672725

research-article2016
ANP0010.1177/0004867416672725ANZJP ArticlesCatts and O’Toole

Key Review

Australian & New Zealand Journal of Psychiatry

The treatment of schizophrenia: Can 2016, Vol. 50(12) 1128­–1138

DOI: 10.1177/0004867416672725

we raise the standard of care? © The Royal Australian and

New Zealand College of Psychiatrists 2016
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
anp.sagepub.com

Stanley Victor Catts1,2,3 and Brian Ignatius O’Toole2

Abstract
Objective: There is evidence that over time health outcomes of people with schizophrenia are deteriorating rather
than improving both in terms of mortality rate and levels of morbidity, even in Australia where service resourcing is
substantial. Our objective was to examine the evidence of whether poor outcomes reflect decreases in treatment
effectiveness and, if so, what are the barriers to improving standards of care. This review will argue that the confidence of
clinicians to diagnose schizophrenia early, and provide assertive and long-term care, may be being undermined by a series
of controversies in the published literature and discrepancies in clinical practice guidelines.
Method: A critical review was conducted of the evidence regarding six issues of high clinical relevance to the treatment of
schizophrenia formulated as questions: (1) Is schizophrenia a progressive disease? (2) Does relapse contribute to disease
progression and treatment resistance? (3) When should the diagnosis of schizophrenia be made? (4) Should maintenance
antipsychotic medication be discontinued in fully remitted first-episode patients? (5) Do antipsychotic medications cause
deleterious reductions in cortical grey matter volumes? and (6) Are long-acting injectable antipsychotics more effective
in reducing relapse rate compared to oral formulations?
Results: There is reliable evidence for schizophrenia being a progressive disease with emergent treatment resistance in
most cases, that relapse contributes to this treatment resistance, that maintenance antipsychotic medication should not
be discontinued in remitted first-episode patients, that antipsychotic medication does not appear to cause deleterious
grey matter volume changes, that maintenance antipsychotic medication reduces the mortality rate in schizophrenia and
that long-acting injectable antipsychotics are more effective in preventing relapse than oral formulations.
Conclusion: There is an urgent need to re-engineer the early management of schizophrenia and to routinely evaluate this
type of innovation within practice-based research networks. A proposal for an assertive treatment algorithm is included.

Keywords
Schizophrenia, treatment, outcomes, medication, algorithm

Introduction
The standard index of progress being made in a disease field
at a population level is mortality rate (MR) – greater treat-
ment effectiveness indicated by reductions in the MR of
patients over time. Other metrics used to compare outcomes
across disease areas, which capture both fatal and non-fatal
health losses, are quality-adjusted life years (QALYs) or
disability-adjusted life years (DALYs); however, rarely are
sets of time series data on these indices collected: certainly
schizophrenia (Saha et al., 2007). Meta-analysis of MRs of
people with schizophrenia show that in the 1970s standard-
ised MRs were increased 1.84-fold over those of the general
population, in the 1980s they were increased 2.98-fold and
1Disciplineof Psychiatry, Royal Brisbane Clinical School, School of
Medicine, The University of Queensland, Herston, QLD, Australia
2Brain and Mind Centre, The University of Sydney, Camperdown, NSW,

they do not exist for mental disorders (Doessel et al., 2010).
Despite the partial nature of MR as a health outcome meas-
ure, it has been informatively applied to mental disorders,
where there is a clear trend for mental disorder–related MR
to be increasing in Australia over time (Doessel et al., 2010),
this trend being particularly marked for people with
Australia
3Neuroscience Research Australia, Randwick, NSW, Australia
Corresponding author:
Stanley Victor Catts, K Floor, Mental Health Centre, Royal Brisbane and
Women’s Hospital, Herston, QLD 4029, Australia.
Email: s.catts@uq.edu.au

Australian & New Zealand Journal of Psychiatry, 50(12)

