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Randomized Controlled Trial of Interventions Designed to Reduce the Risk of Progression to First-Episode Psychosis in a Clinical Sample With Subthreshold Symptoms
Patrick D. McGorry, PhD, FRANZCP;
Alison R. Yung, FRANZCP;
Lisa J. Phillips, MPsych;
Hok Pan Yuen, MSci;
Shona Francey, MPsych;
Elizabeth M. Cosgrave, MA;
Dominic Germano, MPsych(Clinical);
Jenny Bravin, MPsych(Neuro);
Tony McDonald, MPsych;
Alison Blair, MRCPsych;
Stephen Adlard, FRANZCP;
Henry Jackson, PhD
Arch Gen Psychiatry. 2002;59:921-928.
ABSTRACT
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Background Most disability produced by psychotic illnesses, especially schizophrenia,
develops during the prepsychotic period, creating a case for intervention
during this period. However, only recently has it been possible to engage
people in treatment during this phase.
Methods A randomized controlled trial compared 2 interventions in 59 patients
at incipient risk of progression to first-episode psychosis. We termed this
group ultra-high risk to emphasize the enhanced risk
vs conventional genetic high-risk studies. Needs-based intervention was compared
with specific preventive intervention comprising low-dose risperidone therapy
(mean dosage, 1.3 mg/d) and cognitive behavior therapy. Treatment was provided
for 6 months, after which all patients were offered ongoing needs-based intervention.
Assessments were performed at baseline, 6 months, and 12 months.
Results By the end of treatment, 10 of 28 people who received needs-based intervention
progressed to first-episode psychosis vs 3 of 31 from the specific preventive
intervention group (P = .03). After 6-month follow-up,
another 3 people in the specific preventive intervention group became psychotic,
and with intention-to-treat analysis, the difference was no longer significant
(P = .24). However, for risperidone therapy–adherent
patients in the specific preventive intervention group, protection against
progression extended for 6 months after cessation of risperidone use.
Conclusions More specific pharmacotherapy and psychotherapy reduces the risk of
early transition to psychosis in young people at ultra-high risk, although
their relative contributions could not be determined. This represents at least
delay in onset (prevalence reduction), and possibly some reduction in incidence.
INTRODUCTION
THE NOTION OF intervention in the prepsychotic phase of schizophrenia
and related psychoses is not new.1-2
However, the dramatic recent growth of research and clinical programs in early
psychosis3-4 has made it possible
to systematically explore preventive interventions in this symptomatic but
prepsychotic phase of disorder for the first time.
Prepsychotic intervention is based on the concept of prodrome. Until
recently, the entire period before clearcut diagnosis in schizophrenia has
been referred to as the premorbid phase. Studies5 of childhood antecedents have demonstrated statistically
significant but clinically trivial differences between control subjects and
those who later develop schizophrenia. These studies were originally interpreted
as providing support for the neurodevelopmental hypothesis of schizophrenia,6 but they paradoxically highlight the quiescence of
the illness during this phase of life, showing it to be a true premorbid or
latent phase. In fact, as Häfner and colleagues7
revealed, these illnesses really begin to have clinical and social consequences
after puberty, typically during adolescence and early adult life. Most patients
with broadly defined schizophrenia experience a lengthy prodromal period of
nonspecific symptoms and growing functional impairment before the full emergence
of the more diagnostically specific positive psychotic symptoms. The development
of disability during the prodromal period creates a ceiling for eventual recovery
and is the key rationale for prepsychotic intervention.
