The OPUS YOUNG Study. The Efficacy of Early Intervention Service Versus Treatment as Usual for Adolescents Aged 12 - 17 With First-episode Psychosis, a Pragmatic Randomized Clinical Trial
Phase: NA
Conditions: Schizophrenia, Schizotypal Disorder, Delusional Disorder, Acute and Transient Psychotic Disorder, Unspecified, Schizoaffective Disorder, Non-Organic Psychosis, Depression Severe, Substance Induced Psychoses
Sponsor: Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital

07-07-2023 
2023 
OPUS YOUNG 
EFFICACY OF EARLY INTERVENTION SERVICE VERSUS TREATMENT 
AS USUAL FOR ADOLESCENTS AGED 12-17 YEARS WITH A FIRST-
EPISODE PSYCHOSIS. AN INVESTIGATOR-INITIATED, RANDOMIZED 
CLINICAL TRIAL. 
PROTOCOL VERSION 6.1 – JULY 2023 
The Ethics Committee of Capital Region: H-20064085 (20-04-2021) 
Danish Data Protection Agency: P-2020-1081 (20-11-2020) 

 
 
2 
Summary .............................................................................................................................................. 6 
Purpose ................................................................................................................................................. 7 
Background .......................................................................................................................................... 7 
Aim....................................................................................................................................................... 9 
Hypotheses ........................................................................................................................................... 9 
Method and procedures ........................................................................................................................ 9 
Design ............................................................................................................................................... 9 
Participants, patient selection ......................................................................................................... 10 
Patient inclusion criteria ............................................................................................................ 11 
Patient exclusion criteria ............................................................................................................ 11 
Standard referral and clinical assessment of patients prior to study recruitment. .......................... 11 
Registration of medication and use of health care during study ................................................ 16 
Register-based information ........................................................................................................ 16 
Randomization ............................................................................................................................ 16 
Blinding ....................................................................................................................................... 17 
The OPUS YOUNG intervention and Treatment as Usual ................................................................ 18 
Experimental intervention, OPUS YOUNG .................................................................................. 18 
The OPUS YOUNG team ............................................................................................................ 19 
Cognitive Behavioural Case Management (CBCM) .................................................................. 20 
Psychoeducational family-based intervention ............................................................................ 21 
Psycho-educational multifamily groups (MFG) ......................................................................... 22 
Sibling psycho-educational groups............................................................................................. 22 
Social Cognition and Interaction Training (SCIT) ..................................................................... 23 
Cognitive Behavioural Therapy (CBT) ....................................................................................... 24 
Pharmacological treatments ....................................................................................................... 25 
Special components of OPUS YOUNG ......................................................................................... 26 
1) 
Special transition support ................................................................................................... 26 
2) 
Individual school/employment support. .............................................................................. 27 
3) 
Prevention and treatment of substance abuse ..................................................................... 27 
Experts by experience ................................................................................................................. 28 
A phase-specific individual tailored treatments course in OPUS YOUNG ................................... 28 
Treatment as usual (TAU) .............................................................................................................. 29 

 
 
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Fidelity monitoring ......................................................................................................................... 30 
Recruitment of staff, training, and preparation of OPUS YOUNG treatment ............................... 30 
Cooperation with the OPUS organization for adults ...................................................................... 31 
Hierarchy of outcome measures ..................................................................................................... 32 
Primary outcome ............................................................................................................................ 32 
Secondary outcome measures ..................................................................................................... 33 
Exploratory outcomes: ................................................................................................................ 33 
Sample size calculation .................................................................................................................. 33 
Power calculation for secondary outcome measures ...................................................................... 35 
Evaluation of cost-effectiveness of OPUS YOUNG .................................................................... 36 
Data-management .............................................................................................................................. 37 
Statistical analyses .......................................................................................................................... 37 
Ethical considerations ........................................................................................................................ 38 
Written informed consent................................................................................................................... 38 
Feasibility of the study ....................................................................................................................... 41 
Strengths and limitations .................................................................................................................... 42 
Perspectives ........................................................................................................................................ 42 
Project organization and management ............................................................................................... 43 
Principal investigator ................................................................................................................. 43 
Co-investigator (until December 2021) ...................................................................................... 43 
Steering committee ...................................................................................................................... 43 
Advisory board: .......................................................................................................................... 44 
Management of the project (co-ordinating investigator). .......................................................... 44 
Sharing of depersonalized data .......................................................................................................... 44 
Publications and dissemination policy ............................................................................................... 44 
Reference List .................................................................................................................................... 47 
 
 

 
 