Catts and O’Toole 1129
in the 1990s they were increased 3.20-fold (Saha et al.,
2007). These high MRs appear likely to have continued into
the last decade (Reininghaus et al., 2015; Torniainen et al.,
2015). That is, mental illness is the only broad disease field
in the Australian healthcare system that has not shown at
least numeric improvement in MRs in recent decades
(Doessel et al., 2010), with people with schizophrenia show-
ing a large deterioration in MRs (Saha et al., 2007).
Complementing studies of MR are morbidity data sug-
gesting that low treatment effectiveness for people with
schizophrenia should be of concern. First, there is evidence
that the overall recovery rate in schizophrenia is very low,
when strictly defined as it was in the most recent meta-anal-
ysis of longitudinal studies of schizophrenia (Jaaskelainen
et al., 2013). This meta-analysis, which included 8994
patients from 20 different countries including Australia,
estimated the median recovery rate to be 13.5% – that is,
for every 100 patients with schizophrenia, only 1 or 2 will
meet recovery criteria per year. As Jaaskelainen et al. note,
their most ‘sobering’ finding was that studies from recent
decades reported numerically the lowest recovery rates.
Second and also consistent with reduced or at least non-
improving treatment effectiveness are the two recent
Australian national surveys of people living with psychosis
carried out 10 years apart in 1997–1998 and 2010 (Morgan
et al., 2012). In the 10 years between the two national sur-
veys of people living with psychosis, there were no measur-
able improvements in major indicators of disability.
Specifically, these surveys (Morgan et al., 2012) show that
pension rates had not changed (86.9% in 1997–1998 vs
87.4% in 2010), and there was a numeric increase in rates
of deterioration from premorbid level of function (80.2% in
1997–1998 vs 93% in 2010) despite there being equivalent
relatively high rates of good premorbid work/social adjust-
ment prior to first presentation (68.0/65.6% in 1997–1998
vs 69.0/64.9% in 2010). Also, there was almost a doubling
of rates of lifetime co-morbid drug abuse/dependence
(30.4% in 1997–1998 vs 56.4% in 2010). Considering that
government expenditure on Australian public mental health
services more than doubled across the same period of time
(Department of Health and Ageing, 2013: Figure 5), the
figures above indicate a need for change in clinical practice
if additional investment is to show measurable improve-
ments in health outcomes for people with schizophrenia.
This paper is predicated on the view that health out-
comes and therefore treatment effectiveness are deteriorat-
ing over time for people with schizophrenia, although this
view may be contrary to the position adopted in the recently
published revision of the Royal Australian and New
Zealand College of Psychiatrists (RANZCP) Clinical
Practice Guidelines (CPG) for the Management of
Schizophrenia and Related Disorders (Galletly et al., 2016;
hereafter referred to as the 2016 RANZCP CPG). This
review is also based on the assumption that confidence of
clinicians to diagnose schizophrenia early, and provide
assertive and long-term care, may be being undermined by
a series of uncertainties and controversies in the published
literature, which include discrepancies in CPG. These con-
troversies are the subject matter of this review.
Approach to the reviewing process
The six clinical issues reviewed were selected because (1)
the authors considered them highly relevant to the clinical
practice of psychiatrists treating schizophrenia and likely to
be impactful on health outcomes, (2) they have been the sub-
ject of extended and unresolved debate in the published lit-
erature and (3) their controversial nature is reflected in
discrepancies across influential sets of CPG. Six questions
that confront clinicians are as follows: (1) Is schizophrenia a
progressive disease? (2) Does relapse contribute to treatment
resistance? (3) When should the diagnosis of schizophrenia
be made? (4) Should maintenance antipsychotic medication
be discontinued in fully remitted first-episode patients? (5)
Do antipsychotic medications cause deleterious reductions in
cortical grey matter volumes? (6) Are long-acting injectable
antipsychotics (LAIAs) more effective in reducing relapse
rate compared to oral formulations?
This critical review results from a series of focused litera-
ture searches on each of the six questions. Although a system-
atic review would have been desirable, a critical review
approach was the only feasible way to integrate the vast litera-
ture and to advance an understanding of the issues arising.
Selection of material was strongly weighted by relevance,
after fatally flawed studies were excluded. The review sug-
gests that a re-engineering of the first hospital admission might
substantially raise the standard of care. The word ‘patients’
with schizophrenia is used with the aim of conveying a sense
of doctor responsibility for leading practice reform. The
review is presented under the six question subheadings.
Is schizophrenia a progressive disease?
The notion of disease progression in schizophrenia is often
conceptualised as involving neurodegenerative cell loss as
Kraepelin initially proposed, but obvious cell loss has not
been confirmed in post-mortem brain tissue studies of
schizophrenia (Joshi et al., 2015). In a recent paper titled
‘The myth of schizophrenia as a progressive disease’, lead-
ing researchers (Zipursky et al., 2013) argued that schizo-
phrenia is not inherently progressive at all, despite the
well-established finding of progressive magnetic resonance
imaging (MRI)-indexed grey matter volume loss occurring
following the first episode, a finding not disputed by these
researchers. Although Zipursky et al. concur with us that
‘the majority of people with schizophrenia have the poten-
tial to achieve long-term remission and full recovery’, logi-
cally they appear to call into question the value of assertive
early intervention because it can be argued that a non-­
progressive disease does not require specialised early
Australian & New Zealand Journal of Psychiatry, 50(12)
1130 ANZJP Articles
intervention as a major priority and that indeed early and
sustained treatment may represent a serious risk as these
researchers propose that antipsychotic medication exposure
rather than disease progression accounts for much of the
accelerated brain volume loss after the first episode (see
Question 5 below), loss that has been linked to a worse
prognosis (Van Haren et al., 2008). The 2016 RANZCP
CPG endorsement of a staged model for schizophrenia
appears to give tacit support for schizophrenia being a pro-
gressive disease, as this review concludes.
Progression could be a more subtle molecular level pro-
cess, yet still cause persistent or irreversible effects such as
progressive emergence of treatment resistance. Most
patients (65–69%) have a good premorbid function (Morgan
et al., 2012) consistent with the possibility that they may
have the prospect of a good long-term outcome (Wiersma
et al., 1998). Antipsychotic drug treatment is extremely
effective in the first episode of schizophrenia with at least
70–80% of patients achieving a full remission in the short
term (Lieberman et al., 1993; Malla et al., 2006; Zipursky
et al., 2013). Put another way, at illness onset only 20–30%
of patients show significant treatment resistance when first
treated with antipsychotic medication. After two trials of
antipsychotics, one of which should preferably be an LAIA
(2016 RANZCP CPG), this subgroup of patients is immedi-
ately eligible for clozapine and other effective treatment
strategies and should receive these in a timely manner.
Irrespective of the favourable outcomes at the first episode,
overall the rate of recovery for the total population of
patients with schizophrenia declines to 13.5% (Jaaskelainen
et al., 2013). This decline in treatment responsiveness
appears to occur during the 5 years after the first episode
(Robinson et al., 2004). In the seminal Hillside Hospital
first-episode schizophrenia study, 84% of patients recov-
ered (i.e. 16% did not remit) from the first episode
(Lieberman et al., 1992). However, within 5 years of first
presentation, 86.3% of patients failed to meet full criteria
for recovery (Robinson et al., 2004). That is, in this study,
70.3% (i.e. 86.3%–16%) of the patients who achieved full
remission after the first episode developed treatment resist-
ance by the 5-year time point (Robinson et al., 1999, 2004).
The major treatment history events that interceded between
the high recovery rates at first episode and the low recovery
rates 5 years later were repeated episodes of non-compli-
ance and relapse, with at least 80% of patients in this expert
treatment study relapsing in the intervening period
(Robinson et al., 1999). This leads to the question of
whether relapse has a mediating role in the emergence of
treatment resistance after the first episode.
Does relapse contribute to disease
progression and treatment resistance?
An obvious conundrum is that schizophrenia goes from
being a relatively treatment-responsive disorder at first
