication (Kane and
Malhotra, 2003; Berk et al., 2008a). Critical issues in long-term
adherence are engagement with the treating clinician or team,
the therapeutic alliance and illness acceptance (Macneil et al.,
2009). As schizophrenia and bipolar disorder are typically
lifelong disorders needing long-term management, adherence
has the capacity to powerfully shape the long-term prognosis.
The person's initial clinical experience often shapes their view of
the disorder, its treatment and issues such as self-stigma, and
consequently, adherence. A psychotherapeutic treatment model
that emphasises psychoeducation, support, engagement and
alliance at the beginning of treatment may have core benefits in
the long-term pharmacotherapy of these disorders. A stepwise
approach which may well lead to most patients accepting
antipsychotic medications on an experiential and more sustain-
able basis may produce more dividends for the patient.
4.4. Effectiveness of new psychosocial interventions in early
Recently, there has been increased interest in psycholog-
ical interventions, particularly cognitive-behaviour therapy
(CBT) and family interventions, for schizophrenia and other
psychotic disorders. CBT for psychosis derives from strategies
for treating mood and anxiety problems. It largely involves
utilising strategies for managing positive psychotic symp-
toms, such as identifying and changing cognitive styles and
behavioural patterns that may contribute to these symptoms,
and promoting insight into illness (Garety et al., 2000; Garety
and Freeman, 1999; Morrison, 2001, 2002). In a recent
review, consistent evidence was found that CBT reduces
persistent positive symptoms in patients with chronic
schizophrenia, and has modest effects in hastening recovery
from acute episodes (Tarrier, 2005). There is evidence in both
schizophrenia and bipolar disorder that the impact of CBT is
greatest in the early stages of the illness (Scott et al., 2006;
Tarrier, 2005). In trials of CBT used specifically in FEP, CBT and
supportive counseling were found to have significant advan-
tages over routine care [the SoCRATES trial (Lewis et al.,
2002)], CBT was superior to befriending in symptom and
functioning outcome [the ACE project (Jackson et al., 2008)],
and Cognitively Oriented Psychotherapy for Early Psychosis
(COPE) led to an improved adaptation to illness (Jackson
et al., 2001, 2005). In a review of psychosocial interventions
for FEP, Penn et al. (2005) found that CBT was effective in the
treatment of auditory hallucinations (Lewis et al., 2002;
Tarrier et al., 2004), decreased hopelessness (Power et al.,
2003), increased adaptation to illness (Jackson et al., 2001),
contributed to better treatment adherence (Haddock and
Lewis, 2005), and that CBT and supportive counseling were
both effective in reducing comorbid substance abuse
(Edwards et al., 2006).
Other, non-CBT psychosocial interventions have also been
foundto deliver positiveoutcomes. Family interventions have
been shown to lead to shorter periods of hospitalisations in
FEP patients, assisting parents in supporting their children
within the community (Lenior et al., 2001). A family
psychosocial module was also an essential component in a
relapse prevention intervention, 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). Furthermore, it appears
that individual CBT and family interventions are highly
acceptable to FEP patients (Haddock and Lewis, 2005). The
Danish OPUS study found that integrated care, consisting of
assertive community treatment, psychoeducational multi-
family groups and social skills training, led to better course
and outcome in young patients with schizophrenia-spectrum
disorders compared to patients treated with standard care. At
the 1-year follow-up the integrated care group demonstrated
significantly less hopelessness, reduction in psychotic symp-
toms was greater, and clients and families were more
satisfied with treatment (Nordentoft et al., 2002). Vocational
recovery has also been a recent focus of psychosocial
interventions for FEP (Killackey et al., 2008).
suchassymptom type and other clinical phenomena, degree of
cognitive impairment, patient treatment preference, comorbid
substance use, triggers and stressors, and side effect tolerance,
highlighted, the boundary or threshold for “caseness” for first
onset of psychosis, or at least use of antipsychotic medications,
UHR cases, symptomatically subthreshold for “psychosis,” may
in fact benefit from treatment with antipsychotics, while some
FEP patients, technically above threshold, may not, or at least
may not derive extra benefit from antipsychotic treatment in
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
yet known which patients will benefit most from which
treatments. Further intervention research is required in order
to shed light on these issues.
5. Can the introduction of antipsychotic medication be
delayed and what are the consequences of this?
As described above, one of the most prominent reforms in
international mental health care over the last decade has
been the focus on early psychosis and the associated
imperative to provide rapid optimal treatment. The aim of
this approach is to prevent biological and psychosocial
deterioration during the so-called “critical phase” or early
years after psychosis onset (Birchwood, 2000). Within this
paradigm, it has been accepted that optimal treatment
includes the early introduction of novel atypical antipsycho-
tics at low doses in order to minimise DUP (Group, 2005).
However, it has not yet been established that antipsychotic
medication is an essential component of effective treatment
for all FEP cases, particularly in the context of comprehensive
psychosocial care which is a common feature of many, even
most, early psychosis programs.
Even prior to the era of early detection and shorter DUP,
some have claimed a benefit for psychosocial interventions
with minimal or no use of antipsychotic medications. In a
recent meta-analysis, Bola (2006a) found a small, non-
significant advantage for initially non-medicated groups
with established schizophrenia over medicated groups in
terms of improved outcomes (see also Bola et al., 2009).
