Schizophrenia Bulletin vol. 39 no. 2 pp.

436–448, 2013
doi:10.1093/schbul/sbr165
Schizophrenia Bulletin
doi:10.1093/schbul/sbr165
Advance Access publication November 29, 2011

A Randomized Controlled Trial of Relapse Prevention Therapy for First-Episode

Psychosis Patients: Outcome at 30-Month Follow-Up
Follow-up

*,1
John F. M. Gleeson1, , Sue M. Cotton2, Mario Alvarez-Jimenez2, Darryl Wade3, Donna Gee4, Kingsley Crisp4,
*,
Tracey Pearce , Daniela Spiliotacopoulos2, Belinda Newman2, and Patrick D. McGorry2
4

1
School of Psychology, Australian Catholic University, Level 2, 115 Victoria Parade Fitzroy, VIC 3065, Australia; 2Orygen Youth Health

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Research Centre, Centre for Youth Mental Health, University of Melbourne, Australia; 3Australian Centre for Posttraumatic Mental
Health, Department of Psychiatry, University of Melbourne, Australia; 4Orygen Youth Health, Australia
*To whom correspondence should be addressed; tel: þ61-3-9953-3108, fax: þ61-3-9953-3205, email: john.gleeson@acu.edu.au

The effectiveness of a novel 7-month psychosocial treat-
ment designed to prevent the second episode of psychosis
was evaluated in a randomized controlled trial at 2 spe-
cialist first-episode psychosis (FEP) programs. An indi-
vidual and family cognitive behavior therapy for relapse
prevention was compared with specialist FEP care.
Forty-one FEP patients were randomized to the relapse
prevention therapy (RPT) and 40 to specialist FEP
care. Participants were assessed on an array of measures
at baseline, 7- (end of therapy), 12-, 18-, 24-, and 30-
month follow-up. At 12-month follow-up, the relapse
rate was significantly lower in the therapy condition com-
pared with specialized treatment alone (P 5 .039), and
time to relapse was significantly delayed for those in
the relapse therapy condition (P 5 .038); however, such
differences were not maintained. Unexpectedly, psychoso-
cial functioning deteriorated over time in the experimental
but not in the control group; these differences were no lon-
ger statistically significant when between-group differen-
ces in medication adherence were included in the model.
Further research is required to ascertain if the initial
treatment effect of the RPT can be sustained. Further re-
search is needed to investigate if medication adherence
contributes to negative outcomes in functioning in FEP
patients who have reached remission, or, alternatively,
if a component of RPT is detrimental.
Key words: first-episode psychosis/early psychosis/relapse
prevention/randomized controlled trials
Introduction
The aims of specialized first-episode psychosis (FEP)
treatment programs have included early recognition of
psychosis and timely engagement of patients in
The
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treatments tailored to specific stages of the disorder,
with the ultimate goal of recovery.1 FEP programs reduce
hospital readmissions and the need for supported accom-
modation compared with standard community care.2
However, some important gaps remain between the
stated aims of FEP programs and the clinical and psycho-
social outcomes that patients achieve—especially over
the longer term.2 This includes the common problem
of psychotic relapse.
Approximately 35%–70% of FEP patients will be ad-
versely affected by relapse.3 The clinical imperative to re-
duce relapse rates in FEP stems from the patients’
distress, carers’ burden, the potential for relapse to derail
hard-won progress in psychosocial recovery, the risk of
persistent psychosis after each new episode, and the
added economic burden of treating relapse.4
There is a paucity of rigorously designed randomized
controlled trials (RCTs) for the prevention of relapse fol-
lowing FEP. Our recent meta-analysis showed that there
was a total of only 9 published pharmacological and non-
pharmacological RCTs of an appropriate standard.5The
interpretation and comparison of these findings are
somewhat compromised by lack of consensus regarding
the definition and measurement of relapse.6 Despite this,
it does appear that specialist FEP programs have led to
improved relapse rates compared with standard treat-
ments. The reported relapse rate in specialist FEP care
of approximately 35% over 2-year follow-up is favorable
when compared with previously published relapse rates
of 55%–70%.3 Furthermore, first-generation antipsy-
chotic medications have produced improvements in
relapse rates compared with placebo and second-
generation antipsychotics may reduce relapse rates com-
pared with first-generation antipsychotic medications.
Obviously, the potential direct preventive benefits of med-
ication are unrealized among the estimated 20%–56% of
PsychiatricResearch
ResearchCenter.
Center.All
Allrights
rightsreserved.
reserved.

