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Background
The GET UP multi-element psychosocial intervention proved duration of untreated psychosis, premorbid adjustment and
to be superior to treatment as usual in improving outcomes insight predicted outcomes regardless of treatment. Only age
in patients with first-episode psychosis (FEP). However, to at first contact with the services proved to be a moderator
guide treatment decisions, information on which patients of treatment outcome (patients aged 535 years had greater
may benefit more from the intervention is warranted. improvement in psychopathology), thus suggesting that the
intervention is beneficial to a broad array of patients with
Aims FEP.
To identify patients characteristics associated with (a) a
better treatment response regardless of treatment type (non- Conclusions
specific predictors), and (b) a better response to the specific Except for patients aged over 35 years, no specific
treatment provided (moderators). subgroups benefit more from the multi-element psychosocial
Method intervention, suggesting that this intervention should be
Some demographic and clinical variables were selected recommended to all those with FEP seeking treatment in
a priori as potential predictors/moderators of outcomes at mental health services.
9 months. Outcomes were analysed in mixed-effects random
regression models. (Trial registration: ClinicalTrials.gov, Declaration of interest
NCT01436331.) None.
Consistent evidence has been accumulated showing that early multi-element interventions could be delivered effectively in
interventions facilitate recovery and reduce long-term disability routine mental health services. Moreover, compared with patients
in patients with psychosis.1,2 Literature has also shown that early receiving routine care, those treated with the early multi-element
interventions should be provided on an integrated basis (i.e. interventions displayed greater reductions in overall symptom
multi-element) and be grounded in evidence-based psychosocial severity, and greater improvements in global functioning,
treatments.35 However, there is as yet no consensus on a service emotional well-being and the subjective burden of delusions.10
model for the provision of early interventions for patients with Overall, the study findings were consistent with those of a large
first-episode psychosis (FEP), nor do we know to what extent early trial conducted in the Recovery After an Initial Schizophrenia
intervention services are generalisable.68 The GET UP (Genetics, Episode (RAISE) initiative, which compared a comprehensive,
Endophenotypes, Treatment: Understanding early Psychosis) multidisciplinary, team-based treatment approach for FEP,
PIANO (Psychosis: early Intervention and Assessment of Needs designed for implementation in the USA healthcare system, with
and Outcome) trial9 was set up to fill this gap. It was designed routine community care (i.e. patients in the experimental arm
to assess early multi-element psychosocial interventions in experienced greater improvement in quality of life, psychopathology
epidemiologically representative samples of patients treated in and social functioning).11
routine generic mental health settings. A previous paper reported In the present study we sought to identify, among baseline
the feasibility and effectiveness of adding a multi-element psycho- demographic and clinical characteristics, predictors and moderators
social intervention to the standard treatment of patients with of treatment outcomes at 9 months. Existing literature provides
FEP. At 9-month follow-up it was clear, based on the retention some information on predictors of treatment outcome in patients
rates of patients and families in the experimental arm, that early with FEP.1217 Available data, however, are rarely based on
epidemiological samples compared with controls, and this
*The full list of authors included in the GET UP Group appears in the online increases the risk of underestimating the complexities of treating
supplement to this paper. FEP in real-world services.18 The present study attempted to deal
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Predictors and moderators of treatment outcome for an early psychosis intervention
with this gap, and, in particular, aimed to understand: (a) which medication in the past 3 months, for an identical or similar mental
patients characteristics are associated with a better treatment disorder; (b) mental disorders because of a general medical
response, regardless of treatment type (non-specific predictors); condition; (c) moderate-severe intellectual disability diagnosis
and (b) which characteristics are associated with a better response assessed by a clinical functional assessment; and (d) diagnosis
to the specific FEP treatment provided in the GET UP trial other than ICD-10 for psychosis25 (with the exception of non-
(moderators). Predictors of outcome across treatment groups psychotic disorders comorbid with a primary diagnosis of
provide prognostic information by clarifying which patients will psychosis). All eligible patients who achieved clinical stabilisation
respond more favourably to treatment in general, whereas were invited to provide written informed consent for assessment.
treatment moderators provide prescriptive information about They were told of the nature, scope and possible consequences of
optimal treatment selection.19 Although there are clinical the trial and that they could withdraw consent at any time. They
benefits in establishing baseline predictors of overall treatment were also asked to give consent for family member assessments;
success,20 identifying treatment moderators (who will do better family members who agreed to participate provided written
in which treatment) may have more important clinical and cost- informed consent.