While this finding was based on a small number of studies, it
suggests that an initial period without medication, but with
other active non-pharmacological interventions, may in fact
produce superior outcomes than immediate introduction of
medication. At the very least, the results of Bola and Mosher
(2003) indicate that long-term harm is not caused to
psychotic patients by short-term medication-free periods, at
least under certain conditions, i.e., that other forms of
treatment are available, such as in the Soteria study. In this
quasi-experimental study, patients with early episode schizo-
phrenia-spectrum psychosis were treated either with anti-
psychotic medications in a hospital environment (“usual”
intervention) or in an intensive psychosocial milieu that
minimised use of antipsychotics for an initial 6-week period
(the Soteria intervention; Bola and Mosher, 2003). Two-year
outcome data favoured the Soteria intervention, in terms of
psychopathology, vocational rehabilitation, and social func-
tioning. Further evidence is provided by the RCT of three
antipsychotic medications of Johnstone et al. (1999), plus a
fourth placebo arm, with the aim of examining the potential
effects of delaying antipsychotic medication for a 4-week
period. At the 2.5-year follow-up, the occupational function-
ing, psychopathology, treatment needs and cognitive func-
tioning of those who experienced the 4-week non-
medication period was no different from those who were
initially medicated. The authors concluded that a 4-week
delay in the introduction of antipsychotic medication does
not produce long-term deleterious effects, compared to those
who receive medication. Consistent with this, Carpenter
(1997) reviewed the evidence on medication-free intervals
in schizophrenia and concluded that there was no evidence of
later harm from such intervals. Together, these findings have
led some researchers to advocate the provision of psychoso-
cial interventions with short-term withholding of medication
(Bola, 2006b; Bola et al., 2006; Carpenter et al., 2003;
Lehtinen et al., 2000).
However, there is a paucity of quality research addressing
the effects of delaying medication in schizophrenia, in
situations where active non-pharmacological treatment is
provided, mainly due to the ethical concerns about conduct-
ing such research (Bola, 2006a; Bola et al., 2009). However,
the ethical perspectives of this issue may be changing. In a
series of commentaries on the Bola (2006a) paper, a number
of eminent schizophrenia researchers endorsed the notion
that medication-free trials are ethical, even in patients with
established illness, given the capacity of patients to provide
informed consent and the lack of evidence of harm demon-
strated from medication-free intervals (see below) (McGla-
shan, 2006; McNulty, 2006; Schooler, 2006). Some authors
(e.g., Schooler, 2006) have emphasised that medication-free
research, at least for short periods, may be especially
illuminating in medication-naïve patients or those who
have experienced relatively brief exposure to medication
because this allows study of the processes of early psychosis
without the potentially confounding effects of medication. It
also has the potential to shed light on the efficacy of non-
pharmacological treatment at the earliest stages of illness
without the confounding effects of medication.
6. Current medication-free RCT for first episode psychosis
This background has led us to examine the issue of
medication-free intervention for FEP in an experimental
setting.TheTIPSstudy tooka traditional line thatwithholding
of antipsychotics for FEP was unethical (McGlashan and
Johannessen, 1996) and hence studying the effect of changing
DUP experimentally through an RCT design was not appro-
priate, prompting themtoadopt a quasi-experimental design.
However, with falling DUP levels and in the context of our
staging model, we disagreed with this position, believing that
there could be circumstances under which an RCT could be
ethically conducted to not only test the “DUP hypothesis” but
to explore other key issues, and have consequently spent
some years crafting such a design.
We recently started recruiting to an RCT at EPPIC with FEP
patients randomised to one of two groups: antipsychotic
medication plus intensive psychosocial intervention or placebo
plus intensive psychosocial intervention. The FEP participants
must give fully informed consent to be randomised. The
intervention period is for up to 6 months. The primary outcome
end of the six-month treatment period, with the hypothesis
medication plus intensive psychosocial intervention (i.e., a non-
inferiority design). This primary outcome is in line with the
recent trend of focusing on functional outcomes, rather than
Yung, 2007; Malla et al., 2005). Clinical symptoms, remission
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
and recovery are being assessed as secondary outcomes.
Outcomes up to 2 years post study entry will be assessed. Strict
withdrawal criteria are in place. These include worsening of
symptoms, persistent symptoms (continuing for 3 months),
increase in suicidality or hostility, or breakdown of community
The intensive psychosocial intervention consists of four
1. Case management. A case manager is assigned to each
study participant. Case management includes patient
engagement, problem solving, and advocacy and support,
as described in (EPPIC, 2001).
2. Close monitoring and crisis response. Participants are seen
up to twice per week by their case manager and weekly by
their psychiatrist during the first 2 months of the study,
and continue to be seen frequently throughout the study.
In addition, all study participants are “on alert” with a
crisis response team andan individually tailored crisis plan
isin place so thatrapidassessmentandintervention canbe
provided should this be required.
3. Cognitive-Behaviour Therapy (CBT). The CBT provided in
the trial is a specific therapy developed for the first episode
psychosispopulation (EPPIC,2001). It focuses on symptom
and stress reduction, facilitating adaptation to illness, and
treatment of secondary morbidity such as anxiety, depres-
sion, and substance abuse. The case manager provides this
formulation-driven psychological therapy within the case
management setting. Therapists receive regular individual
and group supervision and draw on appropriate therapy
resource materials, in addition to completing a checklist of
interventions to ensure adherence with the protocol.
4. Family support and education. Families of participants are
seen by the case manager who provides information and
education about psychosis and recovery in young people.
In addition, a specialist family worker is available for
further input and can provide regular supportive counsel-
ing sessions when required as determined by the needs of
each participating family.
The study will allow us to experimentally investigate
whether a subgroup of FEP patients can achieve improved
functioning, symptom reduction and remission with inten-
sive psychosocial treatment in the absence of antipsychotic
medication (i.e., a long drug naive time period but with
intensive psychosocial treatment). It will also allow us to
identify clinical predictors of recovery from FEP with
intensive psychosocial treatment in the absence of antipsy-
chotic medication. A wide range of factors, including DUP,
diagnosis, demographic variables, substance use and social
support, will be assessed with respect to their importance in
determining response to type of treatment (psychosocial,
medication or a combination of the two) in FEP.