436
1
J. F. M. Gleeson et al.
young FEP patients who do not adhere with medication.7
Side effects, such as the risks of weight gain and meta-
bolic syndrome in FEP, are also significant issues for
clinicians when considering maintenance antipsychotic
treatment.8
The limitations of pharmacological treatments high-
light the importance of evaluating novel psychosocial
interventions in order to achieve incremental improve-
ment in relapse rates in FEP. In evaluating such treat-
ments, it is important that comparison control
treatments should be based upon treatment guidelines
for FEP. Recently, an advantage of FEP programs in
the prevention of relapse compared with standard psychi-
atric care has been noted.
We have conducted an RCT of a 7-month multimodal
relapse prevention therapy (RPT) designed for young
FEP patients who had reached remission on positive
psychotic symptoms. We compared our manualized
and combined individual and family cognitive behaviour
therapy (CBT)-based RPT intervention, plus specialist
treatment within an FEP program, with specialist treat-
ment alone. Participants were assessed over 30 months on
an array of clinical, functioning, and quality of life (QoL)
measures. At the end of treatment (7 months), the RPT
group had a significantly reduced relapse rate and longer
time to relapse than the treatment as usual (TAU)
group.9 We subsequently reported that at 30 months after
baseline, carers who received RPT reported a significantly
improved experience of caregiving compared with carers
randomized to specialist FEP care alone.10
Preventative interventions need to be evaluated at ap-
propriate intervals extending beyond the treatment
phase. Hence, we report on the final follow-up outcomes
for patient participants in our trial, including results at 30
months after baseline.
Our primary hypothesis was that the rate of, and time
to, relapse would be significantly lower for FEP partic-
ipants randomized to RPT compared with TAU within
a specialized FEP service as assessed at 6 intervals
over a 30-month follow-up period. Secondary hypotheses
were that awareness of illness, secondary morbidity,
QoL, medication adherence, and substance abuse would
be significantly improved in the RPT compared with
TAU as assessed at 6-monthly intervals over a 30-month
follow-up period.
Methods
Our method was previously reported,9 and we describe
only the major features here.
Design
The Episode II RCT compared a combined family and
individual RPT plus TAU within 2 specialist FEP serv-
ices. There were 6 assessment time points: baseline, 7, 12,
18, 24, and 30 months.
2 437
Relapse Prevention for FEP
Participants
Patients from the Early Psychosis Prevention and Inter-
vention Centre (EPPIC) in Melbourne and from JIG-
SAW, Barwon Health in Geelong, Victoria, Australia,
were recruited between November 2003 and May 2005.
The study inclusion criteria were a diagnosis of a first
episode of a Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV)11 psychotic disor-
der, less than 6 months of prior treatment with antipsy-
chotic medications, age 15–25 years inclusive, and
remission on positive symptoms of psychosis. Remission
was defined as 4 weeks or more of scores of 3 (mild) or
below on the subscale items hallucinations, unusual
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thought disorder, conceptual disorganization, and suspi-
ciousness on the expanded version of the Brief Psychiatric
Rating Scale (BPRS).12 Exclusion criteria were ongoing
active positive psychotic symptoms, severe intellectual
disability, inability to converse in or read English, and
participation in previous CBT trials. All patient partici-
pants provided written informed consent to participate
and provided additional consent for their family to be
approached to be involved. Family members also
provided informed consent.
Treatments
Relapse Prevention Therapy. The RPT individual re-
search therapist also adopted the role of outpatient
case manager for the duration of their treatment and
remained involved, at the EPPIC site, as the case manager
after the period of treatment had concluded. Research
therapists functioned as members of the treatment
team allowing the effectiveness of RPT to be evaluated
within existing ‘‘real-world’’ clinical roles. Patients had
continued routine treatment with their outpatient psychi-
atrist and had access to home-based treatment and group
interventions.
The individual therapy intervention comprised 5
phases of therapy underpinned by a CBT framework.
The aims of the first phase included engagement and as-
sessment of recovery and risk for relapse. In the second
phase, the formulation and therapy agenda were agreed
upon with the patient, with a focus upon risk factors for
relapse. The third phase focused upon reducing the risks
for setbacks, and in the fourth, the potential early warn-
ing signs of relapse were identified and a relapse plan for-
mulated. The fifth phase included optional modules
addressing client-specific relapse factors. The final phase
included a review and termination session. In addition to
psychoeducation specific to each module, the therapists
utilized supportive interventions and CBT techniques in-
cluding motivational interviewing, behavioral experi-
mentation, and socratic questioning.13 Modules were
provided within a 7-month therapy window, approxi-
mately fortnightly matching the recommended frequency
of TAU sessions.14
J. F. M. Gleeson et al.
The family intervention was provided by a trained fam-
ily therapist. It was informed by cognitive behavioural
family therapy for schizophrenia15 and family interven-
tions for FEP.16 The phases of family therapy were (1)
assessment and engagement, (2) assessment of family
communication, (3) burden and coping, (4) psychoeduca-
tion regarding relapse risk, and (5) a review of early warn-
ing signs and documentation of a relapse prevention plan.
Treatment manuals are available by request.
Treatment fidelity was ensured via the following pro-
cedures: (1) the manualization of the intervention techni-
ques, (2) clinical supervisors (J.F.M.G. and D.W.)
provided feedback to research therapists in weekly clin-
ical supervision sessions, and (3) the review of audiotapes
of individual therapy sessions. A representative sample of
sessions (n = 46) stratified by therapy phase was rated on
a specifically designed fidelity measure (Relapse Preven-
tion Therapy-Fidelity Scale [RPT-FS]) designed to assess
both treatment adherence and therapist competence as
defined in the intervention manual.13 The scale included