However, the prodrome concept is retrospective, and clinical definitions
compatible with a prospective approach are needed. From 1994, we conducted
a series of naturalistic prospective studies to define operational criteria
for a clinical sample at ultra-high risk (UHR) for progression to psychotic
disorder.8-10 This
approach differs not only from the retrospective one7, 11
but also from the conventional genetic high-risk paradigm.12-13
Cornblatt et al14 have since termed it the
"clinical high-risk" approach. The rate of progression within 12 months for
a sample meeting UHR criteria approaches 40%,10, 15
much higher than the conventional genetic high-risk rate and several thousand
times higher than the annual population risk.16
A full account of the development of this clinical research strategy and associated
ethical issues is available elsewhere.9, 17-22
Other centers have subsequently adopted and adapted these UHR criteria.14, 23
Progression to psychosis in these first-generation studies seemed neither
inevitable nor predetermined, although it was high. Progression occurred despite
supportive psychosocial treatment that included active treatment of depression
and anxiety. Without such intervention, the rate could have been even higher.
Nevertheless, we concluded that research examining more specific interventions
was justified. We did not assume that the psychobiologic characteristics of
the prepsychotic phase are the same as those in later phases of illness, and
we believe that a range of potentially neuroprotective interventions may ultimately
be useful. However, our strategy for this initial study was to include "best
bet" specific therapies in a single enhanced intervention package to determine
whether it was possible to delay the onset of psychosis. We hypothesized that
low-dose atypical antipsychotic medication combined with cognitive behavior
therapy (CBT), effective interventions in manifest psychotic illness, would
reduce the risk of early progression to psychosis when added to needs-based
intervention (NBI) in contrast to the latter provided alone.
PATIENTS AND METHODS
PATIENTS
The study was performed in a specially designed setting, the PACE (Personal
Assessment and Crisis Evaluation) Clinic,8
an extension of the Early Psychosis Prevention and Intervention Centre (EPPIC).17 The clinic is located within a generic youth health
service, the Centre for Adolescent Health. The venue and the name were chosen
to avoid stigma and to promote help seeking among young people; this has been
a successful strategy. A fuller description is provided elsewhere.9, 19, 21 Referrals between
October 1, 1996, and January 31, 1999, were considered and were derived from
educational settings, primary care settings, mental health professionals,
and other youth services; however, many came via EPPIC.17
Patients were eligible for the study if they (1) were aged 14 to 30
years; (2) lived in the Melbourne metropolitan area; and (3) met criteria
for 1 or more of 3 operationally defined UHR groups. The rationale and validation
of these criteria are fully described elsewhere,9, 20
and the precise criteria are available from the authors. The first group comprised
patients with a family history of psychotic disorder in a first-degree relative
plus nonspecific symptoms and impaired functioning resulting in a decrease
of 30 points on the Global Assessment of Functioning scale24
within the previous 12 months. The second group included those with attenuated
positive psychotic symptoms that, although sustained for at least a week,
remained below the threshold for frank psychosis. The third group was characterized
by brief episodes of psychotic symptoms above the threshold but not sustained
beyond a week.
The key outcome of interest was the development of suprathreshold levels
of psychosis. The severity threshold was operationally defined using the Brief
Psychiatric Rating Scale25 and the Comprehensive
Assessment of Symptoms and History26 as follows:
a score of 3 or more on the hallucinations subscale, a score of 4 or more
on the unusual thought content subscale (plus a score  3 for delusional
conviction on the Comprehensive Assessment of Symptoms and History), or a
score of 4 or more on the conceptual disorganization subscale of the Brief
Psychiatric Rating Scale. These levels had to be sustained for at least 1
week. The preventive outcome target was therefore not the onset of a schizophrenia
diagnosis, which if it occurred was usually a later development. Although
somewhat arbitrary, these exit criteria marked the threshold (linked to positive
symptoms) at which we believed that antipsychotic medication should usually
be commenced. All patients defined by these criteria as having progressed
met the criteria for a DSM-IV psychotic disorder.
Patients were also withdrawn from the study if they developed a full manic
syndrome. The many diagnostic complexities in early psychosis beyond the scope
of this article are addressed elsewhere.3, 17
Patients were excluded from the study if they had (1) a previous psychotic
or manic episode, (2) previous treatment with an antipsychotic or mood stabilizing
agent, (3) a substance-induced psychotic disorder, (4) an IQ lower than 70,
or (5) an inadequate command of the English language.