Aside from investigating whether intensive psychosocial
treatment in a specialised early intervention service constitutes
also a direct experimental test of whether prolonging DUP (in
terms of antipsychotic medication) leads to worse symptomatic
and functional outcome. To date, reduction in DUP has been a
cornerstone of the rationale for the early intervention move-
ment, but has not been directly experimentally tested. The TIPS
study (Johannessen et al., 2005) has been the closest test of this
premise to date, finding differences in favour of an early
detection program at baseline on a number of symptomatic
variables (Melle et al., 2004), as well as reduced suicidality
(Melle et al., 2006).
The final important aspect of this trial is an experimental
seen in the early phase of psychotic disorders, such as grey
matter loss and reduced hippocampal volume (Dorph-Petersen
et al., 2005; Konopaske et al., 2007; Lieberman et al., 2005b;
Pantelis et al., 2003; Velakoulis et al., 2006), are due to
neurobiological processes associated with psychosis and to
possible toxic effect of early introduction of antipsychotic
medication). There is some evidence that these changes can
occur in the absence of medication (Job et al., 2005), and that
medication does not necessarily induce brain changes (Thomp-
son et al., 2001), but long-term antipsychotic treatment of
primates has been shown to have a widespread effect on brain
our study, we will investigate the extent of these changes over
the intervention period (6 months). If both intervention groups
display similar structural brain changes over the course of
intervention then we can infer that these changes are more
likely to be associated with the progression of psychosis rather
than due to antipsychotic medication, especially if the experi-
mental groups are similar in other respects. However, if certain
structural brain changes only occur in the group treated with
medication then these changes are more likely to be related to
medication. Of course it is entirely possible that antipsychotic
medications could be neuroprotective and retard or prevent
brain changes which derive from underlying neuroprogressive
changes (DeLisi, 2008; Lieberman et al., 2005a).
7. Ethical issues
Clearly, this study is not without ethical issues. The basis for
this being a study that is ethically acceptable derives from the
belief that the question we are examining has come into clinical
equipoise by virtue of the earlier diagnosis of patients with
psychotic syndromes, the lack of harm that appears to be
derived from conducting medication-free research in estab-
lished illness, and the increasingly appreciated risks identified
with antipsychotic medications. In addition, by focusing on a
clinically low risk sample who can give informed consent to
participation and using multiple strategies to maximise the
safety of participants the risks associated with the study can be
minimised to acceptable levels. Although this strict patient
selectionprocedure may limit generalisability of theresults, it is
approaches to clinical trials in schizophrenia in the light of the
2002 Clarificationof the 2000 Declaration of Helsinki, Carpenter
et al.(2003)list five criteriathatresearchstudiesmust satisfyin
criteria are listed below along with reasons why the current
study meets all of these specifications.
1) The likelihood that the intervention being tested has a clinical
advantage over existing treatments. The risk–benefit ratio has
changed as a result of earlier diagnosis in the context of the
staging model principles, more serious adverse effects of
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
psychosocial treatment without medication could have
clinically significant advantages over existing treatments
for at least a subset of patients, as the psychosocial
intervention is a more benign treatment option which may
et al., 2006) and avoid the long-term adverse effects of
antipsychotic medication, including neurologic, endocrine
and metabolic effects (see Gardner et al., 2005 for a review).
The non-trivial side effects of and adherence problems with
antipsychotic medication provide a compelling reason to
seek new treatments that are effective and have fewer
adverse effects than those that are currently available
(Carpenter et al., 2003). Finally, the evidence base for
antipsychotics in FEP does not necessarily extend to the
“new FEP” cohorts described above, some of whom at least
may, in line with the clinical staging model, have different
2) The application of careful informed consent procedures.
Entry to the study is contingent upon informed consent
provided by the participant and a family member.
in the non-medication arm are issued a placebo in order to
maintain the blind with those receiving medication. This
provides a proper, rigorous control for taking active
medication. These participants are not denied all forms of
treatment, only antipsychotic medication.
4) The selection of participants that minimises potential serious
adverse consequences. All patients referred to our first
episode service are screened in order to assess their
eligibility for the study and only those with low risks to
themselves and others and adequate community support
are recruited into the trial. The enhanced care at EPPIC,
including close monitoring and 24 hour crisis response,
minimises potential serious adverse consequences. We
note that the study may not be considered safe in other
early psychosis or standard settings that do not have these
additional supports in place.
5) A risk-versus-benefit analysis that favours the advantages
from placebo use over the risk to participants. With
predetermined strict withdrawal criteria, any participant
whose symptoms worsen or become unacceptable to the
participant or who experiences a further decline in
functioning, is withdrawn from the trial and then offered
antipsychotic medication. This should become apparent
within a matter of weeks. Furthermore, if a more benign
treatment option such as the intensive psychosocial
treatment is found to be effective, the benefits for those
with FEP will outweigh the risks of being assigned to the
Service reform focused on early intervention for psychotic
FEP. Consequently, FEP patients are now being identified and
treated very early in the course of their symptoms. The early
the essential components of efficacious treatment for early
psychosis. In line with the clinical staging model (McGorry,
2007a; McGorry et al., 2007b), it is possible that more benign
forms of treatment, such as psychosocial intervention and close
monitoring, may be sufficient to enable satisfactory recovery for
a subset of FEP patients without the risks and side effects caused
by even the most modern antipsychotic medications. Addition-
may not be harmful for other FEP patients if they are well
supported with psychosocial interventions. The evidence that
psychosocial intervention can be effective in reducing symptom
severity, improving functioning and in reducing the number of
psychotic episodes supports this treatment model, at least for a
subgroup of FEP patients. The moderate transition rates in
prodromal studies and the epidemiological data revealing that
there are surprisingly high rates of psychotic-like experiences in
community samples that are not associated with significant
the clinical staging model of intervention). Conversely, with the
ments and the potential harm of longer DUP, withholding
antipsychotic medication may further negatively affect the early
course of psychosis in FEP patients. There is also the possibility
that such medications can cause structural changes which have
been previously interpreted as deriving from the pathology of
the underlying illness.