Australian & New Zealand Journal of Psychiatry, 50(12)
presentation to one that is treatment resistant in almost all
multi-episode patients. Robustly supporting the likelihood
that relapse is directly associated with progressive emer-
gence of treatment refractoriness and psychosocial deterio-
ration is the body of literature that shows (1) there are
step-wise increases in the number of patients who do not
recover (i.e. who do not respond well to medication if
received) after successive relapses (Bleuler, 1978 [1972];
Ciompi, 1980; Emsley et al., 2012, 2013; Shimazono, 1973;
Watt et al., 1983; Wiersma et al., 1998); (2) there is
increased time to antipsychotic treatment response for
recurrent episodes versus first-episode schizophrenia
(Emsley et al., 2012, 2013; Lieberman et al., 1996; Wyatt,
1991); (3) the dose of medication needed to achieve remis-
sion in first-episode patients is lower than that recom-
mended for multi-episode patients (McEvoy et al., 1991;
Merlo et al., 2002; Oosthuizen et al., 2004); and (4) un-
medicated patients who are allowed to relapse and subse-
quently placed on medication do not achieve the same level
of remission compared with patients maintained on medi-
cation who do not relapse (Gopal et al., 2011; McEvoy
et al., 1991; Merlo et al., 2002; Oosthuizen et al., 2004;
Wyatt, 1991). Duration of relapse, defined as the sum of the
duration of all relapse episodes that occurred between MRI
scans, has been reported to be related to the extent of brain
volume changes (Andreasen et al., 2013). In a cohort study
in which 80% of patients deteriorated over a 7-year follow-
up period, there was a highly significant correlation
between the number of relapses and degree of social dete-
rioration (Curson et al., 1985).
These studies are clinical cohort studies and only offer
evidence of an association between relapse and emergent
treatment resistance. They raise the question of whether the
treatment resistance emerging after the first episode would
have happened irrespective of what treatment the patient
received. That is, are relapses simply a manifestation of a
pre-existing genetic and developmental proneness to treat-
ment resistance that is hard-wired into the brain prior to the
first episode in poor prognosis patients? Or in 70–80% of
patients is emergent treatment resistance induced by long
periods of non-adherence to antipsychotic medication and
multiple prolonged relapses (similar to the relationship
between duration of illness/number of relapses and evi-
dence of disease progression/poorer outcomes in major
depression and bipolar disorder [Bora et al., 2010; Sheline
et al., 2003; Treadway et al., 2015]). The main argument for
relapse as the cause of treatment resistance in schizophre-
nia is the temporal relationship between the two: relapses
occur before treatment resistance emerges. Particularly
compelling studies are those of un-medicated patients who
are allowed to relapse and who are subsequently placed on
medication. These patients do not achieve the same level of
remission compared with patients maintained on medica-
tion who do not relapse (Gopal et al., 2011; McEvoy et al.,
1991; Merlo et al., 2002; Oosthuizen et al., 2004; Wyatt,
Catts and O’Toole 1131
1991). In studies of patients with disease onsets occurring
substantially before the discovery and introduction of
antipsychotic medication, the greater duration of untreated
illness is associated with greater gross functional deteriora-
tion (Scully et al., 1997; Waddington et al., 1995), suggest-
ing in these patients that the delay in treatment contributed
to poor prognosis independently of constitutional predispo-
sition. However, is the converse true: Is avoidance of
relapse associated with better long-term outcomes? We are
aware of only one first-episode study with long-term fol-
low-up (up to 9 years) in which adherence was very high
and relapse rate was very low (Girgis et al., 2011). In this
study of 160 Chinese patients living in China randomised
to either clozapine or chlorpromazine for up to 2 years and
thereafter given naturalistic treatment, adherence was
objectively monitored using pill counts, and remission/
relapse status was the primary outcome measure. Patients
took medication most days over the 9-year follow-up (77%
for clozapine and 66% for chlorpromazine), and there were
few relapses (about 10% of patients relapsing over the
7-year period). In contrast to long-term follow-up studies
of patients with poor adherence, high relapse rates and poor
outcomes, Girgis et al. found that high levels of adherence
and low relapse rate were associated with maintenance of
remission status 9 years after the first episode (78% for
both groups). Regrettably, there is not a single biological
study that directly assesses the pathophysiological conse-
quences of relapse and whether some of the brain changes
associated with relapse are permanent and cause emerging
treatment resistance. This type of study would require a
large multi-centre sample, long-term follow-up and
repeated biomarker assessment in and out of relapses, and
on and off medication. Currently, such a clinically impor-
tant study is not likely to happen in Australia under current
research funding processes.
Clinicians are reminded that CPG only offer guidance:
they are not based on certainty; all treatment recommenda-
tions have only a probability of being correct. Clinical
judgement remains the final arbiter. Until there is absolute
adequacy of research, clinicians are individually left to
decide whether or not to prioritise relapse prevention as the
most powerful modifiable risk factor for long-term poor
outcome in schizophrenia. Most experienced acute care cli-
nicians know too well that keeping remitted first-episode
patients on maintenance medication avoids the worst
aspects of the otherwise almost inevitable deterioration in
psychosocial function that currently occurs in most patients
(Robinson et al., 1999, 2004). The main problem clinicians
confront in keeping first-episode patients well is how to
maintain long-term medication adherence. Irrespective of
gaps in direct evidence about the damaging effects of
relapse, one might think that the deteriorating outcomes for
schizophrenia associated with our current system might
stimulate urgent innovation and evaluation of assertive
approaches to the prevention of relapse right from the first
episode, approaches that may also be effective in reducing
rates of suicide, co-morbid substance misuse and physical
health co-morbidity and for these approaches to be consid-
ered best practice. But these approaches require that the
diagnosis of schizophrenia be made as early as possible.
When should the diagnosis of schizophrenia
be made?
An unfortunate by-product of the early psychosis interven-
tion paradigm has been the encouragement of delayed and
imprecise diagnosis, especially in the case of schizophre-
nia. There are explicit statements discouraging clinicians
from making and telling patients about the diagnosis of
schizophrenia in early psychosis training manuals:
An early and definitive diagnosis of schizophrenia, for
example, may damage the patient and family, by stigmatising
them and affecting the way that they are viewed and managed
by healthcare professionals. In addition, such a diagnosis does
not contribute anything positive in terms of guiding treatment.
(McGorry and Edwards, 1997)
This advice has persisted into the second edition of the
Australian Clinical Guidelines for Early Psychosis
(ACGEP; Early Psychosis Guidelines Writing Group,
2010):
the traditional pessimism associated with the diagnosis of
schizophrenia has permeated professional and popular culture
to some extent. Making a rigid and too specific diagnosis may
therefore not only be unreliable but have iatrogenic effects on
both the clinician and client optimism and the potential for
recovery.
As far as the authors are aware, schizophrenia is the only
disease for which CPG encourage delayed diagnosis. Delay
appears to be justified on two grounds. One purported rea-
son is the belief that the diagnosis of schizophrenia is unsta-
ble over time, despite this view not being supported by
empirical evidence (Farooq et al., 2016). On occasion, the
initial diagnosis of schizophrenia will be wrong, so regular
diagnostic review especially in the first 6–12 months is
essential. The other reason appears to relate to the belief
that disclosure of bad news will cause anguish and deny
patients hope: this old fashioned view has been addressed
by communication training for clinicians in physical medi-
cine (Farooq et al., 2016).
Not making the diagnosis of schizophrenia as early as
possible may have serious consequences if it leads to a less
assertive approach to medication adherence and relapse
prevention, and not urgently providing psychoeducation
about the need for long-term maintenance antipsychotic
therapy as soon as the diagnosis is made. Currently, advice
against early diagnosis appears to be coupled with giving
medication adherence a lower priority by proponents of
Australian & New Zealand Journal of Psychiatry, 50(12)
1132 ANZJP Articles
early psychosis services. That is reflected in an absence of
recommendations about evidence-based objective adher-