STUDY DESIGN AND INTERVENTIONS
The study was designed as a single-blind, randomized controlled trial,
with research interviewers intended to be blind to the interventions received.
However, this was difficult to achieve because the 2 intervention groups were
treated by different clinicians, a feature that was difficult to conceal from
raters. Clinicians and patients were not blinded. Patients who met intake
criteria and gave written informed consent for randomization were assigned
by the study coordinator to one of the treatment groups using simple randomization
without replacement.
The study was approved by the research and ethics committees of North-West
Health (Melbourne, Australia). All participants received detailed information
about the study, including a plain-language statement. The distinction between
treatment of manifest conditions (treatment as usual) and intervention aimed
at risk reduction of psychosis (the research focus) was clearly explained.
For participants younger than 18 years, informed consent was obtained from
a parent or guardian as well as the patient when possible. Only patients of
the clinic who were judged to be fully competent to give informed consent
for participation and who did so were included. Participation could be withdrawn
at any time, and nonparticipation in the research in no way affected access
to clinical care.
The 2 interventions were offered for 6 months. Following this, NBI continued
to be offered.
Needs-Based Intervention
Needs-based intervention focused on the presenting symptoms and problems
already manifest. Patients assigned to this group received needs-based supportive
psychotherapy primarily focusing on pertinent issues such as social relationships
and vocational and family issues. Therapists also performed a case management
role, providing assistance with accommodation, education or employment, and
family education and support. Although patients in this group did not receive
antipsychotic medication, they could receive antidepressants (sertraline hydrochloride)
if moderate to severe depression was present or benzodiazepines for insomnia
(usually temazepam).
Specific Preventive Intervention
Specific preventive intervention (SPI) involved all elements of NBI
and 2 additional treatment components hypothesized to have greater specificity
for the reduction of risk of progression to psychosis. Hence, SPI, in common
with NBI, aimed to treat features already manifest and, in addition, to reduce
the risk of progression. The first additional component was administration
of 1 to 2 mg of risperidone daily for 6 months, and the second was modified
CBT. Risperidone therapy was commenced at 1 mg/d and increased to and held
at 2 mg/d provided that no adverse effects were experienced. If adverse effects
occurred, the dosage was reduced to 1 mg/d. Antidepressants or benzodiazepines
were again used when appropriate.
Cognitive behavior therapy was conducted according to a manual developed
by us. The overall aims were to develop an understanding of the symptoms experienced,
to learn strategies to enhance control of these symptoms, and to reduce associated
distress. These strategies were drawn from mainstream CBT for nonpsychotic
disorders and, where appropriate, by adapting psychological techniques that
are useful in more established psychotic disorders.27
The following modules were offered flexibly: Stress Management, Depression/Negative
Symptoms, Positive Symptoms, and Other Comorbidity (including substance abuse,
obsessive-compulsive features, and social anxiety).
Several psychiatrists (P.D.M., A.R.Y., A.B., and S.A.) managed the drug
therapy for both groups. Adherence was assessed via verbal report from patients
and relatives of the percentage of doses taken as prescribed. This was believed
to be sufficiently accurate given the voluntary basis and cooperative atmosphere
of the study. The psychological therapists (L.J.P., S.F., E.M.C., D.G., and
J.B.) were all experienced therapists. In contrast to the pharmacotherapy,
the psychological treatments were delivered by separate teams of therapists
(CBT, L.J.P., E.M.G., and D.G.; and supportive therapy, S.F. and J.B.). Varying
the frequency and duration of sessions accommodated the differing needs and
tolerance of the individual patients. All therapists were supervised weekly
by senior clinical psychologists experienced in psychotherapy research methods
(S.F. and H.J.) to enhance adherence to the treatment paradigm. However, no
formal measures of treatment fidelity were used.