effectiveness implications. Despite the value of identifying the The specific ICD-10 codes for psychosis (F1x.4; F1x.5; F1x.7;
subgroups of patients and the circumstances associated with the F2029; F30.2, F31.2, F31.5, F31.6, F32.3, F33.3) were assigned
effectiveness of early multi-element psychosocial interventions at 9 months; the best-estimate ICD-10 diagnosis was made by
for psychosis, there is as yet little information about moderators consensus of a panel of clinicians taking into account all available
of outcome. These findings would be extremely relevant in order information on the time interval from patients intake by
to clarify generalisability issues of the experimental intervention completing the Item Group Checklist (IGC) of the Schedule for
effectiveness. The present study aims to fill this knowledge gap. Clinical Assessment in Neuropsychiatry (SCAN).26
Based on the existing literature, we hypothesised that, regardless
of treatment, symptomatic improvement at 9 months would be Treatments
poorer in men,12 and in people with an early age at onset,13 lower
The experimental treatment consisted of a multi-element psycho-
levels of education,16 a longer duration of untreated psychosis
social intervention, adjunctive to routine care. It included the
(DUP),11,21,22 poor premorbid functioning,12,15,16 poor insight,14
delivery of cognitivebehavioural therapy (CBT) for psychosis to
lower adherence to medication,23 diagnosis of non-affective
patients,27,28 and of psychosis-focused family intervention29 to
psychosis,24 and higher baseline symptom severity.12,15,16 Given the
families, together with case management30 involving both patients
lack of available information (with the exception of the DUP as
and their families. It was provided by CMHC staff, trained in the
reported by the RAISE study11), no specific a priori hypotheses
previous 6 months and supervised by experts. The intervention
could be made about moderators; thus, moderator analyses will be
began as soon as patients achieved clinical stabilisation (i.e. a
exploratory and use the same set of variables analysed as predictors.
condition in which they could collaborate in a brief clinical
Method examination). Core baseline measures were taken. Control arm
CMHCs provided only treatment as usual (TAU), which, in Italy,
The GET UP PIANO trial comprises personalised out-patient psychopharmacological treat-
The GET UP PIANO trial is a large multicentre randomised ment and non-specific supportive clinical management by the
controlled trial comparing an add-on multi-element psychosocial CMHC.31 Family interventions in TAU consisted of non-specific
early intervention with routine care for patients with FEP and informal support sessions.
their relatives provided within Italian public general mental
health services. Of the 126 community mental health centres Measures
(CMHCs) located in two northern Italian regions (Veneto and A set of core outcome instruments (Positive and Negative
Emilia-Romagna) and the urban areas of Florence, Milan and Syndrome Scale (PANSS),32 Global Assessment of Functioning
Bolzano, 117 (92.9%) participated, covering an area of 9 304 093 (GAF),33 Hamilton Rating Scale for Depression (HRSD)34) was
inhabitants. The assignment units (clusters) were the CMHCs, administered by a panel of 17 independent evaluators at baseline
and the units of observation and analysis were patients and their (after clinical stabilisation and before treatment was initiated) and
families. The trial received approval by the ethics committees of at 9-month follow-up. For the PANSS the three traditional sub-
the coordinating centre (Azienda Ospedaliera Universitaria scales were considered positive symptoms, negative symptoms
Integrata di Verona) and each participating unit and was and general psychopathology.
registered with ClinicalTrials.gov (NCT01436331). Full details of An extensive set of standardised instruments was also
the protocol of the GET UP study and the main findings of the administered at baseline, including the Premorbid Social
GET UP PIANO trial can be found elsewhere.9,10 Adjustment scale (PSA)35 for premorbid functioning, the
Schedule for Assessment of Insight (SAI-E)36 for insight into
Participants illness and a modified version of the Nottingham Onset Schedule
During the index period, all CMHCs participating in the GET UP (NOS)37 for the DUP. These clinical measures, together with base-
PIANO trial were asked to refer individuals with potential cases of line sociodemographics (gender, age at first contact, citizenship,
psychosis at first contact to the study team. The inclusion criteria education) were analysed as putative predictors/moderators.