These issues are best addressed in the context of well-
and low thresholds for withdrawal. We have recently com-
menced such a trial. While not without ethical and practical
implementation issues, the trial represents a unique attempt to
investigate whether intensive psychosocial treatment alone in a
specialised early intervention service constitutes effective
treatment of FEP in a selected subgroup of FEP patients. It will
psychotic symptoms before treatment with antipsychotic med-
ication results in a worse outcome than a shorter duration of
symptoms and the extent to which neurobiological changes
associated with early psychosis are attributable to medication
effects or to progression of illness. The findings should provide a
basis for future larger scale studies and will ultimately have
important clinical implications for early intervention treatment
strategies for psychotic disorders.
Role of funding source
All authors contributed to and have approved the final manuscript.
Conflict of interest
Michael Berk receives research support from Stanley Medical Research
Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Founda-
tion, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis,
Mayne Pharma, Servier and acts as a consultant for Astra Zeneca, Bristol
Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, and
Servier. No other declarations of interest.
We acknowledge the support of the Janssen-Cilag. BN was supported by
a Ronald Philip Griffith Fellowship and a NARSAD Young Investigator Award.
SJW was supported by a NHMRC Clinical Career Development Award.
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
Addington, D., Addington, J., 2008. First-episode psychosis. In: Mueser, K.T.,
Jeste, D.V. (Eds.), Clinical Handbook of Schizophrenia. Guildford Press,
New York, pp. 367–379.
Allison, D.B., Casey, D.E., 2001. Antipsychotic-induced weight gain: a review
of the literature. J. Clin. Psychiatry 62 (Suppl 7), 22–31.
Alvarez-Jimenez, M., Gonzalez-Blanch, C., Crespo-Facorro, B., Hetrick, S.,
Rodriguez-Sanchez, J.M., Perez-Iglesias, R., et al., 2008. Antipsychotic-
induced weight gain in chronic and first-episode psychotic disorders: a
systematic critical reappraisal. CNS Drugs 22 (7), 547–562.
Amminger, G. P., Schäfer, M., Papageorgiou, K., Klier, C. M., Cotton, S. M.,
Harrigan, S. M., et al., 2010. Long-Chain Omega-3 Fatty Acids for
Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-
Controlled Trial. Archives of General Psychiatry 67 (2), 146–154.
Becker, H. E., Nieman, D. H., Wiltink, S., Dingemans, P. M., van de Fliert, J. R.,
Velthorst, E., et al. Neurocognitive functioning before and after the first
psychotic episode: does psychosis result in cognitive deterioration? Psychol
Berger, G.E., Wood, S.J., Pantelis, C., Velakoulis, D., Wellard, R.M., McGorry,
P.D., 2002. Implications of lipid biology for the pathogenesis of schizo-
phrenia. Aust. NZ J. Psychiatry 36 (3), 355–366.
Berger, G.E., Wood, S., McGorry, P.D., 2003. Incipient neurovulnerability and
neuroprotection in early psychosis. Psychopharmacol. Bull. 37 (2), 79–101.
Berger, G.E., Wood, S.J., Ross, M., Yung, A.R., Nelson, B., Hamer, C., et al., 2008.
Neuroprotective effects of low dose lithium in individuals at ultra-high
risk for psychosis. Early Interv. Psychiatry 2 (1), A28.
Berk, M., 2009. Neuroprogression: pathways to progressive brain changes in
bipolar disorder. Int. J. Neuropsychopharmacol. 12 (4), 441–445.
Berk, M., and Parker, G., 2009. The elephant on the couch: side effects of
psychotherapy. Aust N Z J Psychiatry 43 (9), 787–794.
Berk, M., Hallam, K.T., McGorry, P.D., 2007. The potential utility of a staging
model as a course specifier: a bipolar disorder perspective. J. Affect
Disord. 100 (1–3), 279–281.
Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., et al., 2008a.
N-acetyl cysteine as a glutathione precursor for schizophrenia—a
double-blind, randomized, placebo-controlled trial. Biol. Psychiatry 64
Berk, M., Ng, F., Dean, O., Dodd, S., Bush, A.I., 2008b. Glutathione: a novel
treatment target in psychiatry. Trends Pharmacol. Sci. 29 (7), 346–351.
Bertelsen, M., Jeppesen, P., Petersen, L., Thorup, A., Ohlenschlaeger, J.,
le Quach, P., et al.,2008. Five-year follow-up of a randomized multicenter
trial of intensive early intervention vs standard treatment for patients
with a first episode of psychotic illness: the OPUS trial. Arch. Gen.
Psychiatry 65 (7), 762–771.
Birchwood, M., 2000. Early intervention and sustaining the management of
vulnerability. Aust. NZ J. Psychiatry 34, S181–184 Suppl.
Bola, J.R., 2006a. Medication-free research in early episode schizophrenia:
evidence of long-term harm? Schizophr. Bull. 32 (2), 288–296.
Bola, J.R., 2006b. Psychosocial acute treatment in early-epsiode schizophre-
nia disorders. Res. Soc. Work Pract. 16, 263–275.
Bola, J.R., Mosher, L.R., 2003. Treatment of acute psychosis without
neuroleptics: two-year outcomes from the Soteria project. J. Nerv.
Ment. Dis. 191 (4), 219–229.
Bola, J.R., Lehtinen, K., Aaltonen, J., Rakkolainen, V., Syvalahti, E., Lehtinen, V.,
2006. Predicting medication-free treatment response in acute psychosis:
cross-validation from the Finnish Need-Adapted Project. J. Nerv. Ment.
Dis. 194 (10), 732–739.
Bola, J.R., Lehtinen, K., Cullberg, J., Ciompi, L., 2009. Psychosocial treatment,
antipsychotic postponement, and low-dose medication strategies in
first-episode psychosis: a review of the literature. Psychosis: Psychol.
Soc. Integr. Approaches. 1 (1), 4–18.