45 items arranged into 7 subscales, which corresponded
to 6 of the therapy modules and a general therapeutic
factors scale. Items on each subscale corresponded to
therapist’s behavior and raters identified whether the
behavior was present or absent.13 Fidelity to the adherence
modules was determined in 43 of the 46 sessions rated.13
Treatment as Usual. Patients randomized to TAU con-
tinued with their routine treatment, which was coordi-
nated via an outpatient case manager and outpatient
consultant psychiatrist.17 All case managers were orien-
tated to early psychosis treatment guidelines.18 Fidelity
was managed via approximately fortnightly one-to-one
supervision for all case managers with a senior clinician
and via weekly compulsory multidisciplinary case review.
TAU case managers were expected to provide family
work including psychoeducation and support where indi-
cated. Separate family therapy was available for more
complex family cases.
Key differences between TAU and RPT included: (1)
the shared written individualized formulation regarding
relapse risk, (2) the systematic approach to relapse pre-
vention via a range of cognitive behavioral interventions,
(3) the parallel individual and family sessions focused
upon relapse prevention, and (4) supervision specifically
focused upon relapse prevention.
Assessment Procedures
Research assistants (B.N. and D.S.) who were blind to
treatment allocation administered all assessment meas-
ures. The Structured Clinical Interview for DSM-IV, in-
cluding the modules for psychoses, mood disorders and
substance use disorders,19 and personality disorders,20
was completed at baseline. All diagnostic interviews
and available clinical material were reviewed in regular
438
Relapse Prevention for FEP
diagnosis consensus meetings attended by 3 of the
researchers (J.F.M.G., D.W., and B.N.). Symptom meas-
ures included the Montgomery-Asberg Depression Rat-
ing Scale,21 BPRS, Schedule for the Assessment of
Negative Symptoms (SANS),22 and the Scale for the Un-
awareness of Mental Disorder.23 Medication was not
controlled for but was treated as a background factor.
Medication adherence was measured via the Medication
Adherence Rating Scale (MARS),24 which is a self-report
questionnaire including items regarding adherence be-
havior and attitudes to medication. Medication side
effects were measured using the Liverpool University
Neuroleptic Side-effects Rating Scale (LUNSERS).25
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Pre-morbid intelligence quotient was estimated via the
Wechsler Test of Adult Reading.26 A range of psychoso-
cial functioning measures included the Premorbid Adjust-
ment Scale,27 the Social and Occupational Functioning
Assessment Scale (SOFAS),28 and the Australian version
of the WHO Quality of Life instrument.29 Measures of
substance abuse included the WHO Alcohol, Smoking
and Substance Involvement Screening Test30 and the Al-
cohol Use Disorders Identification Test. Severity of sub-
stance dependence was assessed using the Severity of
Dependence Scale (SDS).31 Face-to-face interviews were
completed at 6 time points, including baseline, 7-, 12-,
18-, 24-, and 30-month follow-up. At the follow-up time
points, all efforts were made to recontact study participants
by the study research assistants (RAs); however, because of
the well-known clinical challenges in following up this
complex population, there was an allowance made for
a maximum of a 3-month window in which assessments
were undertaken. Additional interim telephone calls were
also undertaken at 6-weekly intervals in order to complete
ratings on the psychotic items of the BPRS to enable pro-
spective assessment of psychotic relapses and psychotic
exacerbations.
Relapse definitions were based upon criteria utilized
in a series of studies at University of California, Los
Angeles.32 Criteria for relapse include increases from
3 (mild) or below to ratings of 6 or 7 (severe and very
severe) on any one of the following 3 BPRS items: (1) un-
usual thought content, (2) hallucinations, and (3) concep-
tual disorganization, with a duration criterion of 1 week.
Significant psychotic exacerbations following remission
were defined by an increase from 3 or below (for at least
1 month) on all the 3 scales followed by a score of 5 (mod-
erate) on any of the 3 items plus a 2-point increase on one
of the other scales (again with the addition of a duration
criterion of 1 week) or a rating of 5 on any one of the 3
scales for at least 1 month. Significant psychotic exacer-
bation following persisting psychotic symptoms (or fol-
lowing a partial remission) was defined as either an
increase in 1 scale of at least 2 points to a rating of 6
or 7 or a 1-point rise to a rating of 6 or 7 with an accom-
panying 2-point rise on one of the other 2 relapse scales,
for a period of at least 1 week. Consistent with previous
3
J. F. M. Gleeson et al.
studies of relapse, exacerbations were combined with
relapses in the final categorization of patient outcome.32
Twenty cases were selected at baseline for the purpose of
checking inter-rater reliability on the total score of the
BPRS, with an independent RA making simultaneous rat-
ings. Intra-class correlation coefficient for the BPRS total
score was 0.93, indicating good inter-rater reliability. In ad-
dition to inter-rater checks, reliability was managed by on-
going weekly supervision of the study RA by senior
members of the research team, which included direct
observation of ratings at approximately 2-monthly intervals.
Data Analyses
Data were screened for outliers, nonnormality, heteroge-
neity of variance, and heteroscedasticity. In the instance
of deviation from the normal Gaussian curve, logarith-
mic (plus a constant where 0 was a valid data value) trans-
formations were used. Descriptive statistics are reported
for untransformed data.
Differences between consenter/nonconsenters and
study completers/noncompleters on baseline demo-
graphic and clinical characteristics were examined using
independent sample t tests and chi-squared analyses (v2).
All primary and secondary analyses were based on the
intent-to-treat paradigm. The primary outcome measures
were the number of relapses and time to relapse (based on
the time to first relapse). Group differences in the propor-
tion of relapses at 30 months were examined using the v2.
Kaplan-Meier analysis was used to estimate survival
(ie, no relapse) in the RPT and TAU groups. The Cox-
Mantel log-rank test was employed to test for differences
in the survival curves of these 2 groups.
To determine group differences on the secondary