were: (a) age 1854 years; (b) residence within the catchment areas All the 17 independent evaluators were trained in the
of the CMHCs; (c) presence of at least one of the following administration and rating of the instruments. For the interrater
symptoms: hallucinations, delusions, qualitative speech disorder, reliability, each evaluator independently rated three videos on
qualitative psychomotor disorder, bizarre, or grossly inappropriate the PANSS, which were recorded and rated by an independent
behaviour; or two of the following symptoms: loss of interest, clinician. High levels of agreement (mean percentage agreement
initiative and drive; social withdrawal; episodic severe excitement; on the items of each scale) were reached between each evaluator
purposeless destructiveness; overwhelming fear; or marked self- and the clinician. Specifically, 85% for the positive scale, 70%
neglect; (d) first lifetime contact with CMHCs, prompted by these for the negative scale and 82% for the general scale. The intraclass
symptoms. Exclusion criteria were: (a) prescribed antipsychotic correlation coefficient was 0.81. Patients, clinicians and evaluators
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Lasalvia et al
could not be masked to the trial arm. Every effort was made to significance of main effects), the variable was considered as a
preserve the evaluators independence; conflicts of interest were moderator. For each variable, the predictor and moderator effect
monitored. size was calculated using the formulae provided by Kraemer.39
In a secondary analysis, missing data on outcomes were
Statistical analyses estimated using a multiple imputation approach by chained
equations (MICE), which generates several different plausible
Analyses were conducted using an intention-to-treat (ITT) imputed data-sets and combines results from each of them. MICE
approach. PANSS, GAF and HRSD scores were analysed separately was applied because it allows one to handle different variable
in mixed-effects random regression models. In order to take into types; specifically, we used predictive mean matching to deal with
account the trial design in which patients (level 1) were nested possible non-normality when imputing continuous variables and
within CMHCs (level 2) (CONSORT guidelines for cluster logistic regression to impute binary variables. The alpha level
randomised trials38), the individual CMHCs were included in was set to 0.05 for all main effects and interactions. All statistical
the models as a random effect. In order to identify predictors analyses were carried out using the Stata software package,
and moderators of treatment outcome according to MacArthurs version 13.
approach,20 we selected a priori, on clinical or empirical grounds
and derived from the literature, a subset of demographic and
baseline clinical variables. Specifically, we investigated gender, Results
age at first contact, citizenship (Italian/non-Italian), educational
level (high/low), DUP, type of psychosis (affective/non-affective), Demographic and clinical variables of the 444 study participants
premorbid functioning (four components: school and social examined as potential predictors or moderators of treatment
functioning, in both childhood and adolescence) and insight into outcome are presented in online Table DS1.
illness (three components: attribution of symptoms, illness
awareness and treatment adherence). Each model included treat-
ment allocation (T coded as + for patients in the experimental Predictors
treatment group and 7 for those in the TAU group), one Some attributes of patients predicted outcomes regardless of
predictor/moderator (M standardised), their interaction (T6M) treatment assignment. Among sociodemographic characteristics
and the baseline score of the outcome investigated (B standardised). (Table 1), higher education predicted lower overall symptoms
When the main effect of a variable was significant but the interaction (b = 70.06, P = 0.034), negative symptoms (b = 70.11, P = 0.009)
was not, the variable was considered a non-specific predictor of and general psychopathology (b = 70.06, P = 0.046) at 9 months.
outcome. When the interaction was significant (regardless of the Several clinical characteristics predicted outcomes at 9 months
PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning; HRSD, Hamilton Rating Scale for Depression.
a. Mixed-effects random regression models estimated for patients who were assessed at both baseline and follow-up (experimental treatment group, n = 239; treatment-as-usual
group, n = 153).
b. See Kraemer for the calculation of predictor and moderator effect size.39
*Predictors/moderators that remained significant (P50.05) after applying multiple imputation procedure by chained equations (MICE).
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Predictors and moderators of treatment outcome for an early psychosis intervention
(Table 2 and Table 3): specifically, a longer DUP predicted (PANSS negative score). A longer DUP predicted a greater severity
higher depressive symptoms (b = 1.42, P = 0.002); poorer of depression (b = 1.11, P = 0.005), and a poorer attribution of
premorbid social functioning in adolescence predicted higher symptoms predicted worse global functioning at follow-up
levels of overall psychotic symptoms (b = 0.07, P = 0.043) and (b = 2.14, P = 0.020).
depressive symptoms (b = 0.90, P = 0.039); and poorer premorbid
scholastic functioning in adolescence predicted higher negative Moderators
symptoms (b = 0.11, P = 0.035). Moreover, poorer attribution of We found a differential effect of age at first contact on PANSS total
symptoms predicted higher severity of overall psychotic symptoms score (b = 70.12, P = 0.032), negative symptoms (b = 70.17,
(b = 70.07, P = 0.036), higher levels of positive symptoms P = 0.042) and general psychopathology (b = 70.14, P = 0.014)
(b = 70.12, P = 0.003) and worse global functioning (b = 2.75, (Table 2). Specifically, the experimental treatment became more
P = 0.008); and poorer treatment adherence predicted higher level beneficial than TAU as age increased. When analyses were rerun
of overall psychotic symptoms (b = 70.08, P = 0.015), positive using multiple imputation of missing data, the finding that age
symptoms (b = 70.08, P = 0.017), negative symptoms (b = 70.11, at first contact was a moderator of PANSS total score
P = 0.031) and general psychopathology (b = 70.06, P = 0.045). (b = 70.11, P = 0.052), negative symptoms (b = 0.18, P = 0.032)
Multiple imputation analysis confirmed that lower education and general psychopathology (b = 70.12, P = 0.030) was confirmed.