Brewer, W.J., Francey, S.M., Wood, S.J., Jackson, H.J., Pantelis, C., Phillips, L.J., et
al., 2005. Memory impairments identified in people at ultra-high risk for
psychosis who later develop first-episode psychosis. Am. J. Psychiatry
162 (1), 71–78.
Brewer, W.J., Wood, S.J., Phillips, L.J., Francey, S.M., Pantelis, C., Yung, A.R.,
risk cohorts: a review highlighting potential vulnerability markers for
psychosis. Schizophr. Bull. 32, 538–555.
Carbone, S., Harrigan, S., McGorry, P.D., Curry, C., Elkins, K., 1999. Duration of
untreated psychosis and 12-month outcome in first-episode psychosis:
the impact of treatment approach. Acta Psychiatr. Scand. 100 (2),
Carpenter Jr., W.T., 1997. The risk of medication-free research. Schizophr.
Bull. 23 (1), 11–18.
Carpenter Jr., W.T., Appelbaum, P.S., Levine, R.J., 2003. The Declaration of
Helsinki and clinical trials: a focus on placebo-controlled trials in
schizophrenia. Am. J. Psychiatry 160 (2), 356–362.
Coldham, E.L., Addington, J., Addington, D., 2002. Medication adherence of
individuals with a first episode of psychosis. Acta Psychiatr. Scand. 106
Corson, P.W., Nopoulos, P., Miller, D.D., Arndt, S., Andreasen, N.C., 1999.
Change in basal ganglia volume over 2 years in patients with schizo-
phrenia: typical versus atypical neuroleptics. Am. J. Psychiatry 156 (8),
Crow, T.J., MacMillan, J.F., Johnson, A.J., Johnstone, E.C., 1986. The Northwick
study of first episodes of schizophrenia. Br. J. Psychiatry 148, 120–127.
DeLisi, L.E., 2008. The concept of progressive brain change in schizophrenia:
implications for understanding schizophrenia. Schizophr. Bull. 34 (2),
Dorph-Petersen, K.A., Pierri, J.N.,Perel, J.M., Sun, Z.,Sampson, A.R.,Lewis, D.A.,
2005. The influence of chronic exposure to antipsychotic medications on
brain size before and after tissue fixation: a comparison of haloperidol
and olanzapine in macaque monkeys. Neuropsychopharmacol. 30 (9),
Guide to Establishing Early Psychosis Services. Dunitz, London.
Edwards, J., Elkins, K., Hinton, M., Harrigan, S.M., Donovan, K., Athanasopou-
los, O., et al., 2006. Randomized controlled trial of a cannabis-focused
intervention for young people with first-episode psychosis. Acta
Psychiatr. Scand. 114 (2), 109–117.
EPPIC, 2001. Case Management in Early Psychosis: A Handbook. Melbourne:
Early Psychosis Prevention and Intervention Centre.
Fava, G.A., Kellner, R., 1993. Staging: a neglected dimension in psychiatric
classification. Acta Psychiatr. Scand. 87, 225–230.
Gardner, D.M., Baldessarini, R.J., Waraich, P., 2005. Modern antipsychotic
drugs: a critical overview. CMAJ 172 (13), 1703–1711.
Garety, P.A., Freeman, D., 1999. Cognitive approaches to delusions: a critical
review of theories and evidence. Br. J. Clin. Psychol. 38, 113–154.
Garety, P.A., Fowler, D., Kuipers, E., 2000. Cognitive-behavioral therapy for
medication-resistant symptoms. Schizophr. Bull. 26 (1), 73–86.
Gleeson,J.F., Cotton, S.M., Alvarez-Jimenez,M., Wade, D., Gee,D., Crisp,K., etal.,
2009. A randomized controlled trial of relapse prevention therapyfor first-
episode psychosis patients. J. Clin. Psychiatry 70 (4), 477–486.
Group, I.E.P.A.W., 2005. International clinical practice guidelines for early
psychosis. Br. J. Psychiatry 187 (Supplement 48), s120–s124.
Haddock, G., Lewis, S., 2005. Psychological interventions in early psychosis.
Schizophr. Bull. 31 (3), 697–704.
Harrigan, S.M., McGorry, P.D., Krstev, H., 2003. Does treatment delay in first-
episode psychosis really matter? Psychol. Med. 33 (1), 97–110.
Hetrick, S.E., Parker, A.G., Hickie, I.B., Purcell, R., Yung, A.R., McGorry, P.D.,
2008. Early identification and intervention in depressive disorders:
towards a clinical staging model. Psychother. Psychosom. 77 (5),
Jackson, H., McGorry, P., Henry, L., Edwards, J., Hulbert, C., Harrigan, S., et al.,
2001. Cognitively oriented psychotherapy for early psychosis (COPE): a
1-year follow-up. Br. J. Clin. Psychol. 40 (Pt 1), 57–70.
Jackson, H., McGorry, P., Edwards, J., Hulbert, C., Henry, L., Harrigan, S., et al.,
2005. A controlled trial of cognitively oriented psychotherapy for early
psychosis (COPE) with four-year follow-up readmission data. Psychol.
Med. 35 (9), 1295–1306.
Jackson,H.J., McGorry,P.D., Killackey, E.,Bendall,S.,Allott,K.,Dudgeon,P., etal.,
2008. Acute-phase and 1-year follow-up results of a randomized
controlled trial of CBT versus befriending for first-episode psychosis: the
ACE project. Psychol. Med. 38 (5), 725–735.
Job, D.E., Whalley, H., Johnstone, E.C., Lawrie, S.M., 2005. Grey matter changes
over time in high risk subjects developing schizophrenia. NeuroImage
Johannessen, J.O., McGlashan, T.H., Larsen, T.K., Horneland, M., Joa, I., Mardal,
S., et al., 2001. Early detection strategies for untreated first-episode
psychosis. Schizophr. Res. 51 (1), 39–46.