ence monitoring (e.g. electronic medication event monitor-
ing, pill counts or checking pharmacy refill records). There
is no reference to evidence-based adherence improvement
interventions (e.g. multi-component interventions combin-
ing unit-of-use packaging, patient motivational counselling
and family psychoeducation [Dolder et al., 2003; Valenstein
et al., 2011; Velligan et al., 2008; Zygmunt et al., 2002])
when oral antipsychotic formulations are prescribed, in
either the 2016 RANZCP CPG or the ACGEP.
Compounding this issue is the inclusion of highly ambiva-
lent or negative statements about the use of LAIA, e.g., in
the 2005 RANZCP CPG Team for the Treatment of
Schizophrenia and Related Disorders (2005) it is stated that
‘Excessive use of depot antipsychotics as a crude response
to the widespread lack of adherence to oral medications had
been another unfortunate feature of the landscape of care,
especially in Australia’. This sentiment dilutes advice
against early use of LAIAs in the 2016 RANZCP CPG:
‘Oral SGAs should be prescribed as first- and second line
treatments for people with FEP’. These recommendations
may be affecting the practice of early psychosis clinicians
who appear to typically use oral formulations without
implementing evidence-based adherence monitoring and
improvement interventions (Brown and Gray, 2015; Farooq
and Farooq, 2014). If the diagnosis of schizophrenia is
made, objective adherence monitoring and improvement
interventions are arguably essential in all cases where oral
antipsychotic medications are prescribed because patient
self-report of their adherence to antipsychotics and the doc-
tor’s opinion about which of their patients are adherent or
non-adherent with oral antipsychotics are completely unre-
liable (Byerly et al., 2007; Velligan et al., 2007), and
because of the high rates of service disengagement and
non-adherence particularly in first-episode patients (see
Question 6 below and the ACGEP). Given the major treat-
ment implications of the diagnosis of schizophrenia for
early and sustained care, it is in the patient’s interest to
make this diagnosis as early as possible.
Should maintenance antipsychotic
medication be discontinued in fully remitted
first-episode patients?
There are marked discrepancies across influential CPG and
medication algorithms about the recommended period of
maintenance antipsychotic medication and if and when to
discontinue it (Takeuchi et al., 2012). Takeuchi et al. identi-
fied 14 CPG and medication algorithms and found that only
5 had clear definitions of the maintenance phase and its
treatment; 6 of them did not argue against antipsychotic
discontinuation after 1–2 years of treatment in patients with
first-episode schizophrenia, while in chronically ill patients,
10 of the 11 recommended continuation of medication for
Australian & New Zealand Journal of Psychiatry, 50(12)
5 years but not indefinitely. The 2016 RANZCP CPG do
not recommend against discontinuation or for indefinite
maintenance antipsychotic medication in patients with
schizophrenia: ‘The person should have made a full recov-
ery and been well for at least 12 months before cessation of
medication is considered’. The ACGEP also do not give
recommendations for long-term (indefinite) medication for
schizophrenia: ‘There is no clear evidence in FEP as to the
period of time following remission that an individual
should stay on an antipsychotic medication’, but later
states, ‘This suggests maintenance treatment as a rule of
thumb if remission has been achieved for six months or
less; at least one year following remission would be recom-
mended on current practice and previous placebo controlled
trials ...’. Reinforcing a permissive attitude towards medi-
cation discontinuation has been the prominence given to a
recent multi-flawed study (Wunderink et al., 2013), promi-
nence added to by its citation in the 2016 RANZCP CPG.
Wunderink et al. concluded but did not demonstrate that
long-term recovery rates might be higher in remitted first-
episode patients with schizophrenia who discontinue medi-
cation 6 months after remission. Because of the unacceptable
quality of the study (the 2016 RANZCP CPG list five
serious flaws in the study, but there were others including
the following: highly questionable blinding in the first 2
years of the study, and no blinding whatsoever from 2 to 7
years; selective exclusion of patients likely to be uncoop-
erative; and low power making any finding unreliable),
this is an invalid conclusion, and flies in the face of the
overwhelming evidence of the benefits of maintenance
medication, especially in remitted first-episode patients
(see below; Gaebel et al., 2016). Antipsychotic medication
is highly effective in preventing relapse. A recent system-
atic review of antipsychotic discontinuation studies in
remitted first-episode patients with a schizophrenia-related
diagnosis who had been stabilised on medication for an
average of 15 months (range: 12–24 months) showed that
discontinuation of medication was associated with a 77%
relapse rate by the end of the first year and 90% relapse rate
by the end of the second year, while the 1-year relapse rate
in patients who continued maintenance mediation was 3%
(Zipursky et al., 2014).
Apart from relapse prevention, what else has the patient
to gain from maintenance antipsychotic medication? Even
if you question whether maintenance medication prevents
emergent treatment resistance, there are other major bene-
fits. First and foremost, maintenance medication is a life-
saving intervention, especially in first-episode patients
(Torniainen et al., 2015). In first-episode schizophrenia
patients who do not receive antipsychotic medication, the
relative MR is 10 times that of the general population,
whereas the relative MR only shows a twofold increase in
those taking average doses of antipsychotic medication
(Torniainen et al., 2015). One of the saddest results of how
we currently treat schizophrenia is the 20-fold increase in
Catts and O’Toole 1133
suicide rate in first-episode patients during the first 10 years
of their illness compared to region-matched general popu-
lation controls (Reininghaus et al., 2015). Relapse (and
chronic residual psychotic symptoms) has many distressing
consequences, especially for young people who have mul-
tiple socially and vocationally disastrous relapses (Ascher-
Svanum et al., 2006), but the risk that overshadows all
others is the risk of suicide. Although the life-saving bene-
fits of antipsychotics are apparent at all stage of the illness
(Torniainen et al., 2015), they are most obvious in the early
years after first presentation. Despite evidence of adverse
metabolic effects of antipsychotics, these effects were not
found to contribute at all to the raised MR in schizophrenia
in this large (involving an entire national Swedish sample
of 21,492 patients with schizophrenia and 1230 patients
with first-episode schizophrenia prospectively followed
up) methodologically sound study (Torniainen et al., 2015),
clearly implicating unhealthy life style behaviours (e.g.
smoking) and poor preventive medical care as the major
culprits in relation to cardiovascular-related mortality in
patients with schizophrenia. For unknown reasons, this
high-quality pivotal study containing critically important
findings for clinical practice was not cited in the 2016
RANZCP CPG.
Our review strongly supports an early intervention
approach to treatment of schizophrenia: making the diagno-
sis early and initiating assertive long-term care as soon as
possible. The difficulty in finding the right language to ini-
tially inform patients and their families that long-term care
is indicated so early in their treatment should not be under-
estimated: nor the difficulty in overcoming insight deficits
with the effective use of psychotherapeutic frameworks
that have been developed in relation to the cognitive treat-
ment of delusions, motivational interviewing or narrative
therapy (see Table, Supplementary Material). However,
effective early intervention implies these efforts are critical,
and one aim of this review is to increase clinician confi-
dence in presenting the case for long-term maintenance
medication: discontinuation of medication early or late in
the illness denies the patient a life-saving intervention. It is
most effectively started at the first episode (Torniainen
et al., 2015), an intervention that may offer the patient the
best chance of maintaining long-term recovery.
Do antipsychotic medications cause
deleterious reductions in cortical grey matter
volumes?
What has the patient to lose by continuing maintenance
antipsychotic medication? There are researchers (e.g.
Zipursky et al., 2013) who attribute much of the progres-
sive grey matter volume loss seen after the first episode to
antipsychotic medication and not the disease process itself.
Given that volume loss is related to poor prognosis (Van
Haren et al., 2008), one might reasonably assume that the
loss is deleterious. Therefore, this controversy creates a
quandary faced by proponents of long-term antipsychotic
medication, who may have to make the opposing case in