predicted a higher severity of symptoms at follow-up (PANSS total In order to determine the age cut-off at which the experimental
score, b = 70.10, P = 0.016) and that a poorer attribution of treatment started to be significantly superior to TAU, age was
symptoms predicted a higher severity of positive symptoms categorised using different cut-offs (20, 25, 30, 35 years) in a
(PANSS positive score). Notably, lower educational level sensitivity analysis. This analysis showed that starting from
(b = 70.10, p = 0.016), poorer school performance in adolescence 35 years of age there was a significant treatment effect on PANSS
(b = 0.11, P = 0.022) and poorer treatment adherence (b = 70.10, (PANSS total: b = 70.12, P = 0.023, moderator effect size = 70.06;
P = 0.042) predicted a higher severity of negative symptoms PANSS negative: b = 70.18, P = 0.032, moderator effect
Table 2 Duration of untreated psychosis (DUP), insight (Schedule for Assessment of Insight (SAI)) and diagnosis as potential
predictors/moderators of treatment outcome a
b (95% CI), P r(DO, DM)b
Outcome at follow-up Interaction with treatment, Predictor Moderator
(adjusted for baseline) Main effect, prediction moderation effect size effect size
DUP (months)
PANSS total 0.04 (70.02 to 0.09), 0.171 0.00 (70.11 to 0.11), 0.967 0.04 0.00
PANSS positive 0.03 (70.03 to 0.09), 0.266 0.01 (70.11 to 0.13), 0.855 0.03 0.00
PANSS negative 0.08 (70.00 to 0.17), 0.055 0.01 (70.16 to 0.18), 0.927 0.05 0.00
PANSS general 0.03 (70.02 to 0.09), 0.267 0.00 (70.11 to 0.12), 0.978 0.03 0.00
GAF score 70.84 (72.46 to 0.77), 0.308 0.15 (73.04 to 3.34), 0.927 70.03 0.00
HRSD score 1.42 (0.53 to 2.31), 0.002* 70.83 (72.62 to 0.95), 0.361 0.08 70.03
SAI attribution of symptoms
PANSS total 70.07 (70.14 to 70.00), 0.036 70.04 (70.18 to 0.09), 0.538 70.08 70.02
PANSS positive 70.12 (70.20 to 70.04), 0.003* 70.06 (70.21 to 0.09), 0.447 70.11 70.03
PANSS negative 70.09 (70.19 to 0.01), 0.084 70.16 (70.36 to 0.04), 0.120 70.06 70.06
PANSS general 70.06 (70.13 to 0.01), 0.108 70.01 (70.14 to 0.13), 0.919 70.06 0.00
GAF score 2.75 (0.71 to 4.80), 0.008* 72.08 (75.98 to 1.82), 0.297 0.10 70.04
HRSD score 70.87 (71.75 to 0.00), 0.051 0.10 (71.64 to 1.84), 0.910 70.07 0.00
SAI illness awareness
PANSS total 0.02 (70.07 to 0.10), 0.711 0.10 (70.06 to 0.26), 0.231 0.02 0.06
PANSS positive 70.02 (70.10 to 0.07), 0.668 0.02 (70.16 to 0.19), 0.852 70.02 0.01
PANSS negative 0.04 (70.08 to 0.17), 0.471 0.08 (70.17 to 0.32), 0.534 0.04 0.03
PANSS general 0.01 (70.07 to 0.09), 0.865 0.13 (70.04 to 0.29), 0.125 0.01 0.07
GAF score 70.29 (72.72 to 2.14), 0.815 72.17 (77.17 to 2.83), 0.394 70.01 70.04
HRSD score 70.11 (71.27 to 1.05), 0.858 2.32 (0.02 to 4.62), 0.048 70.01 0.09
SAI treatment adherence
PANSS total 70.08 (70.14 to 70.02), 0.015 70.07 (70.20 to 0.05), 0.268 70.08 70.04
PANSS positive 70.08 (70.15 to 70.01), 0.017 70.07 (70.20 to 0.06), 0.312 70.08 70.03
PANSS negative 70.11 (70.21 to 70.01), 0.031* 70.11 (70.31 to 0.08), 0.265 70.07 70.04
PANSS general 70.06 (70.13 to 70.00), 0.045 70.07 (70.19 to 0.06), 0.285 70.07 70.04
GAF score 1.30 (70.56 to 3.16), 0.170 1.75 (71.88 to 5.38), 0.344 0.05 0.03
HRSD score 70.51 (71.32 to 0.29), 0.212 70.72 (72.34 to 0.89), 0.381 70.04 70.03
Type of psychosis (reference affective)
PANSS total 0.02 (70.04 to 0.07), 0.558 70.02 (70.14 to 0.09), 0.659 0.02 70.01
PANSS positive 0.03 (70.03 to 0.08), 0.310 70.02 (70.13 to 0.10), 0.763 0.03 70.01
PANSS negative 0.02 (70.06 to 0.10), 0.645 70.06 (70.23 to 0.11), 0.471 0.01 70.02
PANSS general 0.01 (70.04 to 0.07), 0.631 70.02 (70.13 to 0.10), 0.779 0.01 70.01
GAF score 71.38 (72.92 to 0.15), 0.077 70.15 (73.18 to 2.88), 0.922 70.05 0.00
HRSD score 0.47 (70.35 to 1.30), 0.261 70.88 (72.54 to 0.77), 0.296 0.03 70.03
PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning; HRSD, Hamilton Rating Scale for Depression.