Johannessen, J.O., Larsen, T.K., Joa, I., Melle, I., Friis, S., Opjordsmoen, S., et al.,
2005. Pathways to care for first-episode psychosis in an early detection
healthcare sector: part of the Scandinavian TIPS study. Br. J. Psychiatry
Suppl. 48, s24–28.
Johns, L.C., van Os, J., 2001. The continuity of psychotic experiences in the
general population. Clin. Psychol. Rev. 21 (8), 1125–1141.
Johnstone, E.C., Owens, D.G., Crow, T.J., Davis, J.M., 1999. Does a four-week
delay in the introduction of medication alter the course of functional
psychosis? J. Psychopharmacol. 13 (3), 238–244.
Kahn, R.S., Fleischhacker, W.W., Boter, H., Davidson, M., Vergouwe, Y., Keet, I.P.,
et al., 2008. Effectiveness of antipsychotic drugs in first-episode schizo-
phrenia and schizophreniform disorder: an open randomised clinical trial.
Lancet 371 (9618), 1085–1097.
Kane, J.M., Malhotra, A., 2003. The future of pharmacotherapy for
schizophrenia. World Psychiatry 2 (2), 81–86.
Keshavan, M.S., Amirsadri, A., 2007. Early intervention in schizophrenia:
current and future perspectives. Curr. Psychiatry Rep. 9 (4), 325–328.
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
Killackey, E., Yung, A.R., 2007. Effectiveness of early intervention in
psychosis. Curr. Opin. Psychiatry 20 (2), 121–125.
Killackey, E., Jackson, H.J., McGorry, P.D., 2008. Vocational intervention in
first-episode psychosis: individual placement and support v. treatment
as usual. Br. J. Psychiatry 193 (2), 114–120.
Konopaske, G.T., Dorph-Petersen, K.A., Pierri, J.N., Wu, Q., Sampson, A.R.,
Lewis, D.A., 2007. Effect of chronic exposure to antipsychotic medication
on cell numbers in the parietal cortex of macaque monkeys. Neuropsy-
chopharmacol. 32 (6), 1216–1223.
Lambert, T.J., Chapman, L.H., 2004. Diabetes, psychotic disorders and antipsy-
chotic therapy: a consensus statement. Med. J. Aust. 181 (10), 544–548.
Larsen, T.K., Melle, I., Auestad, B., Friis, S., Haahr, U., Johannessen, J.O., et al.,
2006. Early detection of first-episode psychosis: the effect on 1-year
outcome. Schizophr. Bull. 32 (4), 758–764.
Laurens, K.R., Hodgins, S., Maughan, B., Murray, R.M., Rutter, M.L., Taylor, E.A.,
2007. Community screening for psychotic-like experiences and other
putative antecedents of schizophrenia in children aged 9–12 years.
Schizophr. Res. 90 (1–3), 130–146.
Le Grange, D., Loeb, K.L., 2007. Early identification and treatment of eating
disorders: prodrome to syndrome. Early Intervent. in Psychiatry 1, 27–39.
Lehtinen, V., Aaltonen, J., Koffert, T., Rakkolainen, V., Syvalahti, E., 2000. Two-
year outcome in first-episode psychosis treated according to an
integrated model. Is immediate neuroleptisation always needed? Eur.
Psychiatry 15 (5), 312–320.
Lenior, M.E., Dingemans, P.M., Linszen, D.H., de Haan, L., Schene, A.H., 2001.
Social functioning and the course of early-onset schizophrenia: five-year
follow-up of a psychosocial intervention. Br. J. Psychiatry 179, 53–58.
Lewis, S., Tarrier, N., Haddock, G., Bentall, R., Kinderman, P., Kingdon, D., et al.,
2002. Randomised controlled trial of cognitive-behavioural therapy in
early schizophrenia: acute-phase outcomes. Br. J. Psychiatry 181 (Suppl
Lieberman, J.A., Stroup, T.S., McEvoy, J.P., Swartz, M.S., Rosenheck, R.A.,
with chronic schizophrenia. N. Engl. J. Med. 353 (12), 1209–1223.
Lieberman, J.A., Tollefson, G.D., Charles, C., Zipursky, R., Sharma, T., Kahn, R.S.,
et al., 2005b. Antipsychotic drug effects on brain morphology in first-
episode psychosis. Arch. Gen. Psychiatry 62 (4), 361–370.
Linszen, D., Lenoir, M., De Haan, L., Dingemans, P., Gersons, B., 1998. Early
intervention, untreated psychosis and the course of recent onset
schizophrenia. Br. J. Psychiatry 172 (Suppl 33), 84–89.
Llorca, P.M., Chereau, I., Bayle, F.J., Lancon, C., 2002. Tardive dyskinesias and
antipsychotics: a review. Eur. Psychiatry 17 (3), 129–138.
Loebel, A.D., Lieberman, J.A., Alvir, J.M., Mayerhoff, D.I., Geisler, S.H.,
Szymanski, S.R., 1992. Duration of psychosis and outcome in first-
episode schizophrenia. Am. J. Psychiatry 149 (9), 1183–1188.
Macneil, C.A., Hasty, M.K., Redlich, C., Berk, M., 2009. The therapeutic
alliance: is it necessary or sufficient to engender positive outcomes? Acta
Neuropsychiatrica 2, 95–98.
Malla, A.K., Norman, R.M., Joober, R., 2005. First-episode psychosis, early
intervention, and outcome: what have we learned? Can. J. Psychiatry 50
Marshall, M., Lewis, S., Lockwood, A., Drake, R., Jones, P., Croudace, T., 2005.
Association between duration of untreated psychosis and in cohorts of
first-episode outcome patients — a systematic review. Arch. Gen.
Psychiatry 62 (9), 975–983.
McGlashan, T.H., 1998. Early detection and intervention of schizophrenia:
rationale and research. Br. J. Psychiatry 172 (Suppl 33), 3–6.