outcome measures, a series of mixed model repeated
measures (MMRM) analyses were employed. The
within-groups factor was time (baseline, 7, 12, 18, 24,
30 months) and group served as the between-subjects
factor. From the model, the main effects for group (ie,
overall are the RPT and TAU groups different?) and
time (ie, how do ratings change over time?) can be exam-
ined along with the interaction between these variables. A
Toeplitz covariance structure was used to model the
relationship between observations. Significant interac-
tions were followed by simple main effects analyses (ie,
time within group and group within time). With the
MMRM, a series of planned comparisons (endpoint anal-
yses) were conducted to determine whether there were any
between group differences in the overall rate of change
from baseline to 30 months. MMRM is the preferred
method of examining the outcomes of clinical trials.33
Results
Patient Characteristics
Of 399 patients assessed for eligibility, 213 were initially
deemed eligible and 86 of these patients consented to
4 439
Relapse Prevention for FEP
participate in the study. Four of these patients did not
meet entry criteria as determined by presence of positive
psychotic symptoms at the baseline assessments. The re-
fusal rate in relation to the number of eligible participants
was 59.6% (n = 127) (refer to figure 1). The main reasons
recorded for their refusal included: not interested in the
study (n = 80), did not want to change case manager
(n = 41), already a participant in another research project
(n = 3), and other (n = 3). Data were not available for 9
families in the RPT group due to patients refusing to con-
sent to their family being involved (n = 6) or families not
consenting (n = 3). Similarly, data were not available for 9
families from the TAU group (patients refused family
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involvement, n = 5; families refused involvement, n = 4).
Randomization and Attrition
At baseline, 1 participant dropped out after randomiza-
tion to the TAU group, and no data were available for
this patient (thus, n = 41 in RPT and n = 40 in TAU).
Of the 81 patients for whom baseline data were available,
77 were recruited from EPPIC and 4 were recruited from
Barwon Health. At 30 months, 74.1% (n = 60) of patients
were assessed and 25.9% (n = 21) cases lost to follow-up
(16 cases dropped out and 5 missed assessment). There
are no significant differences between the 2 groups with
respect to percentages of cases that were lost to follow-up
(RPT, n = 11; TAU, n = 10; v2 (1) = 0.035, P = .851).
Baseline Characteristics
Patients had been in the service on average 29.96 weeks
(SD = 13.32 weeks) prior to being recruited into the study.
There were no between-group differences on demo-
graphic, diagnostic, baseline symptom measures, rates
of medication use, or days of hospitalization prior to en-
tering the study (see tables 1 and 2).
Completers at 30-month follow-up were contrasted with
participants who had dropped out (n = 16) or who had
missed their assessment (n = 5) on a range of demographic
and baseline clinical variables. The case in the TAU group
that did not have a baseline assessment was excluded from
these analyses. Noncompleters had significantly higher
premorbid functioning during childhood (completers,
M = 0.3, SD = 0.2 and noncompleters, M = 0.2, SD =
0.1; t(73) = 2.09, P = .040) and early adolescence
(completers, M = 0.3, SD = 0.2 and noncompleters,
M = 0.2, SD = 0.1; t(50.7) = 3.18, P = .003). No other differ-
ences between these 2 groups were found for demographic,
diagnostic (Axis I including substance use disorder and
Axis II disorders), and baseline clinical characteristics.
Importantly, functioning at entry to the study was
comparable between completers and noncompleters.
Treatment Received
Patients who were assigned to RPT completed an average
of 8.51 (SD = 4.87) therapy sessions, and 25 (61%)
J. F. M. Gleeson et al.
Fig. 1. CONSORT flowchart depicting participation through various stages of the study. This applies to the primary outcome measure of
relapse within the 30-month period.
completed a full course of individual RPT, which was de-
fined as the completion of all relevant phases of therapy
including the termination phase. Completers of therapy
received a mean of 11.84 sessions (SD = 1.55).
Treatment Outcomes
Data on relapses were available for 30 patients in the
RPT group and 30 patients in the TAU group. Within
the 30-month follow-up period, there were no significant
differences between the relapse/exacerbation rates for the
2 groups (RPT, 30.0%, n = 9 and TAU, 43.3%, n = 13,
v2(1) = 1.15, P = .284). Five cases in each group met
the relapse criteria. In the RPT, 4 cases had an exacerba-
tion compared with 8 cases in the TAU group. There were
3 cases in the RPT group and 1 in the TAU group who
had 2 events. The 3 cases in the RPT group each had an
exacerbation followed by a period of recovery and then
another exacerbation. The 1 case in the TAU group with
multiple events had a relapse followed by a period of re-
covery and then an exacerbation.
The cumulative proportion surviving at each of the
main study time points is detailed in table 2. The mean
440
Relapse Prevention for FEP
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survival time for the RPT group (M = 823.50, SE =
43.45) was greater than for the TAU group (M =
734.87, SE = 59.47); however, the difference in survival
curves was not significant at the 30-month time point,
Log rank v2 (1) = 1.330, P = .246; (see figure 2). On ex-
amination of figure 2, it appeared that there may be dif-
ferences in cumulative survival at earlier assessment time
points in the study. Indeed, in our earlier article,9 a differ-
ence in survival curves between the 2 groups was noted at
7 months at the end of therapy. To determine the sustain-
ability of treatment effects, a series of secondary survival
analyses for each assessment time point were performed.
The difference between groups was sustained at the 12-
month time point (see figure 3), Log rank v2(1) = 4.28,
P = .038 (see figure 2). The percentage of relapses at
12 months also differed between the 2 groups; the relapse
rate in the TAU (28.2%, n = 11) group was nearly 3 times
greater than for the RPT group (10.0%, n = 4, v2(1) = 4.26,
P = .039).
The results for the MMRMs for the other clinical and
functional measures are depicted in tables 3 and 4; figure
3. Over the 30 months, there were no significant between
5
J. F. M. Gleeson et al. Relapse Prevention for FEP