discussions with patients and their families, requiring a full
understanding of the relevant findings. While three meta-
analyses have reported a statistical association between
higher antipsychotic medication dose and increased grey
matter volume reduction (Fusar-Poli et al., 2013; Haijma
et al., 2013; Vita et al., 2015), all of the studies included in
these meta-analyses were not experimentally designed to
test the hypothesis that antipsychotic medication causes
grey matter volume loss and are confounded by indication;
i.e., poor prognosis patients who lose brain volume faster
are likely to be given higher doses of medication by indica-
tion. In an attempt to control for this type of confounding,
researchers statistically ‘partial out’ the effect of prognosis
using ad hoc measures of prognosis they may have col-
lected. However, satisfactory measures of illness prognosis
were not collected a priori. Indeed, measurement of prog-
nosis is not currently possible as the pathophysiology of
schizophrenia remains unknown. That is, these meta-analy-
ses are of clinical interest but do not provide proof that
medication causes grey matter volume loss, leaving the
alternative more probable explanation for the loss being
related to disease processes. The view that volume loss is
related to antipsychotic medication rather than disease pro-
gression is also challenged by evidence from studies of
medication-naïve schizophrenia patients in the prodromal
phase (Pantelis et al., 2003), at first episode (Ren et al.,
2013) and with chronic long-term illness (Zhang et al.,
2015), clearly showing sequential brain volume changes.
However, if weight is given to any aspect of these meta-
analyses, it should be given to the most recent and largest
meta-analysis of cohort studies assessing the effect of medi-
cation on grey matter volume changes (Vita et al., 2015),
which not only refuted the idea that second-generation (atyp-
ical) antipsychotic medications are associated with loss of
grey matter volume but also reported that these medications,
if they do anything to grey matter volume, either slow or
reverse the accelerated rate of grey matter volume loss
observed in first-episode schizophrenia patients. Importantly,
this association is unlikely to be confounded by indication
because patients with less volume loss tend to have better
prognosis and not have an indication for higher doses of
medication. This interpretation is consistent with evidence of
neurotropic actions of these drugs (Fernandes et al., 2015;
Kusumi et al., 2015). Also, there are studies showing second-
generation antipsychotics either prevent loss (Lieberman
et al., 2005) or reverse it (Van Haren et al., 2007). There are
antipsychotic challenge studies in healthy non-human pri-
mates that show cortical volume loss, but again none of these
studies should be given any weight in the clinic because
whether there was dopamine D2 receptor occupancy in the
treated animals comparable to that associated with human
therapeutic use was not determined. Antipsychotic dosing in
Australian & New Zealand Journal of Psychiatry, 50(12)
1134 ANZJP Articles
animal studies tends to be in substantial excess of what
induces therapeutic levels of D2 occupancy in humans, as we
found in a rodent study (Naiker et al., 2006). In summary, the
clinician should have confidence in recommending long-
term use of antipsychotic medication for schizophrenia in the
knowledge that grey matter volume reductions seen in schiz-
ophrenia are almost certainly disease-related and that sec-
ond-generation antipsychotic medication, if anything,
protects against these volume changes.
Are LAIAs more effective in reducing relapse
rate compared to oral formulations?
This question challenges the belief that LAIAs are no more
effective than oral formulations. This belief is based on meta-
analysis of randomised controlled trials (RCTs) of oral ver-
sus injectable medications (Kishimoto et al., 2014; Leucht
et al., 2011), which find little advantage for LAIAs over
orals. The view that RCT methodology is always the best
design to test intervention effectiveness, promoted by the
Cochrane Reviews, on occasion may have the potential to
mislead schizophrenia CPG designers. For certain interven-
tions, RCTs can result in completely invalid conclusions
(Catts et al., 2010; Kane et al., 2013). This is because totally
inappropriate patients, who can comply with an experimen-
tal protocol over long periods of time, are recruited to such
studies providing no useful information about the treatment
of real-world patients. Because eligible patients for RCT
studies of interventions such as LAIAs and community treat-
ment orders are rare and completely atypical, samples sizes
are very often unacceptably low, a methodological fault hid-
den by agglomerating data in meta-analysis. But the faults
remain – in a recent meta-analysis of LAIA versus oral for-
mulations (Leucht et al., 2011), the median sample size of
included RCTs was 55 patients – unacceptable in any other
field of medicine. For this type of intervention, large-scale
epidemiologically sound studies that include complete sam-
ples of real-world patients are far superior. There is a land-
mark study of this calibre assessing the effectiveness of
LAIAs involving the total national population (avoiding
ascertainment bias) of schizophrenia patients in Finland,
with unbiased methods for determining medication use and
rates of re-admission to hospital (Tiihonen et al., 2011). This
study found that real-world patients with schizophrenia tak-
ing LAIA medication had one-third the rate of re-hospitalisa-
tion. Although this methodologically sound study is much
more applicable to clinical practice than the 10–20 small
RCTs bundled into meta-analysis, it was not cited in the 2016
RANZCP CPG for schizophrenia. Additionally, a systematic
review of mirror-image studies found similarly large benefits
in favour of LAIAs (Kishimoto et al., 2013), another study
not cited in the 2016 RANZCP CPG. We believe these obser-
vational studies should leave no doubt in the clinician’s mind
that LAIAs are best practice as first-line treatment in all
patients as soon as the diagnosis of schizophrenia is made,
Australian & New Zealand Journal of Psychiatry, 50(12)
when there is no obvious contra-indication. Logically, their
prescription should begin at the first hospital admission and
be continued indefinitely for three main reasons: (1) non-
adherence with oral antipsychotics occurs early – within 60
days post-hospitalisation in first-episode patients – in about
60% of patients (Tiihonen et al., 2011); (2) this high level of
non-adherence with oral antipsychotics persists into the
chronic phase of the illness (Dolder et al., 2002; Gilmer
et al., 2004; Lacro et al., 2002; Velligan et al., 2003); and (3)
psychiatrists are completely unreliable in determining which
of their patients are non-adherent (Byerly et al., 2007;
Velligan et al., 2007). We are not alone in recommending
LAIAs as best practice: there are highly respected CPG that
recommend LAIAs as maintenance treatment from the first
episode of schizophrenia (Llorca et al., 2013), contrary to the
recommendations in the 2016 RANZCP CPG.
Proposal for change: re-engineering
the first hospital admission for
schizophrenia
In this paper, we propose that the first psychiatric admis-
sion to hospital for psychosis, especially into public acute
psychiatry wards, be radically re-engineered (see Figure 1).
Rather than discharge the patient with an indefinite diagno-
sis of early psychosis or drug-induced psychosis, every
effort is made to establish whether the patient has the typi-
cal developmental and prodromal trajectory of schizophre-
nia – and if so, the diagnosis of schizophrenia be made then
and there. In accordance with the 2016 RANZCP CPG, this
will involve comprehensive investigation to exclude non-
psychiatric medical conditions (e.g. encephalopathies,
including that mediated by N-methyl-D-aspartate [NMDA]
receptor autoantibodies; temporal lobe epilepsy; cushing
disease; thyroid disease; Vitamin B12 deficiency; ovarian/
small cell lung cancer; diabetic hypoglycaemia; hyponatrae-
mia; hypercalcaemia; hypocalcaemia; hypomagnesaemia;
systemic lupus erythematosus; cytogenetic abnormalities;
Wilson’s disease; porphyria) (Freudenreich et al., 2009;
Griswold et al., 2015). Urine analysis and blood levels
should be checked for substance- and medication-induced
disorders (e.g. anticholinergics, digoxin, steroids, narcotics,
cimetidine, anti-Parkinson’s disease drugs) (Freudenreich
et al., 2009; Griswold et al., 2015). Occasionally, the initial
diagnosis of schizophrenia will be wrong, and in fact the
patient will have bipolar disorder or borderline personality
disorder, so regular diagnostic review especially in the first
6–12 months is essential particularly in those patients who
do not achieve a full remission with medication. Then,
while still in hospital, in all patients who reach diagnostic
criteria for schizophrenia (irrespective of their history of
substance abuse), the key aspects of preventive interven-
tion for psychotic relapse, suicide, and physical health
and substance use co-morbidity be initiated (see Table,
Catts and O’Toole 1135