McGlashan, T.H., 2006. Rationale and parameters for medication-free
research in psychosis. Schizophr. Bull. 32 (2), 300–302.
McGlashan, T., Johannessen, J., 1996. Early detection and intervention with
schizophrenia: rationale. Schizophr. Bull. 22, 201–222.
McGorry, P.D., 2007a. Issues for DSM-V: clinical staging: a heuristic pathway
to valid nosology and safer, more effective treatment in psychiatry. Am. J.
Psychiatry 164 (6), 859–860.
McGorry, P.D., 2007b. The specialist youth mental health model: strength-
ening the weakest link in the public mental health system. Med. J. Aust.
187 (7 Suppl), S53–56.
McGorry, P.D., Yung, A.R., 2003. Early intervention in psychosis: an overdue
reform. Aust. NZ. J. Psychiatry 37, 393–398.
McGorry, P.D., Edwards, J., Mihalopoulos, C., Harrigan, S., Jackson, H., 1996.
EPPIC — an evolving system of early detection and optimal management.
Schizophr. Bull. 22, 305–326.
McGorry, P.D., Hickie, I.B., Yung, A.R., Pantelis, C., Jackson, H.J., 2006. Clinical
staging of psychiatric disorders: a heuristic framework for choosing
earlier, safer and more effective interventions. Aust. NZ J. Psychiatry vol
40 (8), 616–622 Aug 2006.
McGorry, P.D., Killackey, E., Yung, A.R., 2007a. Early intervention in psychotic
disorders: detection and treatment of the first episode and the critical
early stages. Med. J. Aust. 187 (7 Suppl), S8–10.
McGorry, P.D., Purcell, R., Hickie, I.B., Yung, A.R., Pantelis, C., Jackson, H.J.,
2007b. Clinical staging: a heuristic model for psychiatry and youth
mental health. Med. J. Aust. 187 (7), S40–S42.
McGorry, P.D., Killackey, E., Yung, A., 2008. Early intervention in psychosis:
concepts,evidenceand future directions. WorldPsychiatry7 (3), 148–156.
McNulty, J., 2006. Medication-free research in early episode schizophrenia:
why on earth would I choose to participate in such research? Schizophr.
Bull. 32 (2), 305–306.
Melle, I., Larsen, T.K., Haahr, U., Friis, S., Johannessen, J.O., Opjordsmoen, S., et
al., 2004. Reducing the duration of untreated first-episode psychosis:
effects on clinical presentation. Arch. Gen. Psychiatry 61 (2), 143–150.
Melle, I., Johannesen, J.O., Friis, S., Haahr, U., Joa, I., Larsen, T.K., et al., 2006.
Early detection of the first episode of schizophrenia and suicidal
behavior. Am. J. Psychiatry 163 (5), 800–804.
Miller, A.H., Maletic, V., Raison, C.L., 2009. Inflammation and its discontents:
the role of cytokines in the pathophysiology of major depression. Biol.
Psychiatry 65 (9), 732–741.
Morrison, A.P., 2001. The interpretation of intrusions in psychosis: an
integrative cognitive approach to hallucinations and delusions. Behav.
and Cogn. Psychother. 29, 257–276.
Morrison, A.P. (Ed.), 2002. A Casebook of Cognitive Therapy for Psychosis.
Brunner-Routledge, New York.
Muench, J., Carey, M., 2001. Diabetes mellitus associated with atypical
antipsychotic medications: new case report and review of the literature.
J. Am. Board Fam. Pract. 14 (4), 278–282.
Nakamura, M., Salisbury, D.F., Hirayasu, Y., Bouix, S., Pohl, K.M., Yoshida, T.,
et al., 2007. Neocortical gray matter volume in first-episode schizophre-
nia and first-episode affective psychosis: a cross-sectional and longitu-
dinal MRI study. Biol. Psychiatry 62 (7), 773–783.
Nordentoft, M., Jeppesen, P., Abel, M., Kassow, P., Petersen, L., Thorup, A., et al.,
2002. OPUS study: suicidal behaviour, suicidal ideation and hopelessness
among patients with first-episode psychosis: one-year follow-up of a
randomised controlled trial. Br. J. Psychiatry 181 (Suppl 43), s98–s106.
Oehl, M., Hummer, M., Fleischhacker, W.W., 2000. Compliance with
antipsychotic treatment. Acta Psychiatr. Scand. Suppl. 407, 83–86.
Pantelis, C., Yücel, M., Wood, S.J., McGorry, P.D., Velakoulis, D., 2003. Early
and late neurodevelopmental disturbances in schizophrenia and their
functional consequences. Aust. NZ J. Psychiatry 37, 399–406.
Penn, D.L., Waldheter, E.J., Perkins, D.O., Mueser, K.T., Lieberman, J.A., 2005.
Psychosocial treatment for first-episode psychosis: a research update.
Am. J. Psychiatry 162 (12), 2220–2232.
Perkins, D.O., 1999. Adherence to antipsychotic medications. J. Clin.
Psychiatry 60 (Suppl 21), 25–30.
Perkins, D.O., Gu, H., Boteva, K., Lieberman, J.A., 2005. Relationship between
a critical review and meta-analysis. Am. J. Psychiatry 162 (10), 1785–1804.
Poulton, R., Caspi, A., Moffitt, T.E., Cannon, M., Murray, R.M., Harrington, H.,
2000. Children's self-reported psychotic symptoms and adult schizo-
phreniform disorder: a 15-year longitudinal study. Arch. Gen. Psychiatry
Power, P.J.R., Bell, R., Mills, R., Al, E., 2003. Suicide prevention in first episode
psychosis: the development of a randomised controlled trial of cognitive
therapy for acutely suicidal patients with early psychosis. Aust. NZ J.
Psychiatry 37, 414–420.
Riecher-Rossler, A., Pflueger, M.O., Aston, J., Borgwardt, S.J., Brewer, W.J.,
psychosis: a 7-year follow-up. Biol. Psychiatry 66 (11), 1023–1030.