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Abbreviations 
ADM 
Administration modus  
AMHS 
Adult Mental Health Services 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BRIEF 
Behavior Rating Inventory of Executive Function 
CAMHC 
Child and Adolescent Mental Health Center 
CBT 
Cognitive Behavioral Therapy 
CBCM 
Cognitive Behavioral Case Management 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CHU-9D 
The Child Health Utility 
CRF 
Case Report Form 
CVI 
Central Visitation Unit 
ECG 
Electrocardiogram 
EIMT 
Emotional Intensity Morphing Task 
EIS 
Early Intervention Services 
EOP  
Early Onset of Psychosis  
ESQ 
Experience of Service Questionnaire 
EQ-5D 
European Quality of life - 5 Dimensions 
FAD 
McMaster Family Assessment Device 
FEP 
First Episode Psychosis 
GCP 
Good Clinical Practice Guideline 
GSE 
General Self-Efficacy Scale 
HAM-D  
Hamilton Depression Scale  
ICC 
Interclass Correlation Coefficient 
ICD 10 
International Classification of Diseases - 10 
IRAOS 
Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and 
Other Psychoses 
KIDSCREEN-10 
Health-related Quality of Life Screening Instrument for Children and Adolescents (10 items) 
K-SADS-PL 
 
MET 
Kiddie-Schedule for Affective Disorders and Schizophrenia for School-aged children, Present and 
Lifetime Version 
Motivational Enhancement Therapy 
MFG 
Multifamily group 
MIREDIF 
NEQ 
Minimal Relevant Difference 
Negative Effects of psychological treatment Questionnaire 
PSS 
Parental Stress Scale 

 
 
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PSP 
Personal and Social Performance Scale 
REDCap 
Research Electronic Data Capture 
RCT 
Randomized Clinical Trial 
SAPS 
Scale for the Assessment of Positive Symptoms  
SANS 
Scale for the Assessment of Negative Symptoms 
SCAN 
Schedules for Clinical Assessment in Neuropsychiatry 
SD 
Standard Deviation  
SCIT 
Social Cognition and Interaction Training  
SST 
Social Skills Training 
TAU 
Treatment As Usual 
TEM 
Trivsels- og Effekt Monitorerings-skemaet 
ToM 
Theory of Mind 
WAI 
Working Alliance Inventory Scale 
WAIS-IV 
Wechsler Adult Intelligence Scale, IV 
WISC-V 
Wechsler Intelligences Scale for Children, V 
YMRS 
Young Mania Rating Scale 
            
 
 

 
 
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Summary  
The overarching purpose of the OPUS YOUNG trial is to improve the treatment and outcome of 
first-episode psychosis (FEP) in children and adolescents. We will address this ambition by testing 
the hypothesis, that Early Intervention Services (EIS) is superior compared to standard care in the 
treatment of children and adolescents below age 18 years with first-episode psychosis. The 
hypothesis is based on extrapolation of research showing that EIS is superior to standard care in the 
treatment of adults with first-episode psychosis with regards to symptom reduction, function 
improvement, adherence to treatment, lower hospitalization risk, improved recovery, and higher 
cost-effectiveness. However, no trials have investigated EIS in samples of patients below age 18 
years. We will compare the efficacy and cost-effectiveness of EIS to treatment as usual (TAU) in 
adolescents aged 12-17 years (both inclusive) with first-episode psychosis. We will build on a 
Danish evidence-based intervention developed for young adults (OPUS) and adjust the concept to 
meet the specific needs of children and adolescents with early onset psychosis (OPUS YOUNG). 
The OPUS treatment is a coordinated and integrated manualized multimodal treatment building on 
three core elements: modified assertive community treatment with a low patient-case manager ratio; 
psychoeducational family intervention; and social skills training (SST). In OPUS YOUNG we will 
adjust the OPUS program to fit our younger age group by: 1) intensifying the support for caretakers 
and relatives including siblings, 2) instead of SST we are introducing social cognition and 
interaction treatment (SCIT), 3) providing individual cognitive behavioural case management 
(CBCM) to all participants and cognitive behavioural therapy (CBT) when needed, 4) addressing 
the specific challenges of psychopharmacologic treatment in adolescents by providing a treatment 
algorithm, 5) providing intensive supported transition of care (when patients approach transition to 
adult mental health services), 6) providing individualized school support, and 7) providing 
integrated prevention and treatment of substance misuse. Based on sample size estimation, we will 
include a minimum of 284 participants (maximum 304) and randomize them 1:1 to a two-year 
intervention of OPUS YOUNG versus TAU. We will conduct blinded assessment of treatment 
effects after 12 months and at treatment endpoint at 24 months. A further follow-up assessment will 
be performed to evaluate the sustainability of the intervention effects at six months after transition 
from OPUS YOUNG to TAU. Our primary outcome at treatment endpoint will be social function 
measured with Personal and Social Performance Scale (PSP). Secondary key outcomes measures 
are positive and negative symptoms, client satisfaction, and health related quality of life. Further 
outcomes are the broader psychopathology, cognitive functioning, social cognition, self-efficacy, 