a. Mixed-effects random regression models estimated for patients who were assessed at both baseline and follow-up (experimental treatment group, n = 239; treatment-as-usual
group, n = 153).
b. See Kraemer for the calculation of predictor and moderator effect size.39
*Predictors/moderators that remained significant (P50.05) after applying multiple imputation procedure by chained equations (MICE).
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Lasalvia et al
Table 3 Premorbid social adjustment (PSA) scale as potential predictor/moderator of treatment outcome a
b (95% CI), P r(DO, DM)b
Outcome at follow-up Interaction with treatment, Predictor Moderator
(adjusted for baseline) Main effect, prediction moderation effect size effect size
PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Functioning; HRSD, Hamilton Rating Scale for Depression.
a. Mixed-effects random regression models estimated for patients who were assessed at both baseline and follow-up (experimental treatment group, n = 239; treatment-as-usual
group, n = 153).
b. See Kraemer for the calculation of predictor and moderator effect size.39
*Predictors/moderators that remained significant (P50.05) after applying multiple imputation procedure by chained equations (MICE).
size = 70.06; PANSS general: b = 70.13, P = 0.015, moderator experienced some benefit from both treatments, with a higher
effect size = 70.07) (Fig. 1). beneficial effect of experimental treatment in terms of reduction
Table 4 (lower part) shows that in the TAU arm patients in PANSS total, negative and general scores.
with an age of onset 535 years experienced no reduction of These findings were confirmed after multiple imputation of
overall psychotic symptoms, negative symptoms and general missing data (results not shown). In order to identify possible
psychopathology at 9 months (see delta scores), whereas patients reasons for this finding, we carried out secondary analyses comparing
with an age of onset less than 35 years (Table 4, upper part) patients with an age of onset 535 years with the rest of the sample.
Results indicate that patients with age at onset 535 years were
Table 4 Strength of moderation by patients age at first
more often females (41.0% v. 67.0%, w2 test, P50.001), less frequently
contact (535 years, 535 years) on the effect of intervention diagnosed with schizophrenia (19.4% v. 30.7%, w2 test, P = 0.033),
(experimental v. treatment as usual) on the various outcome less frequently unmarried (37.9% v. 91.3%, w2 test, P50.001) and
domains unemployed or students (46.6% v. 70.4%, w2 test, P50.001).
Delta, mean Finally, we found that a greater awareness of illness was
Outcome Treatment-as-usual group Experimental group
associated with a higher severity of depression at follow-up in
the experimental group but not in the control group (b = 2.32,
535 years P = 0.048) (Table 2); this finding, however, was not confirmed in
GAF 15.2 (14.9) 19.4 (16.6)
multiple imputation analysis (b = 0.38, P = 0.736). No moderation
PANSS positive 70.68 (0.81) 70.77 (0.81)
PANSS negative 70.68 (1.02) 70.67 (1.00)
was found for GAF and HRSD.
PANSS general 70.56 (0.70) 70.66 (0.73)
PANSS total score 70.63 (0.68) 70.69 (0.70) Discussion
HRSD 75.8 (13.3) 78.8 (1.0)
535 years This is the first study to investigate in a real-world setting which
GAF 13.0 (12.8) 18.3 (16.6) patient characteristics: (a) predict outcome regardless of treatment
PANSS positive 70.71 (0.78) 70.95 (0.72) assignment (non-specific predictors), and (b) moderate differential
PANSS negative 70.21 (0.69) 70.58 (0.93) response (moderators) to an adjunctive multi-element psychosocial
PANSS general 70.33 (0.51) 70.65 (0.60) intervention supplementing routine care for FEP. It used a large
PANSS total score 70.41 (0.48) 70.70 (0.56)
sample and a robust methodological approach.