Figure 1.  Proposal for a re-engineered treatment algorithm for first-episode schizophrenia.

Step 1: Carry out criteria-based diagnosc assessment (e.g., SCID5-CV (First et al., 2015a; First et al., 2015b) ) with developmental history (in
parcular to ascertain pre-psychoc psychosocial deterioraon and pre -morbid non-psychoc co-morbid diagnoses, e.g. learning
disorders, ADHD, conduct disorder, anxiety disorders, substance use disorders): If criteria are met for schizophrenia or
schizoaffecve disorder, psychometrically assess domains listed in the first column of the Supplementary Table.

Step 2: Commence interim oral second generaon anpsychoc medicaon (when not feasible low dose first generaon
anpsychoc for which both oral and LAIA formulaons are available) with strict adherence monitoring and intervenon, including
blood drug levels (if an outpaent, include unit -of-use packaging, pill counts, and asserve community treatment)

Step 3: Enrol paent and family in an integrated specialist muldisciplinary, mul-component treatment program for the
assessment and management of first episode schizophrenia paents, for example (Breitborde et al., 2015; French et al., 2010) that has the
capability to implement the Australian Clinical Pracce Guidelines for Early Psychosis 2nd Edion (Early Psychosis Guidelines Wring Group, 2010) ,
quality medical care, and a broad range of psychosocial intervenons (Mueser et al., 2013) . Intervene as listed in the second column of
the Supplementary Table.

Step 4: Establish working partnership with a general pracce that uses the Chronic Care Model (Wagner, 2000) (CCM) and link in the
CCM physical healthcare case manager to the specialist mental health team.

Step 5: Within the context of an integrated specialist muldisciplinary, mul-component treatment program commence intensive
family and paent psychoeducaon (beyond informaon toward inspiraon (Roe and Yanos, 2006) ) in a movaonal interviewing
framework (Rusch and Corrigan, 2002) giving feedback about diagnosis and results of psychometric assessments. Central to this
psychoeducaon is addressing paent deficits in insight and family denial of the crical need for maintenance medicaon either as
an LAIA or clozapine

Step 6: When insight deficits and denial have been remediated but no later than three months aer commencing oral
anpsychocs, and aer a second documented diagnosc review, switch to a LAIA formulaon or if impaired insight or residual
disability are indicave of treatment resistance then switch to clozapine (ideally added to a LAIA)

LAIA CLOZAPINE

Step 7: Enrol paent in a youth support group and parents in a mul-family support group with indefinite tenure, and connue
specialist programs as needed unl recovery is achieved

Step 8: When the paent is discharged from the specialist integrated early psychosis team the treang psychiatrist connues
indefinitely to review the paent every three months in the seng of the CCM general pracce.