ASSESSMENTS
The principal outcome of interest was the rate of progression to psychosis,
using a categorical model, to the predetermined threshold of positive psychotic
symptoms. Independent assessments were carried out by a research psychologist
(T.M.) at 3 points: baseline; after the intervention, approximately 6 months
after study entry (mean [SD] 6.6 [0.9] months); and approximately 6 months
later, or 12 months after study entry (mean [SD] 13.0 [1.4] months). Dimensional
measures used were the Brief Psychiatric Rating Scale,25
the Scale for the Assessment of Negative Symptoms,28
the Hamilton Rating Scales for Depression and Anxiety,29-30
the Young Mania Scale,31 the drug and alcohol
component of the Schedules for Clinical Assessment in Neuropsychiatry,32 and the Comprehensive Assessment of At-Risk Mental
States,33 a semistructured interview specifically
designed for monitoring prepsychotic symptoms. The Quality of Life Scale34 and the Global Assessment of Functioning scale24 represent measures of psychosocial functioning.
Clinicians assessed patients approximately every 2 weeks and carefully
monitored them in relation to the psychosis threshold. When patients were
judged to have progressed to psychosis, they were independently reassessed
by the research psychologist (T.M.) using the operationally defined criteria
for the threshold. Most patients were then treated within the EPPIC program.
All patients were independently confirmed by nonproject psychiatrists as meeting
criteria for a psychotic illness requiring antipsychotic medication. Updated
study diagnoses were assigned for all patients using data collected at 12-month
follow-up supplemented by multiple data sources, including medical record
review and informant interview when possible. A consensus method of best-estimate
diagnosis was applied. The clinical presentation of each patient was also
meticulously reviewed in relation to the inclusion criteria and the criteria
for progression to first-episode psychosis where this occurred, ensuring minimal
risk of misclassification. In particular, we are convinced that no patient
was covertly psychotic at study entry and, hence, that all progressions were
genuine transitions to psychosis. The reliability of these procedures has
been assessed in a separate reliability study (n = 21), and pairwise 
values for entry criteria ( = 0.81-1.0) and exit criteria (
= 0.77-1.0) were excellent. All medications and adverse effects were closely
monitored and recorded by psychiatrists using a brief semistructured interview.
STATISTICAL ANALYSIS
Statistical software programs (SPSS for Windows 8.0; SPSS Inc, Chicago,
Ill, and S-PLUS for Windows 4.0; MathSoft Inc, Seattle, Wash) were used for
all statistical analyses. Comparison of the 2 interventions was principally
by intention to treat, although the relationship of outcomes to adherence
to treatment was also examined via an efficacy subset analysis.35
The Fisher exact test and survival analysis were used to carry out the comparison
in terms of transition to psychosis. Use of analysis of covariance enabled
the effect of potential confounders (age, sex, antidepressant drug use, time
to presentation, and accommodation) for other dimensional outcome measures
to be considered. All tests were 2-tailed, and significance was set at P = .05. Using the statistic number needed to treat (NNT)
is a clinically appealing way of summarizing the effect of treatment in terms
of the number of patients a clinician needs to treat with a particular therapy
to prevent an adverse event and is calculated as the reciprocal of the absolute
risk reduction.36 Herein, NNT is defined as
the number of patients who need to be treated with risperidone and CBT in
addition to NBI to prevent 1 from progressing to psychosis.
RESULTS
STUDY SAMPLE
A total of 59 patients were randomized, 28 to the NBI group and 31 to
the SPI group (Figure 1). Twenty-five
patients were female (42%), and mean (SD) age at entry was 20 (3.6) years
(range, 14-28 years). The baseline characteristics of the 2 intervention groups
and of those refusing randomization are presented in Table 1. The data confirm that these young people are highly symptomatic
and moderately disabled by their symptoms, although none are as yet frankly
psychotic. Most patients manifested attenuated psychotic symptoms. Although
there were no significant differences between the randomized SPI and NBI groups,
when the total group of trial participants (n = 59) was compared with refusers
(n = 33), the latter manifested significantly lower levels of symptoms and
disability at baseline. Therefore, perhaps not surprisingly, the refusers
showed a lower rate of transition to psychosis (12.1% at first follow-up and
18.2% at second follow-up) than the randomized NBI group. Tragically however,
2 members of those refusing randomization committed suicide during follow-up
despite remaining engaged in NBI and apparently progressing well.