HRSD 76.7 (13.0) 77.0 (10.2)
As expected, we found several non-specific predictors of
GAF, Global Assessment of Functioning; PANSS, Positive and Negative Syndrome outcome. Patients with lower education, longer DUP, poorer
Scale; HRSD, Hamilton Rating Scale for Depression.
premorbid functioning in adolescence and poorer insight into
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Predictors and moderators of treatment outcome for an early psychosis intervention
(a)
3 3
2.8 535 years 2.8 535 years
2.6 TAU 2.6 TAU
2.4 2.4
2.2 EXP 2.2 EXP
Total
2 2
1.8 1.8
1.6 1.6
1.4 1.4
1.2 1.2
1 1
Baseline Follow-up Baseline Follow-up
(b)
3 3
535 years 535 years
2.8 2.8
2.6 TAU 2.6 TAU
2.4 EXP 2.4 EXP
Negative
2.2 2.2
2 2
1.8 1.8
1.6 1.6
1.4 1.4
1.2 1.2
1 1
Baseline Follow-up Baseline Follow-up
(c)
3 3
535 years 535 years
2.8 2.8
2.6 TAU 2.6 TAU
2.4 EXP 2.4 EXP
2.2 2.2
General
2 2
1.8 1.8
1.6 1.6
1.4 1.4
1.2 1.2
1 1
Baseline Follow-up Baseline Follow-up
Fig. 1 Strength of moderation by patients age at first contact on the effect of the intervention (experimental EXP) v. treatment-as-usual
(TAU) group) on the Positive and Negative Syndrome Scale (PANSS).
Left-hand graphs 535 years at first contact, right-hand graphs: 535 years at first contact. (a) Total score; (b) negative symptoms; (c) general psychopathology. Mean scores
are reported on the y-axis; 1, absent; 2, minimal; 3, mild; 4, moderate; 5, moderate-severe; 6, severe; 7, extremely severe).
illness showed poorer clinical outcomes at 9 months irrespective It is not completely clear what drives the relationship between
of the type of treatment. These findings are consistent with the age at first contact and experimental treatment outcome in our
literature1117,2023 and suggest that patients with FEP with these sample. However, data showing that patients with age at onset
characteristics warrant specific attention and may require more 535 years were more often women, less frequently diagnosed with
intensive and/or longer treatment. schizophrenia, less frequently unmarried and unemployed or a
We found only one significant moderator that acted only on one student may in part explain the moderating effect of age at first
outcome: patients age at first service contact, which operated on contact on treatment outcome in our sample. We may also
negative symptoms and general psychopathology. Specifically, in speculate that patients developing psychosis at a later stage may
the control group, where the effect of the intervention was overall be more receptive to structured cognitive coping strategies
lower than in the experimental group, the moderation effect by age provided with both individual CBT and family therapy, since these
at first service contact resulted in lower benefit in older compared with patients have been found to be less impaired than younger
younger patients. Thus, the experimental intervention was not only patients on a broad array of cognitive tasks,4245 which are most
overall significantly more effective than TAU, but was also similar in relevant to adaptive functioning and treatment response. This issue
both age groups, showing greater generalisability. has some interesting implications, since the idea of intervening early
The multi-element psychosocial intervention administered at should not be conflated with intervening in the young, as psychosis
the first psychotic episode seems to exert a specific additional has an impact at all stages of life. A new line of research is specifically
beneficial effect on patients who develop onset of psychosis at a focusing on people over 35 years presenting to mental health services
later stage (535 years); these patients, if treated with usual care with a first psychotic episode. This research found that a large
alone, would display no or low symptomatic improvement. proportion (55%) of patients with FEP present after the age of
Moreover, it is important to note that the multi-component 25 years46 and suggested extending early intervention provision
intervention showed a specific beneficial effect on negative to all ages, with treatment tailored to the specific needs of different
symptoms, which in general show relatively poorer response to age groups.47,48 However, future research should further investigate
psychopharmacological treatment in patients with FEP.40,41 the relationship between age and outcome in FEP samples.
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Lasalvia et al
present paper may serve as guidance to researchers for estimating 2 Marshall M, Rathbone J. Early intervention for psychosis. Cochrane Database
Syst Rev 2011; 6: CD004718.
the sample size needed in confirmation studies. In order to test
3 Nordentoft M, Rasmussen JO, Melau M, Hjorthoj CR, Thorup AA. How
hypotheses on moderating effects, confirmatory studies would successful are first episode programs? A review of the evidence for
be needed, including an adequately sized group of patients with specialized assertive early intervention. Curr Opin Psychiatry 2014; 27:
the characteristics of interest (for example, age 535 years), in 16772.
which the outcomes of patients receiving different treatments 4 Orygen Youth Health. The Australian Clinical Guidelines for Early Psychosis.
(i.e. TAU v. GET UP intervention) are compared. Orygen Youth Health, 2008.