Table 1. Premorbid and Baseline Demographic and Diagnostic Characteristics of the Relapse Prevention Therapy (RPT) and Treatment as
Usual (TAU) Groups

Descriptive Total Cohort RPT TAUl Test

Variables Statistic (n = 81) (n = 41) (n = 40) Statistic P-Value

Demographic
Age M (SD) 20.1 (3.1) 20.1 (2.9) 20.1 (3.2) t test .968
Gender, % male % (n) 63.0 (51) 65.9 (27) 60.0 (24) v2 .585
Marital status, % never married % (n) 95.1 (77) 92.7 (38) 97.5 (39) v2 .317
Still attending school?, % yes % (n) 29.6 (24) 26.8 (11) 32.5 (13) v2 .576
Total number of years of education completed
Still at school M (SD) 12.0 (2.0) 11.8 (1.6) 12.2 (2.3) t test .413
Not at school M (SD) 12.0 (1.7) 12.0 (1.7) 12.2 (1.7) t test .746
Employmenta

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Unemployed % (n) 43.2 (35) 51.2 (21) 35.0 (14) v2 .141
Full-time paid work % (n) 12.3 (10) 12.2 (5) 12.5 (5) v2 .967
Part-time paid work % (n) 4.9 (4) 2.4 (1) 7.5 (3) v2 .293
Casual paid work % (n) 14.8 (12) 12.2 (5) 17.5 (7) v2 .502
Lives with family, % yes % (n) 76.5 (62) 73.2 (30) 80.0 (32) v2 .468
Premorbid
DUPb M (SD) 384.8 (567.9) 401.1 (529.1) 368.6 (611.9) t testc .904
FSIQd M (SD) 91.3 (27.8) 90.8 (24.6) 91.8 (30.9) t test .875
Premorbid Adjustment Scalee
Childhood M (SD) 0.2 (0.2) 0.2 (0.1) 0.3 (0.2) t test .299
Early adolescence M (SD) 0.3 (0.2) 0.3 (0.1) 0.3 (0.2) t test .594
Late adolescence M (SD) 0.3 (0.2) 0.4 (0.2) 0.3 (0.2) t test .527
General M (SD) 0.4 (0.2) 0.3 (0.2) 0.3 (0.1) t test .785
Average M (SD) 0.3 (0.1) 0.3 (0.1) 0.3 (0.2) t test .658
Psychotic diagnoses
Schizophrenia % (n) 33.3 (27) 34.1 (14) 32.5 (13) v2 .875
Schizophreniform % (n) 11.1 (9) 7.3 (3) 15.0 (6) v2 .271
Schizoaffective disorder % (n) 4.9 (4) 7.3 (3) 2.5 (1) v2 .317
MDE with psychotic features % (n) 6.2 (5) 2.4 (1) 10.0 (4) v2 .157
Bipolar disorder % (n) 4.9 (4) 7.3 (3) 2.5 (1) v2 .317
Delusional disorder % (n) 1.2 (1) 0.0 (0) 2.4 (1) v2 .308
Substance-induced psychotic disorder % (n) 3.7 (3) 4.9 (2) 2.5 (1) v2 .571
Psychotic disorder NOS % (n) 29.6 (24) 34.1 (14) 25.0 (10) v2 .367
Other diagnoses
MDE without psychotic features % (n) 23.5 (19) 17.1 (7) 30.0 (12) v2 .170
Dysthymic disorder % (n) 8.6 (7) 9.8 (4) 7.5 (3) v2 .718
Past history of MDE % (n) 22.2 (18) 26.8 (11) 17.5 (7) v2 .313
Borderline personality disorderf % (n) 7.6 (6) 10.0 (4) 5.1 (2) v2 .414
Antisocial personality disorderg % (n) 10.4 (8) 10.5 (4) 10.3 (4) v2 .969
Alcohol abuse/dependence % (n) 24.7 (20) 24.4 (10) 25.0 (10) v2 .590
Cannabis abuse/dependence % (n) 51.9 (42) 61.0 (25) 42.5 (17) v2 .096
Opioid abuse/dependence % (n) 7.4 (6) 9.8 (4) 5.0 (2) v2 .414
Cocaine abuse/dependence % (n) 3.7 (3) 2.4 (1) 5.0 (2) v2 .542
Hallucinogen abuse/dependence % (n) 14.8 (12) 12.2 (5) 17.5 (7) v2 .502
Amphetamine abuse/dependence % (n) 18.5 (15) 17.1 (7) 20.0 (8) v2 .735

Note: DUP, Duration of Untreated Psychosis; FSIQ, Full Scale IQ; MDE, Major Depressive Episode.
a
Not mutually exclusive categories.
b
Estimated on the basis of time between onset of symptoms and entry into the service.
c
Test statistic based on logarithmic-transformed data due to the extreme skewness of duration of untreated psychosis.
d
Estimated based on performance on the Wechsler Test of Adult Reading.
e
Scores range from 0.0 to 1.0 with higher scores indicative of ‘‘healthier’’ levels of adjustment.
f
For borderline personality disorder, TAU denominator was 39 and for RPT group denominator was 40.
g
For antisocial personality disorder, TAU denominator was 39 and for RPT group denominator was 38.

group differences with respect to overall psychopathol- were significant interactions between group and time for
ogy, severity of positive psychotic symptoms, insight SANS summary scores, F5,185.5 = 2.28, P = .049; SANS
depressive symptoms, and substance use measures. There alogia, F5,214.1 = 4.15, P = .001; and SANS attention
6 441
J. F. M. Gleeson et al. Relapse Prevention for FEP

Table 2. Cumulative Proportion Surviving (and SE)a at Each of 30 months (P = .001). The rate of improvement on SANS
the Main Study Time Points Attention from baseline to 30 months was significantly
greater in the TAU group (P = .001).
Relapse Prevention Treatment as
There was a significant group by time interaction for
Therapy (RPT) Usual (TAU)
SOFAS scores, F5,128.4 = 2.30, P = .049 (see figure 3l).
7 months 0.976 (0.024) 0.795 (0.065) The RPT group had significantly lower functioning at
12 months 0.897 (0.049) 0.713 (0.073) 30 months compared with the TAU group (P = .043)
18 months 0.832 (0.063) 0.713 (0.073) (see figure 3l). For the TAU group, functioning was sig-
24 months 0.798 (0.069) 0.713 (0.073) nificantly higher at 30 months compared with the base-
30 months 0.728 (0.079) 0.631 (0.085)
line (P = .039). For the RPT group, the SOFAS was
a significantly higher at both 18 months (P = .002) and
Estimated using the Kaplan-Meier statistic.
24 months (P = .003) compared with baseline; however,
functioning at 30 months was not significantly different