Step 9: Never withdraw the support and medical care from the paent and their family. Encourage them to be become mental
health acvists in consumer
1 and community organisaons

Australian & New Zealand Journal of Psychiatry, 50(12)

1136 ANZJP Articles
Supplementary Material). This will involve engagement of the
family and patient in comprehensive and optimistic patient-
focused psychoeducation which includes giving reasons for
the critical necessity of long-term maintenance medication. In
particular, the patient and family need to be informed of the
evidence for the superiority of LAIAs over oral formulations
in preventing re-admission (Tiihonen et al., 2011). But if the
doctor fails to convince the patient of the value of LAIAs (psy-
chiatrists appear to be poor advocates for LAIAs [Weiden
et al., 2015]), then an evidence-based adherence improvement
intervention (Dolder et al., 2003; Valenstein et al., 2011;
Velligan et al., 2008; Zygmunt et al., 2002) needs to be imme-
diately initiated with all patients using oral medication.
Assertive management of unsatisfactory response overall, or
in terms of positive or negative symptoms, co-morbid depres-
sion, anxiety and substance abuse or in cognitive deficits, will
increase rates of sustained recovery after the first episode (see
Table, Supplementary Material). Risk assessments should not
only trigger safety procedures but also focus treatment on pre-
ventive management of treatment resistance. By the time of
first presentation, many patients have already moved towards
an inactive life style, started to smoke and made unhealthy
dietary choices, which render them highly susceptible to the
pro-metabolic effects of antipsychotic medication. An asser-
tive preventive physical healthcare programme (which
includes dental health; Wey et al., 2016) must be immediately
begun and sustained. The general practitioner can play a criti-
cal role in facilitating access to the many effective treatments
and encourage the patient and their family to aim at a full
recovery.
Conclusion
Schizophrenia is a disease in which 80% of patients respond
very well to standard antipsychotic drug treatment at first
presentation, and there are effective treatment strategies
including introduction of clozapine that could prevent fur-
ther deterioration in the remaining 20%. Emergent treat-
ment resistance, which occurs in 70% of remitted
first-episode schizophrenia patients, is potentially avoida-
ble. Relapse prevention is the strongest modifiable risk fac-
tor for emergent treatment resistance. The evidence
reviewed indicates that a major reduction in the occurrence
of emergent treatment resistance will involve more fre-
quent use of LAIAs as maintenance medication from the
first episode of schizophrenia, and early introduction of
clozapine as soon as eligibility criteria are met. LAIAs
appear to be particularly applicable in resource-constrained
service settings (Chiliza et al., 2016). However, the applica-
tion of the principles of personalised medicine to patients
with schizophrenia will depend upon future research that
directly studies the pathophysiology of relapse, remission
and treatment resistance. This urgent research priority will
be feasible only within the framework of health service –
health practitioner – clinical researcher partnerships. Our
Australian & New Zealand Journal of Psychiatry, 50(12)
mental health system needs to be held accountable. One
way of doing this is to evaluate the impact of implementing
best practice in services adopting it. This could be done
either as a sub-study in the next national survey of people
living with psychosis, or evaluation could be carried
out routinely by establishing Practice-Based Research
Networks (McMillen et al., 2009). We can defeat the worst
aspects of this disease now – by collaborating together, we
can certainly manage it vastly better than we currently do.
Declaration of Conflicting Interests
S.V.C. has received funding for acting in the role of an advisory
board member, as a sponsored educational speaker and for
research projects from the following pharmaceutical companies:
Janssen-Cilag Pty Ltd, Eli Lilly Australia Pty Ltd, Lundbeck
Australia Pty Ltd, Novartis Pharmaceuticals Australia Pty Ltd,
Pfizer Australia Pty Ltd, Bristol-Myers Squibb Pty Ltd,
­Sanofi-Aventis Australia Pty Ltd, Hospira Australia Pty Ltd and
AstraZeneca Pty Ltd. He is a Trustee for the Psychosis Australia
Trust and the Queensland Schizophrenia Research Foundation.
He is a board member of Clearthinking Queensland Ltd. B.I.O has
no conflicts of interest to declare.
Funding
The author(s) received no financial support for the research,
authorship and/or publication of this article.
References
Andreasen NC, Liu D, Ziebell S, et al. (2013) Relapse duration, treatment
intensity, and brain tissue loss in schizophrenia: A prospective longi-
tudinal MRI study. American Journal of Psychiatry 170: 609–615.
Ascher-Svanum H, Faries DE, Zhu B, et al. (2006) Medication adherence
and long-term functional outcomes in the treatment of schizophrenia
in usual care. Journal of Clinical Psychiatry 67: 453–460.
Bleuler M (1978 [1972]) The Schizophrenic Disorders: Long-term Patient
and Family Studies (trans. SM Clemens). New Haven, CT: Yale
University Press.
Bora E, Fornito A, Yucel M, et al. (2010) Voxelwise meta-analysis of grey
matter abnormalities in bipolar disorder. Biological Psychiatry 67:
1097–1105.
Breitborde NJK, Bell EK, Dawley D, et al. (2015) The Early Psychosis
Intervention Centre (EPICENTER): Development and six-month out-
comes of an American first-episode psychosis clinical service. BMC
Psychiatry 15: 266.
Brown E and Gray R (2015) Tackling medication non-adherence in severe
mental illness: Where are we going wrong? Journal of Psychiatric
and Mental Health Nursing 22: 192–198.
Byerly MJ, Thompson A, Carmody T, et al. (2007) Validity of electronic
monitored medication adherence and conventional adherence meas-
ures in schizophrenia. Psychiatric Services 58: 844–847.
Catts SV, O’Toole BI, Carr VJ, et al. (2010) Appraising evidence for inter-
vention effectiveness in early psychosis: Conceptual framework and
review of evaluation approaches. Australian & New Zealand Journal
of Psychiatry 44: 195–219.
Chiliza B, Ojagbemi A, Esan O, et al. (2016) Combining depot antip-
sychotic with an assertive monitoring programme for treating first-
episode schizophrenia in a resource-constrained setting. Early
Intervention in Psychiatry 10: 54–62.
Ciompi L (1980) The natural history of schizophrenia in the long term.
British Journal of Psychiatry 136: 420–423.
Catts and O’Toole 1137
Curson DA, Barnes TR, Bamber RW, et al. (1985) Long-term depot main-
tenance of chronic schizophrenic outpatients: The seven year follow-
up of the Medical Research Council fluphenazine/placebo trial: III
relapse postponement or relapse prevention? The implications for
long-term outcome. British Journal of Psychiatry 146: 474–480.
Department of Health and Ageing (2013) National Mental Health Report 2013:
Tracking Progress of Mental Health Reform in Australia 1993–2011.
Canberra, ACT, Australia: Commonwealth of Australia, p. 32, Figure 5.
Doessel DP, Williams RFG and Whiteford H (2010) The trend in mental
health-related mortality rates in Australia 1916–2004: Implications
for policy. Australia and New Zealand Health Policy 7: 3.
Dolder CR, Lacro JP, Dunn LB, et al. (2002) Antipsychotic medication
adherence: Is there a difference between typical and atypical agents?
American Journal of Psychiatry 159: 103–108.
Dolder CR, Lacro JP, Leckband S, et al. (2003) Interventions to improve
antipsychotic medication adherence: Review of recent literature.
Journal of Clinical Psychopharmacology 23: 389–399.
Early Psychosis Guidelines Writing Group (2010) Australian Clinical
Guidelines for Early Psychosis, 2nd Edition. Melbourne, VIC,
Australia: ORYGEN Youth Health.
Emsley R, Nuamah I, Hough D, et al. (2012) Treatment response after
relapse in a placebo-controlled maintenance trial in schizophrenia.
Schizophrenia Research 138: 29–34.
Emsley R, Oosthuizen P, Koen L, et al. (2013) Comparison of treat-
ment response in second-episode versus first-episode schizophrenia.
Journal of Clinical Psychopharmacology 33: 80–83.
Farooq S and Farooq N (2014) Tackling medication nonadherence in psy-
chiatric disorders: Current opinion. Neuropsychiatric Disease and
Treatment 10: 1069–1077.
Farooq S, Naeem F and Singh S (2016) Editorial: Telling the patients
about diagnosis and outcome of schizophrenia: What, when and how?
Early Intervention in Psychiatry 10: 101–102.
Fernandes BS, Steiner J, Berk M, et al. (2015) Peripheral brain-derived
neurotrophic factor in schizophrenia and the role of antipsychotics:
Meta-analysis and implications. Molecular Psychiatry 20: 1108–1119.
First MB, Williams JBW, Karg RS, et al. (2015a) Structured Clinical
Interview for DSM-5 Disorders, Clinician Version (SCID-5-CV).
Arlington, VA: American Psychiatric Association.
First MB, Williams JBW, Karg RS, et al. (2015b) User’s Guide for the Structured
Clinical Interview for DSM-5 Disorders, Clinician Version (SCID-5-CV).
Arlington, VA: American Psychiatric Association.
French P, Smith J, Shiers, et al. (eds) (2010) Promoting Recovery in Early
Psychosis: A Practice Manual, 1st Edition. Oxford: John Wiley &
Sons.
Freudenreich O, Schulz SC and Goff DC (2009) Initial medical work-up
of first-episode psychosis: A conceptual review. Early Intervention in
Psychiatry 3: 10–18.
Fusar-Poli P, Smieskova R, Kempton MJ, et al. (2013) Progressive brain
changes in schizophrenia related to antipsychotic treatment? A meta-
analysis of longitudinal MRI studies. Neuroscience and Biobehavioral
Reviews 37: 1680–1691.
Gaebel W, Riesbeck M, Wolfgang W, et al. (2016) Predictors for symptom
re-exacerbation after targeted stepwise drug discontinuation in first-epi-
sode schizophrenia: Results of the first-episode study within the German
research network on schizophrenia. Schizophrenia Research 170: 168–176.
Galletly C, Castel D, Dark F, et al. (2016) Royal Australian and New
Zealand College of Psychiatrists clinical practice guidelines for the
management of schizophrenia and related disorders. Australian &
New Zealand Journal of Psychiatry 50: 410–472.
Gilmer TP, Dolder CR, Lacro JP, et al. (2004) Adherence to treatment with
antipsychotic medication and health care costs among Medicaid ben-
eficiaries with schizophrenia. American Journal of Psychiatry 161:
692–699.
Girgis RR, Philips MR, Li X, et al. (2011) Clozapine v. chlorpromazine
in treatment-naïve first episode schizophrenia: 9-year outcomes of a
randomised clinical trial. British Journal of Psychiatry 199: 281–288.
Gopal S, Vijapurkar U, Lim P, et al. (2011) A 52 week open-label study of
the safety and tolerability of paliperidone palmitate in patients with
schizophrenia. Journal of Psychopharmacology 25: 685–697.
Griswold KS, Del Regno PA and Berger RC (2015) Recognition and dif-
ferential diagnosis of psychosis in primary care. American Family
Physician 91: 856–863.
Haijma SV, Van Haren N, Cahn W, et al. (2013) Brain volumes in schizo-
phrenia: A meta-analysis in over 18,000 subjects. Schizophrenia
Bulletin 39: 1129–1138.
Jaaskelainen E, Juola P, Hirvonen N, et al. (2013) A systematic review and
meta-analysis of recovery in schizophrenia. Schizophrenia Bulletin
39: 1296–1306.
Joshi D, Catts VS, Olaya JC, et al. (2015) Relationship between soma-