Another potential limitation is the lack of masking in the trial 5 National Collaborating Centre for Mental Health. Schizophrenia: Core
Interventions in the Treatment and Management of Schizophrenia in Primary
(patients, clinicians, other care providers and outcome evaluators and Secondary Care (update), NICE Clinical Guidelines, No. 82. NICE, 2009.
were aware of treatment allocation). The study design (cluster) 6 Singh SP, Fisher HL. Early intervention in psychosis: obstacles and
and the nature of the treatments under investigation did not permit opportunities. Adv Psychiatr Treat 2005; 11: 718.
masking. This limitation is inevitable and common to many cluster 7 Friis S. Early specialised treatment for first-episode psychosis: does it make a
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349
Data supplement to Lasalvia et al. Predictors and moderators of treatment outcome in
patients receiving multi-element psychosocial intervention for early psychosis: results
from the GET UP pragmatic cluster randomised controlled trial. Br J Psychiatry doi:
10.1192/bjp.bp.116.190058
1
THE GET UP GROUP includes:
Project TRUMPET (TRaining and Understanding of Service Models for Psychosis Early Treatment)
Scientific Coordinator: Giovanni De Girolamo (Bologna and Brescia)
Administrative Leading Institution: Agenzia Sanitaria e Sociale Regionale, Regione Emilia
Romagna
Coordinating Centre: Angelo Fioritti, Giovanni Neri, Francesca Pileggi, Paola Rucci
Project GUITAR (Genetic data Utilization and Implementation of Targeted Drug Administration
_in the Clinical Routine)
Scientific Coordinator: Massimo Gennarelli (Brescia)
Administrative Leading Institution: IRCCS Centro S.Giovanni di Dio Fatebenefratelli, Brescia
Coordinating Centre: Luisella Bocchio Chiavetto, Catia Scasselatti, Roberta Zanardini
Project CONTRABASS
COgnitive Neuroendophenotypes for Treatment and RehAbilitation of psychoses: Brain imaging,
InflAmmation and StreSS
Scientific Coordinator: Paolo Brambilla (Udine and Verona)
Administrative Leading Institution: Azienda Ospedaliera Universitaria Integrata, Verona, Regione
Veneto
Coordinating Centre: Marcella Bellani, Alessandra Bertoldo, Veronica Marinelli, Cinzia Perlini,
Gianluca Rambaldelli
2
ENROLLMENT AND TREATMENT RESEARCH UNITS:
RESEARCH UNIT Western Veneto:
Coordinator: Antonio Lasalvia (Verona).
Administrative Leading Institution: Azienda Ospedaliera Universitaria Integrata, Verona.
Coordinating Centre: Mariaelena Bertani, Sarah Bissoli, Lorenza Lazzarotto.
Participating MHCs: TAU Arm: Ulss 3 (Bassano), Ulss 4 Alto Vicentino (Thiene), Ulss 5 Montecchio
(Centro; Sud), Ulss 6 Vicenza ( Secondo), Ulss 18 Rovigo (Rovigo), Ulss 20 Verona ( II Servizio), Ulss 22
Bussolengo (Isola della Scala).
Experimental Arm: Ulss 5 Montecchio (Nord), Ulss 6 Vicenza (Primo; Noventa), Ulss 18 Rovigo ( Badia),
Ulss 19 Adria (Adria), Ulss 20 Verona (I Servizio; III Servizio; La Filanda),Ulss 21 Legnago (Il Tulipano; il
Girasole).
MHCs Reference Persons: Sonia Bardella, Francesco Gardellin, Dario Lamonaca, Antonio Lasalvia, Marco
Lunardon, Renato Magnabosco, Marilena Martucci, Stylianos Nicolau Francesco Nifosi, Michele
Pavanati, Massimo Rossi, Carlo Piazza, Gabriella Piccione, Annalisa Sala, Benedetta Stefani, Spyridon
Zotos.
CBT Staff: Mirko Balbo, Ileana Boggian, Enrico Ceccato, Rosa DallAgnola, Francesco Gardellin, Barbara
Girotto, Claudia Goss, Dario Lamonaca, Antonio Lasalvia, Alessia Mai, Annalisa Pasqualini, Michele
Pavanati, Carlo Piazza, Gabriella Piccione, Stefano Roccato, Alberto Rossi, Spyridon Zotos.
Family Intervention Staff: Flavia Aldi, Barbara Bianchi, Paola Cappellari, Raffaello Conti, Laura De Battisti,
Silvia Merlin,. Tecla Pozzan, Lucio Sarto.
Case Management Staff: Andrea Brazzoli, Antonella Campi, Roberta Carmagnani, Sabrina Giambelli,
Annalisa Gianella, Lino Lunardi, Davide Madaghiele, Paola Maestrelli, Lidia Paiola, Elisa Posteri, Loretta
Viola, Valentina Zamberlan, Marta Zenari.
Biological Sample processing and support to Brain Imaging precedures: Sarah Tosato, Martina Zanoni,
Giovanni Bonadonna, Mariacristina Bonomo.