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F5,154.2 = 2.71, P = .023 (see table 4). For the SANS sum-
mary score, the RPT group had a significantly higher
mean score at 30 months compared with the TAU group
(P = .013). Endpoint analyses indicated that the TAU
group had significantly greater improvement in the
SANS summary score from baseline to 30 months
than the RPT group (P = .018) (see Table 4, figure 3c).
For SANS alogia (see figure 3e), the RPT group had sig-
nificantly higher scores than the TAU group at 7 months
(P = .002), 18 months (P = .031), and 30 months (P =
.041). Endpoint analyses indicated that the TAU demon-
strated significantly greater improvement in alogia from
baseline to 30 months compared with the RPT group (P =
.006). For SANS attention (see figure 3h), the RPT group
had a significantly higher mean score than TAU group at
Fig. 2. Comparison of the cumulative survival from psychotic
relapse of the relapse prevention therapy (RPT) and treatment as
usual (TAU) groups over 30 months.
from baseline (P = .547).
There was a significant group by time interaction for
the MARS, F5,109.8 = 2.35, P = .045 (see figure 3m).
Further analysis indicated that the RPT (P = .002) and
not the TAU (P = .994) group had significant change
over time. For the RPT group, there was significant im-
provement from baseline to 24 months (P = .004) and base-
line to 30 months (P = .015) in terms of medication
adherence. Endpoint analysis was not significant (P = .055).
Other Analyses
In order to attempt to explain differences with the SANS,
SOFAS, and MARS, further analyses were conducted to
determine whether the 2 treatment groups differed with
respect to number of case management sessions, number
of contacts with group program activities, number of hos-
pitalizations, medication dose (chlorpromazine [CPZ]
equivalent units), and medication side-effects (LUNS-
ERS) over the 30 months. The 2 groups had a similar
amount of case management sessions (RPT, M = 29.2,
SD = 17.4 and TAU, M = 28.8, SD = 18.3; P = .916), con-
tacts with group program activities (RPT, M = 6.5, SD =
11.1 and TAU, M = 8.5, SD = 17.1; P = .536), days of
hospitalization (RPT, M = 10.5, SD = 16.3 and TAU,
M = 8.4, SD = 13.0; P = .518), and total CPZ equivalents
over the 30 months (RPT, M = 952.1, SD = 853.9 and
TAU, M = 1111.3, SD = 1175.9; P = .494). There were
no significant interactions between group and time for
LUNSERS total (males F5,70.64 = 1.52, P = .195 and
females, F5,51.24 = 0.72, P = .614) and Red Herring (males
F5,78.86 = 1.49, P = .204 and females, F5,46.67 = 0.42, P =
.832) scores. We also conducted a series of MMRM anal-
yses to determine whether the unexpected findings on the
SANS and SOFAS could be explained by increased med-
ication adherence in the RPT group. A change score was
computed (baseline to 30 months) for medication adher-
ence, and this score was added as a covariate in the
MMRM. For SANS attention and SOFAS, the interaction
between group and time became not significant when
change in medication adherence was controlled for
(SANS attention, F5,56.7 = 0.75, P = .588 and SOFAS
F5,34.91 = 1.89, P = .120). For SANS alogia and SANS

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J. F. M. Gleeson et al. Relapse Prevention for FEP

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Fig. 3. Means (6SE) derived from mixed model repeated measures (MMRM) for symptoms, functioning, and medication adherence.

8 443
J. F. M. Gleeson et al.
Fig. 3. Continued
summary, the interactions between group and time
remained significant even after medication adherence
was controlled for (SANS alogia, F5,50.94 = 2.57, P =
.038 and SANS summary, F5,39.12 = 3.14, P = .018).
Discussion
The overall relapse rates observed in the current study
were similar to previously published relapse rates from
FEP programs.3 However, relapse rates were lower
and the timing of relapses was delayed in the RPT group
compared with the TAU group at the end of therapy
(7 months) and at 12 months. However, these differences
were not sustained at 18, 24, and 30 months.
Thus, RPT in the short-term appears to provide benefit
to patients but may not have a sustained effect, perhaps
due to the limited duration of the treatment. By way of
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Relapse Prevention for FEP
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comparison trials of effective family-based interventions
for the prevention of relapse in schizophrenia have
entailed 9 months of therapy and longer in some stud-
ies.34 A previously published individual CBT therapy
for the prevention of relapse in schizophrenia included
ongoing monitoring of early warnings signs and oppor-
tunistic intervention at the detection of elevated early
warning signs35—an approach which may prolong the
initial treatment effect of RPT.
We found partial support for our secondary hypotheses—
improvements were observed over 30 months in medica-
tion adherence in the RPT group. To our knowledge, this
is the first outcome study that has shown a sustained
treatment effect for improving medication adherence in
FEP compared with specialized treatment, and this is
a rare outcome even in the broader schizophrenia research
literature.
9
J. F. M. Gleeson et al. Relapse Prevention for FEP

Table 3. Tests of Fixed Effects in Mixed-Effects Model Repeated Measures ANOVA for Measures of Psychopathology, Substance Use,
Functioning, Quality of Life, and Medication Adherence

Effect F test df P Effect F test df P

Symptoms Substance use

BPRS total scorea AUDITa
Group 0.07 174.6 .786 Group 0.01 183.2 .918
Time 2.23 5122.6 .055 Time 1.30 5130.1 .272
Group 3 time 1.13 5122.6 .347 Group 3 time 0.73 5130.1 .603
BPRS positive symptomsa SDSa
Group 2.41 180.4 .124 Group 0.42 176.6 .517
Time 1.55 5148.5 .178 Time 1.75 5118.3 .128
Group 3 time 0.41 5148.5 .844 Group 3 time 0.60 5118.3 .703

