A Large Pragmatic Cluster Randomized Controlled Trial of a Multi-element Psychosocial Intervention for Early Psychosis
Condition: Psychosis
MeSH terms: Psychotic Disorders; Mental Disorders
Study type: Interventional

Summary: 
      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%.
    

Detailed description: 
      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).
    

Intervention name(s): Treatment As Usual (TAU); TAU+CBT for pts+Family Intervention+CM.
Intervention type(s): Other; Behavioral
Intervention description(s): Services participating in the trial are routine public Community Mental Health Centres (CMHCs), which operate within the Italian National Health Service. Multi-disciplinary teams operating these CMHCs provide a wide range of integrated programmes, including inpatient care, day care, rehabilitation, outpatient care, home visits, 24-hour emergency services, and residential facilities. Standard care for FEP patients generally consists of personalized outpatient psychopharmacological treatment, combined with non-specific supportive clinical management at the CMHC level. Family interventions generally consist of non-specific informal support/educational sessions. Both specialized individual psychotherapeutic interventions for patients (included CBT) and specialized psycho-educational or cognitive-oriented family interventions are usually not provided, due to lack of trained professionals.; The experimental treatment package is administered by the CMHC staff, after training and with ongoing supervision by experts. Cognitive-behavioural therapy (CBT) is based on the model developed by Kuipers in 1998 and Garety in 2008. A total of 20-30 CBT sessions per patient will be delivered, with weekly sessions during months 1-3 and fortnightly over the following 6 months. Family Intervention is based on the model proposed by Leff in 1982 and further developed by Kuipers in 2002. It includes a total of 10-15 sessions with each individual family: 6 in months 1-3, and at least 1 session/month in the 6 months afterwards. Every patient/family will have a dedicated Case Manager, who will coordinate all planned interventions. Specific training programs have been developed, with assessment of the staff competence. Detailed Manuals based on international standards have been developed and will be used. Fidelity will be measured at the end of the trial.
Other intervention name(s): standard treatment; control treatment; Multi-element intervention; Family psychoeducation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: First episode psychosis; Early Psychosis; Cognitive Behavioural therapy; Psychosocial Intervention; Assertive Community treatment; Family Intervention; Mental Disorders; Psychotic Disorders; Schizophrenia and Disorders with Psychotic Features; Affective Disorders, Psychotic