3
Case Management Staff: Lorenzo Andreose, Mario Boenco, Daniela Bottega, Loretta Bressan, Arianno
Cabbia, Elisabetta Canesso, Romina Cian, Caludia Dal Piccol, Maria Dalla Pasqua, Cinzia De Gasperi,
Anna Di Prisco, Lorena Mantellato, Monica Luison, Sandra Morgante, Mirna Santi, Moreno Sacillotto,
Mauro Scabbio, Patrizia Sponga, MLuisa Sguotto, Flavia Stach, MGrazia Vettorato.
Biological Sample processing and support to Brain Imaging precedures: Oscar Cabianca, Amalia Valente,
Livio Caberlotto, Alberto Passoni, Patrizia Flumian, Luigino Daniel, Massimo Gion, Saverio Stanziale,
Flora Alborino, Vladimiro Bortolozzo, Lucio Bacelle, Leonarda Bicciato, Daniela Basso, Filippo Navaglia,
Fabio Manoni, Mauro Ercolin.
4
Marco Morselli, Alessandro Oggioni, Silvio Oprandi, Walter Paganelli, Morena Passerini, Maria Piscitelli,
Gregorio Reggiani, Gabriella Rossi, Federica Salvatori, Simona Trasforini, , Carlo Uslenghi, Simona
Veggetti,
CBT Staff: Giovanna Bartolucci, Rosita Baruffa, Francesca Bellini, Raffaella Bertelli, Lidia Borghi, Patrizia
Ciavarella, Cinzia DiDomizio, Giuseppe Monna, Alessandro Oggioni, Elisabetta Paltrinieri, Maria
Piscitelli, Francesco Rizzardi, Piera Serra, Damiano Suzzi, Uslenghi Carlo.
Family Intervention Staff: Paolo Arienti, Fabio Aureli, Rosita Avanzi, Vincenzo Callegari, Alessandra
Corsino, Paolo Host, Rossella Michetti, Michela Pratelli,Francesco Rizzo, Paola Simoncelli, Elena Soldati,
Eraldo Succi.
Case Management Staff: Massimo Bertozzi, Elisa Canetti,Luca Cavicchioli, Elisa Ceccarelli, Stefano Cenni,
Glenda Marzola, Vanessa Gallina, Carla Leoni, Andrea Olivieri, Elena Piccolo, Sabrina Ravagli, Rosaria
Russo, Daniele Tedeschini.
Biological Sample processing and support to Brain Imaging precedures: Marina Verenini, Walter Abram,
Veronica Granata, Alessandro Curcio, Giovanni Guerra, Samuela Granini, Lara Natali, Enrica Montanari,
Fulvia Pasi, Umbertina Ventura, Stefania Valenti, Masi Francesca, Rossano Farneti, Paolo Ravagli,
Romina Floris, Otello Maroncelli, Gianbattista Volpones, Donatella Casali.
6
RESEARCH UNIT Neuropsicopharmacology-IRCCS, FBF Brescia Coordinator: Luisella Bocchio Chiavetto
Coordinating Centre: Roberta Zanardini
Administrative Leading Institution: IRCCS Centro S.Giovanni di Dio Fatebenefratelli, Brescia
RESEARCH UNIT Molecular Biology, AFaR, FBF, Roma Coordinator: Mariacarla Ventriglia
Coordinating Centre: Rosanna Squitti
Administrative Leading Institution: Department of Neuroscience, AFaR-Fatebenefratelli Hospital, Rome,
Italy
RESEARCH UNIT Animal Models, Univ. Milano Coordinator: Marco Andrea Riva
Coordinating Centre: Fabio Fumagalli, Raffaella Molteni, Francesca Calabrese, Gianluigi Guidotti,
AlessiaLuoni, Flavia Macchi.
7
Table DS1 Potential predictors/moderators of treatment outcome (experimental treatment group,
n=272; TAU group, n=172).
8
Predictors and moderators of treatment outcome in patients
receiving multi-element psychosocial intervention for early
psychosis: results from the GET UP pragmatic cluster
randomised controlled trial
Antonio Lasalvia, Chiara Bonetto, Jacopo Lenzi, Paola Rucci, Laura Iozzino, Massimo Cellini, Carla
Comacchio, Doriana Cristofalo, Armando D'Agostino, Giovanni de Girolamo, Katia De Santi, Daniela
Ghigi, Emanuela Leuci, Maurizio Miceli, Anna Meneghelli, Francesca Pileggi, Silvio Scarone, Paolo
Santonastaso, Stefano Torresani, Sarah Tosato, Angela Veronese, Angelo Fioritti, Mirella Ruggeri and
the GET UP Group
BJP 2017, 210:342-349.
Access the most recent version at DOI: 10.1192/bjp.bp.116.190058
References This article cites 40 articles, 9 of which you can access for free at:
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