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Figure 1. Randomization of 59 patients at
incipient risk of progression to first-episode psychosis. PACE indicates Personal
Assessment and Crisis Evaluation.
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Table 1. Baseline Characteristics of 59 Patients Randomized to the
Study and 33 Patients Who Refused Randomization*
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TREATMENT EXPOSURE
Although there were no dropouts from the SPI group and adherence was
high for CBT, adherence to risperidone therapy was more variable, which is
also a characteristic of even well-engaged young people. Hence, in addition
to intention-to-treat analysis, the data were analyzed by adherence to risperidone
therapy, divided into full (almost 100% of doses taken) or partial (>50% of
doses taken) adherence and poor adherence (<50% of doses taken). Of the
31 patients in the SPI group, 13 were classified as nonadherent, 4 as partially
adherent, and 14 as fully adherent. The mean (SD) dosage of risperidone for
the SPI group was 1.3 (0.901) mg/d. The use of sertraline was 41.9% (SPI)
and 60.7% (NBI). Although the frequency of medical review was similar in the
2 groups, there was a significant difference in the number of psychological
sessions attended by NBI (mean [SD], 5.9 [4.3]) and SPI (mean [SD], 11.3 [8.4])
patients (t = -3.06; P
= .003), which reflected the greater structure and better engagement inherent
in the CBT model. The supervision process seemed to support differentiation
of the interventions and fidelity.
OUTCOME MEASURES
When analyzed by intention to treat, there was a significant difference
between the groups at first follow-up that was lost by second follow-up because
of the progression to psychosis of another 3 patients from the original SPI
group (Table 2). Final diagnoses
of psychotic and nonpsychotic patients are given in Table 3. Survival analysis (intention to treat) (Figure 2) depicts this pattern, and although the curves were significantly
different at the end of treatment, this significance was lost during subsequent
follow-up. However, when the survival analysis is extended, taking into account
levels of antipsychotic drug adherence, a significant difference is maintained
between the fully adherent SPI group and the NBI group throughout follow-up.
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Table 2. Rate of Transition to Psychosis*
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Table 3. Final Diagnoses of the Psychotic and Nonpsychotic Subgroups
at 12-Month Follow-up
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Figure 2. Survival analysis (intention to
treat) showing the proportion of nonpsychotic patients throughout the study.
SPI indicates specific preventive intervention; SPI-NP, SPI with no or partial
drug adherence; SPI-F, SPI with full drug adherence; and NBI, needs-based
intervention. P = .09, SPI vs NBI;
P = .03, SPI-F vs NBI, both by log-rank test.
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Some psychiatrists believe that antidepressants can trigger psychotic
episodes in vulnerable patients. Because the use of sertraline was 50% higher
in the NBI group than in the SPI group, this could have been a possible explanation
for the increased rate of transition. However, the transition rate within
the NBI group was not significantly different whether or not sertraline was
prescribed.
From data in Table 2, the
NNT for end of treatment is computed as 1/(0.37-0.10), which is 4 (95% confidence
interval, 3-19). This means that 4 patients would need to be treated to prevent
1 from progressing to psychosis over a 6-month period.