Rosen, J.L., Miller, T.J., D'Andrea, J.T., McGlashan, T.H., Woods, S.W., 2006.
Comorbid diagnoses in patients meeting criteria for the schizophrenia
prodrome. Schizophr. Res. vol 85 (1–3), 124–131 Jul 2006.
Sachs, G.S., Thase, M.E., Otto, M.W., Bauer, M., Miklowitz, D., Wisniewski, S.R.,
et al., 2003. Rationale, design, and methods of the systematic treatment
enhancement program for bipolar disorder (STEP-BD). Biol. Psychiatry
53 (11), 1028–1042.
2008. Impact of duration of untreated psychosis on pre-treatment, baseline,
and outcome characteristics in an epidemiological first-episode psychosis
cohort. J. Psychiatry Res. 42 (12), 982–990.
in early episode schizophrenia”. Schizophr. Bull. 32 (2), 297–298.
Scott, J., Paykel, E., Morriss, R., Bentall, R., Kinderman, P., Johnson, T., et al.,
2006. Cognitive-behavioural therapy for severe and recurrent bipolar
disorders: randomised controlled trial. Br. J. Psychiatry 188, 313–320.
Singh, S.P., Burns, T., Amin, S., Jones, P.B., Harrison, G., 2004. Acute and
transient psychotic disorders: precursors, epidemiology, course and
outcome. Br. J. Psychiatry 185, 452–459.
Stahl, S.M., Mignon, L., Meyer, J.M., 2009. Which comes first: atypical
antipsychotic treatment or cardiometabolic risk? Acta Psychiatr. Scand.
119 (3), 171–179.
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10
Subramaniam, M., Pek, E., Verma, S., Chan, Y.H., Chong, S.A., 2007. Diagnostic Download full-text
stability 2 years after treatment initiation in the Early Psychosis
Intervention Programme in Singapore. Aust. NZ J. Psychiatry 41 (6),
Szymanski, S.R., Cannon, T.D., Gallacher, F., Erwin, R.J., Gurr, R.E.,1996. Course
of treatment response in first episode and chronic schizophrenia. Am. J.
Psychiatry 153, 519–525.
Takahashi, T., Malhi, G.S., Wood, S.J., Walterfang, M., Yucel, M., Lorenzetti, V.,
et al., 2009. Increased pituitary volume in patients with established
bipolar affective disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry
33 (7), 1245–1249.
Tarrier, N., 2005. Cognitive behaviour therapy for schizophrenia — a review
of development, evidence and implementation. Psychother. Psychosom.
Tarrier, N., Lewis, S., Haddock, G., Bentall, R., Drake, R., Kinderman, P., et al.,
2004. Cognitive-behavioural therapy in first-episode and early schizo-
phrenia. 18-month follow-up of a randomised controlled trial. Br. J.
Psychiatry 184, 231–239.
Thompson, P.M., Vidal, C., Giedd, J.N., Gochman, P., Blumenthal, J., Nicolson,
R., et al., 2001. Mapping adolescent brain change reveals dynamic wave
of accelerated gray matter loss in very early-onset schizophrenia. Proc.
Natl. Acad. Sci. 98 (20), 11,650–11,655.
et al., 2007. Metabolic side effects of antipsychotic medication. Int. J. Clin.
Pract. 61 (8), 1356–1370.
van der Heijden, F.M., Tuinier, S., Arts, N.J., Hoogendoorn, M.L., Kahn, R.S.,
Verhoeven, W.M., 2005. Catatonia: disappeared or under-diagnosed?
Psychopathol. 38 (1), 3–8.
van Os, J., Hanssen, M., Bijl, R.V., Ravelli, A., 2000. Straus (1969) revisited: a
psychosis continuum in the general population? Schizophr. Res. 45 (1–
Velakoulis, D., Wood, S.J., Wong, M.T., McGorry, P.D., Yung, A., Phillips, L., et
al., 2006. Hippocampal and amygdala volumes according to psychosis
stage and diagnosis: a magnetic resonance imaging study of chronic
schizophrenia, first-episode psychosis, and ultra-high-risk individuals.
Arch. Gen. Psychiatry 63 (2), 139–149.
Warden, D., Rush, A.J., Trivedi, M.H., Fava, M., Wisniewski, S.R., 2007. The
STAR*D Project results: a comprehensive review of findings. Curr.
Psychiatry Rep. 9 (6), 449–459.
Whitty, P., Clarke, M., McTigue, O., Browne, S., Kamali, M., Larkin, C., et al.,
2005. Diagnostic stability four years after a first episode of psychosis.
Psychiatr. Serv. 56 (9), 1084–1088.
Wood, S.J., Brewer, W.J., Koutsouradis, P., Phillips, L.J., Francey, S.M., Proffitt,
T.M., et al., 2007. Cognitive decline following psychosis onset: data from
the PACE clinic. Br. J. Psychiatry Suppl. 51, s52–57.
Yung, A.R., Buckby, J.A., Cotton, S.M., Cosgrave, E.M., Killackey, E.J., Stanford,
C., et al., 2006. Psychotic-like experiences in nonpsychotic help-seekers:
associations with distress, depression, and disability. Schizophr. Bull. 32
Yung, A.R., Yuen, H.P.,Berger,G., Francey, S., Hung, T.C., Nelson, B., et al., 2007.
Declining transition rate in ultra high risk (prodromal) services: dilution
or reduction of risk? Schizophr. Bull. 33 (3), 673–681.
Yung, A.R., Nelson, B., Baker, K., Buckby, J.A., Baksheev, G., Cosgrave, E.M.,
2009. Psychotic-like experiences in a community sample of adolescents:
implications for the continuum model of psychosis and prediction of
schizophrenia. Aust. NZ J. Psychiatry 43 (2), 118–128.
S.M. Francey et al. / Schizophrenia Research 119 (2010) 1–10