tostatin and death receptor expression in the orbital frontal cortex in
schizophrenia: A post-mortem brain mRNA study. npj Schizophrenia
1: Article 14004.
Kane JM, Kishimoto T and Correll CU (2013) Assessing the comparative
effectiveness of long-acting injectables vs oral antipsychotic medica-
tions in the prevention of relapse provides a case study in comparative
effectiveness research in psychiatry. Journal of Clinical Psychiatry
66: S37–S41.
Kishimoto T, Nitta M, Borenstein M, et al. (2013) Long-acting injectable
versus oral antipsychotics in schizophrenia: A systematic review and
meta-analysis of mirror-image studies. Journal of Clinical Psychiatry
74: 957–965.
Kishimoto T, Robenzadeh A, Leucht C, et al. (2014) Long-acting injectable
vs oral antipsychotics for relapse prevention in schizophrenia: A meta-
analysis of randomized trials. Schizophrenia Bulletin 40: 192–213.
Kusumi I, Boku S and Takahashi Y (2015) Psychopharmacology of atypical
antipsychotic drugs: From receptor binding profile to neuroprotection
and neurogenesis. Psychiatry and Clinical Neurosciences 69: 243–258.
Lacro JP, Dunn LB, Dolder CR, et al. (2002) Prevalence of and risk factors
for medication nonadherence in patients with schizophrenia: A com-
prehensive review of recent literature. Journal of Clinical Psychiatry
63: 892–909.
Leucht C, Heres S, Kane JM, et al. (2011) Oral versus depot antipsychotic
drugs for schizophrenia: A critical systematic review and meta-analysis
of randomised long-term trials. Schizophrenia Research 127: 83–92.
Lieberman JA, Alvir JM, Koreen A, et al. (1996) Psychobiological correlates
of treatment response in schizophrenia. Neuropsychopharmacology
14: 13S–21S.
Lieberman JA, Alvir JM, Woerner M, et al. (1992) Prospective study of
psychobiology in first episode schizophrenia at Hillsdale Hospital.
Schizophrenia Bulletin 18: 351–371.
Lieberman JA, Jody D, Geisler S, et al. (1993) Time course and biologi-
cal correlates of treatment response in first-episode schizophrenia.
Archives of General Psychiatry 50: 369–376.
Lieberman JA, Tollefson GD, Charles C, et al. (2005) Antipsychotic drug
effects on brain morphology in first-episode psychosis. Archives of
General Psychiatry 62: 361–370.
Llorca PM, Abbar M, Courtet P, et al. (2013) Guidelines for the use and
management of long-acting injectable antipsychotics in serious men-
tal illness. BMC Psychiatry 13: 340.
McEvoy IP, Hogarty GE and Steingard S (1991) Optimal dose of neuro-
leptic in acute schizophrenia: A controlled study of the neuroleptic
threshold and higher haloperidol dose. Archives of General Psychiatry
48: 739–745.
McGorry P and Edwards J (1997) The Early Psychosis Training Pack.
Melbourne, VIC, Australia: Gardiner-Caldwell Communications Ltd
and the Early Psychosis prevention and Intervention Centre, p. 21.
McMillen JC, Lenze SL, Hawley KM, et al. (2009) Revisiting practice-
based research networks as a platform for mental health services
research. Administration and Policy in Mental Health 36: 308–321.
Malla A, Norman R, Schmitz N, et al. (2006) Predictors of rate and time
to remission in first-episode psychosis: A two-year outcome study.
Psychological Medicine 36: 649–658.
Australian & New Zealand Journal of Psychiatry, 50(12)
1138 ANZJP Articles
Merlo MCG, Hofer H, Gekle W, et al. (2002) Risperidone 2 mg/day vs 4
mg/day in first episode acutely psychotic patients: Treatment efficacy
and effects on fine motor functioning. Journal of Clinical Psychiatry
63: 885–891.
Morgan VA, Waterreus A, Jablensky A, et al. (2012) People living with
psychotic illness in 2010: The second Australian national survey
of psychosis. Australian & New Zealand Journal of Psychiatry 46:
735–752.
Mueser KT, Deavers F and Penn DL Cassisi JE (2013) Psychological
treatments for schizophrenia. Annual Review of Clinical Psychology
9: 465–497.
Naiker DV, Catts SV, Catts VS, et al. (2006) Dose determination of
haloperidol, risperidone and olanzapine using an in vivo dopamine
D2-receptor occupancy method in the rat. European Journal of
Pharmacology 540: 7–90.
Oosthuizen P, Emsley R, Turner HJ, et al. (2004) A randomised controlled
comparison of the efficacy and tolerability of low and high doses of
haloperidol in the treatment of first-episode psychosis. International
Journal of Neuropsychopharmacology 7: 125–131.
Pantelis C, Velakoulis D, McGorry PD, et al. (2003) Neuroanatomical
abnormalities before and after onset of psychosis: A cross-sectional
and longitudinal MRI comparison. The Lancet 361: 281–288.
Reininghaus U, Dutta R, Dazzan P, et al. (2015) Mortality in schizophre-
nia and other psychoses: A 10-year follow-up of the AESOP First-
Episode cohort. Schizophrenia Bulletin 41: 664–673.
Ren W, Lui S, Deng W, et al. (2013) Anatomical and functional brain
abnormalities in drug-naïve first-episode schizophrenia. American
Journal of Psychiatry 170: 1308–1316.
Robinson DG, Woerner MG, Alvir JMJ, et al. (1999) Predictors of relapse
following response from a first episode of schizophrenia or schizoaf-
fective disorder. Archives of General Psychiatry 56: 241–247.
Robinson DG, Woerner MG, McMeniman M, et al. (2004) Symptomatic
and functional recovery from a first episode of schizophrenia or schiz-
oaffective disorder. American Journal of Psychiatry 161: 473–479.
Roe D and Yanos PT (2006) Psychoeducation for people with psychotic
symptoms: Moving beyond information and towards inspiration.
The Behavior Therapist 29: 53–56. Available at: www.abct.org/docs/
PastIssue/29n3.pdf
Royal Australian and New Zealand College of Psychiatrists Clinical
Practice Guidelines (RANZCP CPG) Team for the Treatment of
Schizophrenia and Related Disorders (2005) Royal Australian & New
Zealand College of Psychiatrists clinical practice guidelines for the
treatment of schizophrenia and related Disorders. Australian & New
Zealand Journal of Psychiatry 39: 1–30.
Rusch N and Corrigan PW (2002) Motivational interviewing to improve
insight and treatment adherence in schizophrenia. Psychiatric
Rehabilitation Journal 26: 23–32.
Saha S, Chant D and McGrath J (2007) A systematic review of mortality in
schizophrenia: Is the differential mortality gap worsening over time.
Archives of General Psychiatry 64: 1123–1131.
Scully PJ, Coakley G, Kinsella A, et al. (1997) Psychopathology, execu-
tive (frontal) and general cognitive impairment in relation to duration
of initially untreated versus subsequently treated psychosis in chronic
schizophrenia. Psychological Medicine 27: 1303–1310.
Sheline YI, Gado MH and Kraemer HC (2003) Untreated depression
and hippocampal volume loss. American Journal of Psychiatry 160:
1516–1518.
Shimazono Y (1973) Comment and discussion. In: Mitsuda H and Fukada
T (eds) Biological Mechanisms of Schizophrenia and Schizophrenia-
like Psychosis. Tokyo, Japan: Igaku Shoin Ltd., pp. 126–128.
Takeuchi H, Suzuki T, Uchida H, et al. (2012) Antipsychotic treatment
for schizophrenia in the maintenance phase: A systematic review of
the guidelines and algorithms. Schizophrenia Research 134: 219–225.
Tiihonen J, Haukka J, Taylor M, et al. (2011) A nationwide cohort study of
oral and depot antipsychotics after first hospitalization for schizophre-
nia. American Journal of Psychiatry 168: 603–609.
Australian & New Zealand Journal of Psychiatry, 50(12)
Torniainen M, Mittendorfer-Rutz E, Tanskanen A, et al. (2015)
Antipsychotic treatment and mortality in schizophrenia. Schizophrenia
Bulletin 41: 656–663.
Treadway MT, Waskom ML, Dillon DG, et al. (2015) Illness progression,
recent stress, and morphology of hippocampal subfields and medial pre-
frontal cortex in major depression. Biological Psychiatry 77: 285–294.
Valenstein M, Kavanagh J, Lee T, et al. (2011) Using pharmacy-based
intervention to improve antipsychotic adherence among patients with
serious mental illness. Schizophrenia Bulletin 37: 727–736.
Van Haren NE, Hulshoff Pol HE, Schnack HG, et al. (2007) Focal gray
matter changes in schizophrenia across the course of the illness: A
5-year follow-up study. Neuropsychopharmacology 32: 2057–2066.
Van Haren NE, Hulshoff Pol HE, Schnack HG, et al. (2008) Progressive
brain volume loss in schizophrenia over the course of the illness:
Evidence of maturational abnormalities in early adulthood. Biological
Psychiatry 6: 106–113.
Velligan DI, Diamond PM, Mintz J, et al. (2008) The use of individually
tailored environmental supports to improve medication adherence and
outcomes in schizophrenia. Schizophrenia Bulletin 34: 483–493.
Velligan DI, Lam F, Ereshefsky L, et al. (2003) Perspectives on medica-
tion adherence and atypical antipsychotic medications. Psychiatric
Services 54: 665–667.
Velligan DI, Wang M, Diamond P, et al. (2007) Relationships among
subjective and objective measures of adherence to oral antipsychotic
medications. Psychiatric Services 58: 1187–1192.
Vita A, De Peri L, Deste G, et al. (2015) The effect of antipsychotic treat-
ment on cortical grey matter changes in schizophrenia: Does the class
matter? A meta-analysis and meta-regression of longitudinal magnetic
resonance imaging studies. Biological Psychiatry 78: 403–412.
Waddington JL, Youssel HA and Kinsella A (1995) Sequential cross-sec-
tional and 10-year prospective study of severe negative symptoms in
relation to duration of initially untreated psychosis in chronic schizo-
phrenia. Psychological Medicine 25: 849–857.
Wagner EH (2000) The role of patient care teams in chronic disease man-
agement. British Journal of Medicine 320: 569–572.
Watt DC, Katz K and Shepherd M (1983) The natural history of schizo-
phrenia: A 5-year prospective follow-up of a representative sample of
schizophrenics by means of standardized clinical and social assess-
ment. Psychological Medicine 13: 663–670.
Weiden PJ, Roma RS, Velligan DI, et al. (2015) The challenge of offering
long-acting antipsychotic therapies: A preliminary discourse analysis
of psychiatrist recommendations for injectable therapy to patients
with schizophrenia. Journal of Clinical Psychiatry 76: 684–690.
Wey MC, Loh SY, Doss JG, et al. (2016) The oral health of people with
chronic schizophrenia: A neglected public health burden. Australian
& New Zealand Journal of Psychiatry 50: 685–694.
Wiersma D, Nienhuis FJ, Slooff CJ, et al. (1998) Natural course of schizo-
phrenic disorders: A 15-Year Follow-up of a Dutch incidence cohort.
Schizophrenia Bulletin 24: 75–85.
Wunderink L, Nieboer RM, Wiersma D, et al. (2013) Recovery in remitted
first-episode psychosis at 7 years of follow-up of an early dose reduction/
discontinuation or maintenance treatment strategy: Long-term follow-up
of a 2-year randomized clinical trial. JAMA Psychiatry 70: 913–920.
Wyatt RJ (1991) Neuroleptics and the natural course of schizophrenia.
Schizophrenia Bulletin 17: 325–351.
Zhang W, Deng W, Yao L, et al. (2015) Brain structural abnormalities in
a group of never-medicated patients with long-term schizophrenia.
American Journal of Psychiatry 172: 995–1003.
Zipursky RB, Menezes NM and Streiner DL (2014) Risk of symptom
recurrence with medication discontinuation in first-episode psycho-
sis: A systematic review. Schizophrenia Research 152: 408–414.
Zipursky RB, Reilly TJ and Murray RM (2013) The myth of schizophrenia
as a progressive brain disease. Schizophrenia Bulletin 39: 1363–1372.
Zygmunt A, Olfson M, Boyer CA, et al. (2002) Interventions to improve
medication adherence in schizophrenia. American Journal of
Psychiatry 159: 1653–1664.