The NBI and SPI groups were also compared at the end of the treatment
phase and at the end of follow-up on a range of symptomatic and functional
measures (Table 4). No differences
were observed between the groups on any of these measures, which were performed
at relatively fixed times, and for those making the transition to psychosis,
usually when they had already received treatment for psychosis. Levels of
all symptoms improved in both groups, whereas functional levels were more
stable, perhaps indicating the need for more extensive reparative psychosocial
strategies. These measures were also compared for patients who remained nonpsychotic
(Table 5). Irrespective of treatment
group, and despite having manifested at some point a diagnosable psychiatric
disorder, these patients were in much better shape symptomatically and functionally
after treatment than at study entry. This is also true for SPI patients who
received risperidone and did not become psychotic. Thus, although it is unclear
which of these people were headed for but avoided transition, it seems clear
that the group improved and was not harmed by the interventions. Furthermore,
no other types of harm were detectable through stigmatization (assessed by
routine clinician inquiry), anxiety due to being informed of the risk of progression
to psychosis (all patients were well aware that something potentially serious
was happening to them even before they presented to the clinic), or neuroleptic
adverse effects (minor rigidity in 1 patient and mild sedation in 3 patients,
relieved in all 4 cases by dose reduction). Patients and relatives benefited
from and were generally highly appreciative of the treatment received.
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Table 4. Scores on Symptomatic and Functional Outcome Measures by Assessment
Phase and Treatment Group*
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Table 5. Scores on Symptomatic and Functional Outcome Measures by Assessment
Phase for Patients Remaining Nonpsychotic at Second Follow-up*
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COMMENT
This is the first study, to our knowledge, to suggest it may be possible
to at least delay, and in some cases perhaps even avert, progression to full
diagnostic threshold for psychotic disorder in individuals at UHR of schizophrenia
and related psychotic disorders. The study builds on a foundation of naturalistic
research and careful definition of the UHR clinical state. However, it is
an initial step, and the findings should be investigated further using more
rigorous designs. Our "close-in" research strategy37
contrasts with the traditional high-risk strategy12-13
in that genetic risk markers are only part of the definition of risk, and
early symptomatic and functional changes are required, ensuring that cases
are close to onset. It also differs from the revived focus on nonpsychotic
variants of schizophrenia,38-39
which represents a broadening of the therapeutic focus in schizophrenia, not
a true early intervention approach. In contrast, we identified progressive
positive symptoms as a preventive therapeutic target in their own right, thus
including a broader range of psychotic disorders, not only schizophrenia.
The NNT of 4 for this study indicates that the intervention is relatively
potent and contrasts with an NNT of 13 for drug treatment of moderate hypertension
in the prevention of stroke.35 Furthermore,
if SPI had been compared with monitoring alone, it may have been even more
potent because the transition rate in such a control group may well have been
higher. Several patients in the NBI group recovered even though they had strong
genetic risk and seemed highly "incipient." There were no significant symptomatic
and functional differences between groups at follow-up because although those
avoiding progression had improved, so too had those who had developed psychotic
disorders as a result of timely and effective treatment. Indeed, the latter
were performing much better than at entry. The data initially suggested that
the advantage in risk reduction is especially present during the treatment
phase and may erode when treatment is withdrawn. However, when drug adherence
is taken into account, a more sustained effect emerges. Even a well-timed
6-month "course" of antipsychotic medication plus CBT may conceivably inhibit
progression to psychosis for a more prolonged period. Larger sample sizes
and longer follow-up are essential.
An obvious limitation of this study is the lack of blindness. However,
this is unlikely to account for the robust difference seen in transition rates,
particularly because independent psychiatrists confirmed the diagnosis of
psychosis and all entry and exit decisions in the study were reviewed by expert
consensus. A second limitation is that we could not assess the relative contributions
of risperidone treatment and CBT. A critical question for future research
is whether use of antipsychotic medications is always required to reduce the
risk. Perhaps some patients could be treated with psychological therapy alone
as a first-line strategy, an approach we believe would prove more acceptable
to many patients. Drug therapy could be considered as a conservative second
step for patients who did not improve or who worsened. In continuing research
we are exploring this option using a multiple-cell design under double-blind
conditions. We are also controlling for the amount of psychosocial contact,
which, despite our efforts, was greater here in the SPI group. In future research,
we need to examine other alternatives because neuroprotective agents may ultimately
prove to be safer and more effective. The present results cannot be generalized
beyond the help-seeking subset of UHR patients who accepted randomization.
