A Large Pragmatic Cluster Randomized Controlled Trial of a Multi-element Psychosocial Intervention for Early Psychosis

Multi-element interventions for first-episode psychosis (FEP) are promising but have mostly been conducted on non epidemiologically representative samples in experimental settings, raising the risk thereby of underestimating the complexities involved in treating onset psychosis in "real world" services. The PIANO Trial (Psychosis early Intervention and Assessment of Needs and Outcome) is part of a more broad-based research program (Genetics, Endophenotype and Treatment: Understanding early Psychosis - GET UP) and aims to: 1) test, at 9 months, the effectiveness, as compared to treatment as usual (TAU) of multi-component psychosocial intervention on a large epidemiologically-based cohort of FEP patients and their family members recruited from a 10 million inhabitant catchment area; 2) identify barriers that may hinder its feasibility and patient/family conditions that can render this type of treatment ineffective or inappropriate; 3) identify clinical, psychological, and environmental and service predictors of treatment effectiveness in FEP.

Study participants will be recruited from Community Mental Health Centers (CMHCs) operating for the Italian National Health Service and located in several Northern and Central Regions of Italy. The GET UP PIANO Trial has a pragmatic cluster randomized controlled design, which is considered the gold standard approach for trials that evaluate complex interventions implemented at the institutional level, with the aim of improving health. The assignment units (clusters) are the CMHCs, and the units of observation and analysis are the Centers' patients and their family members.

Patients in the experimental group will receive TAU plus: (a) Cognitive-Behavioural Therapy (CBT) sessions, (b) psycho-educational sessions for family members, and c) a case manager, to serve as the patient's referent. Patient enrollment will take place over a 1 year interval, after a 3 month-long piloting. The fidelity of the experimental interventions and the characteristics of TAU will be regularly monitored. Several psychopathological, psychological, functioning and service use variables will be assessed at baseline and 9 month follow-up by independent evaluators. Assuming an expected incidence rate of 17/100.000 per year for functional psychoses (as previously estimated in Italy), the investigators expect to recruit about 800 patients, and 600 relatives. Assuming an attrition rate of about 50%, the size of the trial would detect at 9 months a difference in terms of primary outcome from 25% for the TAU arm to 10% for the intervention arm, with a power of 80%.

BACKGROUND. It has been shown that most clinical and psychosocial deterioration in psychosis occurs within the first 5 years of illness onset, suggesting thereby that this timeframe is a "critical" period for initiating treatment. Research has therefore more recently focused on early detection and intervention for psychosis, showing that the beneficial effects of antipsychotic medication on first-episode psychosis (FEP) are tempered by the fact that, despite initial symptom reduction, functional recovery is typically poor, even when optimal pharmacological treatment is provided. Family members suffer due to the high emotional burden of being caregivers and frequently show signs of psychological distress. Over the last few years, there has been a growing interest in psychosocial intervention as a means of facilitating recovery and reducing long-term disability associated with psychosis. Literature on psychosocial interventions in FEP can be viewed in terms of two broad categories: 1) studies evaluating specific (i.e. single-element) psychosocial interventions (e.g. individual cognitive behavioral therapy), and 2) studies evaluating comprehensive (i.e. multi-element) interventions, which may include early detection strategies, individual, group, and/or family therapy, and case management (in addition to pharmacological treatment). The latter appear very promising and have been found to be associated with symptom reduction/remission, improved quality of life, increased social and cognitive functioning, low inpatient admission rates, improved insight, high degree of satisfaction with treatment, less time spent in hospital, decreased substance abuse, and fewer self- harm episodes. Most multi-element research programs, however, have been conducted on non-epidemiologically representative samples in experimental settings, raising the risk thereby of underestimating the complexities involved in treating FEP in "real world" services. Moreover, these interventions have rarely tested their efficacy against a control group or, if they have done so, they have used historical or prospective comparison groups, or single-group designs, which track the progress of a single group over a given period of time. With respect to practices, over the last 10 years, some countries have implemented specific early psychosis interventions, but even these have not yet become routinely conducted. Few studies have identified barriers that can hinder the feasibility of these interventions or the pinpointing of patient or family conditions that can render this type of ineffective or inappropriate. Hence, efforts to implement these specific multi-element interventions should be accompanied by rigorous scientific methodology, with the aim of better understanding the actual effectiveness of this approach.