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SANSa ASSIST alcohol
Affect Group 0.44 180.72 .509
Group 0.30 177.8 .589 Time 0.56 5154.1 .729
Time 1.45 5130.9 .209 Group 3 time 1.47 5154.1 .204
Group 3 time 1.14 5130.9 .342 ASSIST Cannabis
Alogia Group 0.35 179.8 .558
Group 3.00 176.5 .089 Time 0.75 5140.9 .588
Time 4.06 5214.1 .002 Group 3 time 0.33 5140.9 .896
Group 3 time 4.15 5214.1 .001 Functioning
Avolition SOFAS
Group 0.52 180.0 .475 Group 0.80 179.1 .374
Time 1.59 5148.1 .168 Time 2.52 5128.4 .033
Group 3 time 1.70 5148.1 .137 Group 3 time 2.30 5128.4 .049
Anhedonia Quality of life
Group 0.02 178.9 .879 Physical
Time 2.62 5144.8 .027 Group 1.00 176.4 .320
Group 3 time 1.50 5144.8 .191 Time 0.79 5135.9 .556
Attention Group 3 time 0.63 5135.9 .676
Group 2.20 178.1 .142 Psychological
Time 0.40 5154.2 .849 Group 1.41 175.9 .239
Group 3 time 2.71 5154.2 .023 Time 1.90 5124.5 .100
Summaryb Group 3 time 0.81 5124.5 .545
Group 1.38 180.6 .243 Social relationships
Time 2.11 5185.5 .066 Group 0.58 176,1 .450
Group 3 time 2.28 5185.5 .049 Time 1.05 5142.4 .392
MADRSa Group 3 time 1.16 5142.4 .331
Group 1.02 172.5 .316 Environment
Time 16.63 5165.9 .001 Group 1.21 176.1 .275
Group 3 time 1.02 5165.9 .406 Time 0.75 5138.1 .591
SUMD Group 3 time 0.56 5138.1 .732
Awareness of disorder (past and current) Medication adherencea
Group 0.04 170.4 .840 Group 0.03 165.2 .866
Time 1.75 5154.9 .127 Time 2.59 5109.8 .030
Group 3 time 0.76 5154.9 .583 Group 3 time 2.35 5109.8 .045
Awareness of medication (past and current)
Group 0.48 1, 71.0 .492
Time 1.15 5, 145.3 .336
Group 3 time 1.29 5, 145.3 .273

Note: BPRS, Brief Psychiatric Rating Scale; SANS, Schedule for the Assessment of Negative Symptoms; SUMD, Scale for
Unawareness of Mental Disorders; MADRS, Montgomery Asberg Depression Rating Scale; AUDIT, Alcohol Use Disorders
Identification Test; SDS, Severity of Dependence Scale; ASSIST, Alcohol, Smoking and Substance Involvement Screening Test;
SOFAS, Social and Occupational Functioning Assessment Scale. Bold values indicate significant effects ( P < .05).
a
Analyses based on logarithmic (plus constant)-transformed data due to extreme positive skewness.
b
Summary score was computed by summing the 5 global items of the SANS.

10 445
J. F. M. Gleeson et al. Relapse Prevention for FEP

Table 4. Secondary Efficacy Endpoints Over 30 Months

Baseline 30 Months
a
Characteristics RPT, M (SE) TAU, M (SE) RPT, M (SE)a TAU, M (SE) tb df P

Symptoms
BPRS totalc 35.4 (1.3) 34.3 (1.3) 33.8 (1.5) 32.2 (1.5) 0.30 46.7 .767
BPRS positive symptomsc 5.3 (0.4) 5.8 (0.4) 5.4 (0.5) 5.6 (0.4) 0.40 48.0 .691
SANSc
Affective 5.4 (1.1) 5.1 (1.1) 4.9 (1.3) 3.1 (1.3) 0.33 74.4 .741
Alogia 2.2 (0.4) 2.5 (0.4) 2.8 (0.4) 1.3 (0.5) 2.80 111.2 .006
Avolition 3.6 (0.8) 3.6 (0.8) 4.9 (0.9) 3.1 (0.9) 1.49 80.8 .140
Anhedonia 5.0 (0.9) 5.0 (0.9) 4.5 (1.1) 2.7 (1.0) 1.80 98.4 .075

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Attention 1.6 (0.4) 2.4 (0.4) 3.2 (0.5) 1.0 (0.5) 3.60 89.0 .001
Summary 4.4 (0.6) 4.8 (0.6) 5.6 (0.7) 2.9 (0.7) 2.40 96.9 .018
SUMD
Awareness of mental disorder 2.0 (0.2) 2.0 (02) 1.6 (0.2) 1.9 (0.2) 0.97 117.3 .337
Awareness of response to medication 1.6 (1.7) 1.5 (0.2) 1.4 (0.2) 1.9 (0.2) 1.92 102.8 .057
MADRSc 9.8 (1.4) 11.1 (1.5) 7.6 (1.7) 7.4 (1.7) 0.03 44.7 .977
Substance use
AUDITc 7.8 (1.0) 6.4 (1.0) 6.2 (1.2) 7.3 (1.1) 1.41 87.1 .161
SDSc 3.3 (0.6) 2.5 (0.6) 2.8 (0.7) 1.6 (0.7) 0.18 104.3 .854
ASSIST alcohol 3.7 (0.5) 2.7 (0.5) 3.3 (0.6) 3.3 (0.6) 1.32 57.6 .192
ASSIST Cannabis 3.8 (0.7) 2.6 (0.7) 3.5 (0.8) 3.5 (0.8) 0.98 127.3 .337
Functioning
SOFAS 61.2 (2.6) 65.2 (2.7) 63.2 (3.1) 72.1 (3.1) 1.05 84.5 .297
Quality of life
Physical 69.3 (2.7) 65.7 (2.7) 71.0 (3.1) 70.6 (3.1) 0.74 72.9 .464
Psychological 56.4 (3.3) 54.3 (3.3) 61.8 (3.8) 57.1 (3.7) 0.53 82.9 .598
Social relationships 63.2 (3.7) 58.5 (3.8) 66.0 (4.4) 57.5 (4.3) 0.58 94.3 .566
Environment 63.5 (2.6) 62.0 (2.7) 66.2 (3.1) 61.6 (3.0) 0.74 102.3 .460
Medication adherence
MARSc 6.7 (0.4) 7.0 (0.3) 8.3 (0.6) 7.1 (0.45) 1.95 77.6 .055

Note: Abbreviations are explained in the first footnote to table 3. BPRS total score (range 18–126), BPRS positive symptoms (4–28),
SANS affective (0–40), SANS alogia (0–25), SANS avolition (0–20), SANS anhedonia (0–25), SANS attention (0–15), SANS summary
(0–25), SUMD (1–5), MADRS (0–60), AUDIT (0–40), SDS (0–15), ASSIST (0–20), SOFAS (0–100), WHOQoL-Bref (1–100), MARS
(0–100). Bold values indicate significant effects ( P < .05).
a
Mean (M) and standard error (SE) estimates derived from the mixed model repeated measures (MMRM).
b
Endpoint analyses are based on planned comparison t tests derived from mixed model repeated measures (MMRM) model. The focus
was on comparing between groups differences in the change from baseline to the 30-month follow-up time point.
c
Analyses based on logarithmic (plus constant)-transformed data due to extreme positive skewness. Descriptive statistics are based on
untransformed data.