We know that most young people in the surrounding community who were eligible
for PACE and participation in this study were not accessed. Those who entered
the clinic but refused randomization were also a somewhat different clinical
population.
All participants understood the study well and were capable of giving,
refusing, or withdrawing informed consent. They were provided with clinical
care that was in no way contingent on participation in the study. Participants
in the clinical trial uniformly benefited, and no obvious harm was detectable.
Moderate improvement across a broad range of psychosocial indicators was noted,
although participants were significantly compromised on these measures at
entry and in many cases could have been expected to deteriorate further in
the absence of treatment. Even those who became psychotic were well engaged
in treatment and thus were treated promptly without needing emergency or inpatient
care. Administration of low-dose risperidone was well tolerated, with minimal
adverse effects. Patients who wanted to discontinue therapy could do so freely.
The most serious adverse outcomes were seen in nonparticipants.
The ethical dimension is complex.18, 22
The concept of subthreshold intervention presents a dilemma. As the NNT parameter
illustrates, there is a false-positive issue for all interventions, and an
acceptable range needs to be defined. This is a decision that ultimately should
be made by patients and families, informed by adequate data on the benefits
and risks of interventions. Further ethically sound studies using a range
of potentially preventive and neuroprotective interventions, biological and
psychosocial, are needed so that robust NNT data can be amassed and shared.
Such studies are presently in clinical equipoise and should be as strongly
supported as they have been in nonpsychiatric fields. To censor this type
of research for pseudoethical reasons would create a much less ethically acceptable
scenario in which no evidence base is developed to guide clinical practice.
However, until such data exist, our general stance is that off-label use of
even novel antipsychotic medications in such patients should not be first-line
treatment.
The potential benefits of prepsychotic intervention are as follows.
First, patients are more easily engaged and can therefore receive treatment
for manifest syndromes, whether or not the preventive treatment of the potential
psychosis turns out to have been unnecessary or ineffective. Second, those
who progress to psychosis have developed a level of trust that enables them
to accept treatment, to have a minimal duration of untreated psychosis and
reduced comorbidity, and to require inpatient care rarely. Third, the psychosocial
impact of the disorder may also be minimized and the ceiling for recovery
set at a higher level. Finally, some people may delay or avoid a first psychotic
episode. For a subset of patients, prepsychotic prevention may prove to be
highly cost-effective. It is an important frontier for further research.
AUTHOR INFORMATION
Submitted for publication February 22, 2001; final revision received
October 30, 2001; accepted November 5, 2001.
This study was supported in part by the Victorian Health Promotion Foundation,
Melbourne; National Health and Medical Research Council, Canberra, Australia;
Australian Research and Development Grants Advisory Scheme, Canberra; National
Alliance for Schizophrenia and Depression, Great Neck, NY; Stanley Foundation,
Muscatine, Iowa; Department of Human Services, Victoria, Australia; and Janssen-Cilag
Australia, Sydney, for partial support through an unrestricted research grant
for this investigator-initiated study.
Corresponding author and reprints: Patrick D. McGorry, PhD, FRANZCP,
PACE Clinic, Orygen Youth Health, Locked Bag 10, Parkville Australia 3052
(e-mail: mcgorry{at}ariel.unimelb.edu.au).
From the Early Psychosis Prevention and Intervention Centre (Dr McGorry);
Orygen Youth Health (Drs McGorry, Yung, Blair, and Adlard; Mss Phillips, Francey,
Cosgrave, and Bravin; and Messrs Germano and McDonald); the Departments of
Psychiatry (Dr McGorry, Mss Phillips and Francey, and Mr Yuen) and Psychology
(Dr Jackson), University of Melbourne; and PACE Clinic (Drs Yung, Blair, and
Adlard; Mss Phillips, Francey, and Bravin; and Mr McDonald), Melbourne, Australia.
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