AIMS. The PIANO Trial (Psychosis early Intervention and Assessment of Needs and Outcome described herein makes up part of the more broad-based research program Genetics Endophenotypes and Treatment: Understanding early Psychosis (GET UP, National Coordinator: Prof. Mirella Ruggeri, Verona), which is financed by the Italian Ministry of Health as part of a Ricerca Sanitaria Finalizzata and is coordinated by the Azienda Ospedaliera Universitaria Integrata in Verona. GET UP Research Programme consists of 4 partner Projects: PIANO (Psychosis: early Intervention and Assessment of Needs and Outcome); TRUMPET (TRaining and Understanding of service Models for Psychosis Early Treatment); GUITAR (Genetic data Utilization and Implementation of Targeted drug Administration in the clinical Routine); and CONTRABASS (COgnitive Neuroendophenotypes for Treatment and RehAbilitation of psychoses: Brain imaging, inflAmmation and StresS). Each of these partner projects pertains to different areas of research, but are linked together in a high degree of harmonization of effort.

The Trial described herein - which is the main component of GET UP PIANO, and the main data collection axis for the overall GET UP Research Program - aims to: 1) test, at 9 months, the effectiveness, as compared to treatment as usual (TAU) of multi-component psychosocial intervention on a large epidemiologically-based cohort of FEP patients recruited from a 10 million inhabitant catchment area; 2) verify the clinical routine limits of this approach, i.e. to identify barriers that may hinder its feasibility and patient/family conditions that can render this type of treatment ineffective or inappropriate; 3) identify clinical, psychological, and environmental and service predictors of treatment effectiveness in FEP, as undertaken in an Italian community mental health care framework.

Study participants will be recruited from Community Mental Health Centres (CMHCs) operating for the Italian National Health Service and located in several Northern and Central Regions of Italy. Specifically, the Participating Units (PU) will be located in the Veneto Region (subdivided in the Western Veneto and in the Eastern Veneto PU), the Emilia-Romagna Region (subdivided in the Emilia and Romagna PUs) and in the provinces of Florence, Bolzano, and Milano (subdivided in the Milan Niguarda and in the Milan San Paolo PUs), and thus, overall, a 10 million-inhabitant catchment area.

DESIGN. The GET UP PIANO Trial has a pragmatic cluster randomized controlled design, which compares the effectiveness of a multi-element psychosocial treatment for FEP patients and their family members, versus the treatment as usual provided by Italian community mental health services. A cluster design was chosen based on feasibility considerations. In fact, a document drafted by members of the MRC Health Services and Public Health Research Board in 2000 indicated cluster randomisation as the gold standard approach for trials that evaluate complex interventions implemented at the institutional level, with the aim of improving health. The assignment units (clusters) will be the catchment area's CMHC, and the units of observation and analysis will be the Centers' patients and their family members.

CMHCs enrollment procedure: The PIANO Trial catchment area has 126 CMHCs (9.951.306 inhabitants), all of which have been officially asked to participate in GET UP; 117 have accepted to participate, covering a catchment area of 9.304.093 inhabitants thereby. In an effort to improve the study design's efficiency, before randomization the investigators divided CMHCs into strata, according to three variables: affiliation to the same community psychiatric service, CMHC catchment area size, urban/mixed vs. rural. The socio-economic levels in the trial catchment area were found to be quite homogeneous, and the variable of urban/mixed vs. rural stratification accounted for most of the differences observed. With the exception of staff members in 5 CMHCS (covering a catchment area of 503.000 inhabitants) the mental health staff of the remaining 112 CMHCs had received no prior training in the intervention used in the trial. These first 5 Centers were therefore forced to the intervention arm, and this subgroup will be used as the expected "gold standard" in the analysis to measure the competence of the remaining professionals. Thus, 112 CMHCs (8.801.093 inhabitants) were available for the randomization procedure and were entered in the randomization procedure, with equal numbers being allocated to each arm. Based on administrative data in these Centers, the at-risk population (18-54 years) was estimated to be approximately 50% of the total inhabitants. Assuming an expected incidence rate of 17/100.000 per year for non affective and affective psychoses (as previously estimated in Italy) the investigators can expect to recruit over one year in the catchment area about 800 patients at their first episode of psychosis, and 600 relatives. Assuming an attrition rate of about 50%, the size of the trial would detect at 9 months a difference in terms of primary outcome from 25% for the TAU arm to 10% for the intervention arm, with a power of 80%.