Conversely, there was no significant additional benefit
of RPT in relation to awareness of illness, secondary mor-
bidity, or quality of life, consistent with the findings of
a previous study comparing CBT with specialist FEP
treatment.36 This may indicate a difficulty with achieving
significant and sustained improvements in outcome in
comparison with specialized FEP care.
There were 2 unexpected findings: group by time inter-
actions with regards to psychosocial functioning, which
showed deterioration only in the RPT group over time,
and a group by time interaction for negative symptoms
with the TAU group improving but not the RPT group.
This could not be explained by differences in the amounts
of other psychosocial treatment received. Both groups
had equal access to psychosocial treatments including vo-
cational and educational activities. Nor were there any
significant differences in antipsychotic medication doses
prescribed or number of hospitalizations, which may
have interrupted recovery in functioning.
It is possible that an unidentified component of our in-
tervention may have a detrimental effects upon function-
ing and negative symptoms.37 For example, perhaps the
intervention increased anxiety, or rational concern, re-
garding relapse, which mediated increased avoidance of
goal attainment, consistent with cognitive models of re-
lapse.38 We would concur with Lilienfeld that replication
is required to definitively draw this conclusion.37 Against
this interpretation, is that the reduction in functioning in

446 11
J. F. M. Gleeson et al.
the RPT group was only apparent at the 30-month time
point, and there is no previously published evidence to
support this conclusion, so we believe this is unlikely.
When differences in medication adherence were con-
trolled for, the group by time interaction was no longer
significant. This finding raised the possibility that for
FEP patients who reach remission on positive symptoms,
adherence to antipsychotic medication may have had an
indirect effect (via side-effects), upon psychosocial func-
tioning over time. This interpretation was not consistent
with the lack of significant effects on the LUNSERS.
However, it is notable that the relative timing of changes
in medication adherence and psychosocial functioning in
the RPT group as depicted in figure 3 show that increases
in adherence (18–24 months) preceded decreases in psy-
chosocial functioning and increases in negative symp-
toms (24–30 months) in the RPT group. This is
consistent with previous research showing an association
between better vocational functioning at 2-year follow-
up and placebo treatment compared with antipsychotic
medication in a first-episode schizophrenia sample.39
Therefore, it remains possible that antipsychotic medica-
tion may be impacting functioning in the absence of
measureable subjective side effects. Other possible
explanations for this finding are that medication adher-
ence scores may reflect other indirect impacts upon func-
tioning, including attitudes to treatment or other clinical
factors, such as personality traits. Finally, it is possible
that this was a spurious finding.
Limitations and Strengths
Our study was the first to test a novel psychosocial inter-
vention for relapse prevention for FEP. The strengths of
our study included the randomization of patients, the
blinding of research assistants, the manualized treat-
ments, the careful management of fidelity, and the dura-
tion of follow-up assessments. Further improvements
could have included the audio taping of case management
sessions to test the fidelity of specialist FEP treatment
and increased sample size to improve the statistical
power. In addition, although quantity of specific treat-
ments was measured across all phases of the study, qual-
ity of treatment was not measured beyond the period of
RPT, which would have enabled us to examine its effects
upon outcomes at follow-up. While we believe we took all
possible steps to ensure that the sample was representa-
tive, it is possible that the severity of cooccurring symp-
toms varied from the population of remitted FEP
patients. In terms of measurement, it is also possible
that the MARS confounded the measurement of atti-
tudes toward medication with actual doses consumed.
A recent validation study with a relatively large sample
of patients with psychosis highlighted concerns regarding
the concurrent validity of the MARS.40 In hindsight,
a multimethods approach, rather than a single self-report
12
Relapse Prevention for FEP
measure, would have been the optimal approach to the
measurement of adherence. In relation to the interven-
tion, we also note that the change in case manager
may have introduced an uncontrolled element to the ex-
perimental condition, which may have reduced the mag-
nitude of treatment effects. Finally, the combination of
individual and family CBT does not enable the analysis
of the specific contribution of these 2 components to
treatment outcomes.
Further Research
Our findings with regards to the primary hypothesis high-
light the need to trial extensions of our intervention. We
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also argue for novel approaches to sustain the relapse
prevention components. We believe that this could be
achieved via information communication technology,
which has been relatively underutilized in this patient
group. We also contend that problems of secondary mor-
bidity and psychosocial functioning require longer term
interventions. Finally, the impact of antipsychotic med-
ication upon functioning in the subgroup of patients, who
maintain remission on positive symptoms should be eval-
uated in an RCT of intensive psychosocial interventions
with and without maintenance medication.
Funding
This Study was funded by an unrestricted grant from Eli
Lilly via the Lilly Melbourne Academic Psychiatry
Consortium. In addition, the study was supported by
the Colonial Foundation and a Program grant from
the National Health and Medical Research Council of
Australia (350241). No funding body had any involve-
ment in any aspect of the study or manuscript. A/Prof.
S.M.C. is supported by the Ronald Phillip Griffith
Fellowship, Faculty of Medicine, Dentistry, and Health
Science, the University of Melbourne.
Acknowledgments
P.D.M. has received honoraria and research grant support
from Janssen Cilag, Eli Lilly, Pfizer, Novartis and Astra
Zeneca. The other authors have declared that there are
no conflicts of interest in relation to the subject of this
study. Australian New Zealand Clinical Trials Registry
(http://www.anzctr.org.au/) Number: 12605000514606.
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