Patient- and family member enrollment procedure: Patient enrollment will take place over a 1 year interval, after a 3 month-long piloting. Interventions begin within one month from intake, and, in any event, as soon as each patient is stabilized. Clinical stabilization is defined as a condition allowing the patient to collaborate in at least a brief examination. Patients in the experimental group will receive treatment as usual plus: (a) Cognitive Behavioural Therapy (CBT) sessions, (b) psycho-educational sessions for family members, and c) a Case Manager (CM), to serve as the patient's referent. Treatment as usual conducted in the control arm CMHSs has been characterized in previous studies. The fidelity of the experimental interventions and the characteristics of treatment as usual will be regularly monitored.

BASELINE ASSESSMENT. Before entering the study, patients screening positive for psychosis will be asked to provide informed consent to participate. When patients are considered clinically stabilized (after intake), they will be assessed by independent evaluators with a set of standardized instruments which measure: substance abuse (Clinical Drug Use Scale, CDUS), symptoms (Positive and Negative Syndrome Scale, PANSS; Hamilton Rating Scale for Depression, HAMD; Bech-Rafaelsen Mania rating Scale, BRMRS); global functioning (Global Assessment of Functioning, GAF); Subjective appraisal of positive symptoms (Psychotic Symptom Rating Scales, PSYRATS), social disability (Disability Assessment Scale, WHO-DAS), insight (Schedule for Assessment of Insight, SAI-E), needs for care (Camberwell Assessment of Need, CAN-EU), quality of life (WHO-QOL), life events (first 14 years of life, one year prior to the onset of psychosis, period following onset measured with ad hoc schedule for Life Events, CECA-Q), parental bonding (Parental Bonding Instrument,PBI), and expressed emotions (Level of Expressed Emotion Scale, LEE). Participating patients will be asked for consent to involve their family members in the trial, and when given, family members also providing informed consent will be assessed regarding burden of care (Involvement Evaluation Questionnaire, IEQ) and emotional distress (General Health Questionnaire, GHQ); they will also be interviewed with respect to the patient's pre-morbid adjustment (Pre-morbid Adjustment Scale, PAS) and obstetric complications at birth.

FOLLOW-UP ASSESSMENT. After 9 months from baseline, patients will be re-assessed for substance abuse, psychotic symptoms (PANSS and PSYRATS) depression (HAMD, BRMS), global functioning (GAF), social disability (WHO DAS), insight (SAI-E), needs for care (CAN), and quality of life (WHO-QoL). Moreover, patients will be evaluated in terms of pharmacological side effects, pattern of clinical course (Life Chart Schedule), and service satisfaction (Verona Service Satisfaction Scale-Patient version,VSSSP ). Family members will be re-assessed with respect to burden of care (IEQ) and emotional distress (GHQ); they will also be assessed for service satisfaction (VSSS-Relative version).

Eligibility Criteria:
Inclusion Criteria:

1. age 18-54 yrs
2. residence in the catchment area of participating Community Mental Health Centres
3. presence of (a) at least 1 of the following symptoms: hallucinations, delusions, qualitative speech disorder, qualitative psychomotor disorder, bizarre or grossly inappropriate behavior, or (b) at least 2 of the following symptoms: loss of interest, initiative and drive, social withdrawal, episodic severe excitement, purposeless destructiveness, overwhelming fear, marked self-neglect
4. first lifetime contact with participating CMHC, occasioned by symptoms enumerated in 3.
5. clinical ICD-10 diagnosis of F20-29; F30.2, F31.2, F31.5, F31.6, F32.3, F33.3, F1x.4; F1x.5; F1x.7;F20-F29, as confirmed after 6 months by using the Schedule for Clinical Assessment in Neuropsychiatry (WHO SCAN)

Exclusion Criteria:

1. prior anti-psychotic medication (\> 3 months) provided by any psychiatric or other medical agencies
2. mental disorders due to a general medical condition