 
 
7 
experience of service, treatment alliance and adherence, the use of pharmacotherapy, school 
adherence, family burden, siblings’ perceived stress, substance misuse, adverse treatment effects, 
and health economic measures. 
Purpose 
The overarching purpose of this study is to improve the treatment outcomes in first-episode 
psychosis in children and adolescents, and to reduce illness socio-economic burden.  
Background 
Early onset of psychosis in childhood and adolescence (i.e., before age 18 years) is associated with 
the same clinical, cognitive, aetiological, and epidemiological markers of illness as found in 
psychosis with onset in adulthood. Yet, it is often characterized by a more insidious illness onset, 
with higher frequencies of  negative symptoms and thought disorders, more disorganized behaviour, 
more pre-morbid neurobiological and neuropsychological vulnerability indicators, more 
developmental delays, more comorbid nonpsychotic mental disorders, and a higher prevalence of 
familial diagnoses within the schizophrenia spectrum [1–3]. Since early onset schizophrenia-
spectrum disorders often persist into adulthood, and treatment response and prognosis are less 
favourable in psychosis with early compared to adult onset [4], early-onset psychosis patients often 
face a long chronic course of illness.  
In general, there is a rising awareness that childhood and adolescence is an important window of 
opportunity for early intervention in mental health [5]. Early onset psychosis is often associated 
with delayed detection and a mean duration of untreated psychosis of approximately 19 months, 
which may be associated with a hampered prognosis [6][7][3]. Furthermore, in patients with 
psychosis below age 18 years antipsychotic treatment is less efficient and associated with more 
adverse effects [4]. The incidence of schizophrenia spectrum disorders is increasing, as shown in a 
Danish study, with rates increasing approximately 25% for men and 40% for women in Denmark in 
the period from 2000 to 2012. This was mainly explained by a sharp and significant increase in 
incidence rate ratios among individuals below 24 years of age, due to a 2–3 fold increase in the 
youngest age groups [8]. A recent study found that 15% of all children and adolescents in Demark 
were diagnosed with a mental disorder before reaching 18 years of age. For schizophrenia spectrum 

 
 
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disorders the risk for girls was higher than boys (0.76% [95%CI, 0.72%-0.80%] vs 0.48% [95%CI, 
0.39%-0.59%]) [9].  
Outcomes in people with schizophrenia spectrum disorders are suboptimal with significant personal 
and societal costs [10], low quality of life and [11], low rate of recovery [12], substance misuse 
[13], higher rates of violence and legal problems [14–16], low educational and vocational 
attainment [17], and a significantly reduced life-expectancy of 15-20 years less than the general 
population [18–21]. Before chronicity and severe functional decline is manifest in adult early-phase 
psychosis, response to treatment is generally better [19]. Informal caregiving puts a large physical, 
social, and financial burden to the families of people with schizophrenia and have an impact on the 
relatives’ mental health such as risk of depression, anxiety, and grief [22–27].  
The above-mentioned factors document the burden of schizophrenia on patients, their families, the 
service system and the wider society, which implies a large economic societal burden especially due 
to lost productivity [26]. The economic impacts of psychosis go well beyond health care systems, 
with more than two-thirds of the costs falling outside of health care systems. The large burden to 
society has increased the focus on providing efficient treatment programs for early intervention.  
In early-phase psychosis of young adults, clinical evidence strongly supports EIS [28], and the 
evidence base on cost-effectiveness of EIS for young adults is growing and support that extra 
investment in EIS generate value for money gains [29,30]. A recent meta-analytic comparison of 
EIS versus TAU by Correll et al. [6], which included 10 randomized controlled trials (RCTs) 
(n=2176 patients, mean age 27.5 years), demonstrated better outcomes for EIS patients on all 
clinical and organisational outcomes at all times (except for general and depressive symptoms at 
18-24 months follow-up). However, no RCTs have tested this type of intervention in patient 
samples below the age of 18 years and a direct extrapolation from the results of the metanalysis to 
early-onset psychosis is difficult, since only a few percent of the participants in the meta-analysed 
studies were below age 18 years.  
Complicating factors that can disrupt care and degrade functional outcome, might serve as 
modifiable targets for intervention especially relevant for youth. Such factors include school 
difficulties, academic failure or drop-out, co-morbid non-psychotic mental disorders and substance 
disorder, and poor coordinated transition to adult mental care services [31]. On the other hand, 
potential resilience factors specific for youth such as strong parent and family involvement, good 

 
 
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somatic health with few somatic comorbidities, involvement in school, less established misuse 
habits, more attention and available support from social services, and a greater neurobiological 
plasticity might represent possible avenues for increasing the chance for establishing interventions 
that work [32].  
The overwhelming individual and socio-economic burdens of psychosis combined with the severe 
prognosis and increasing incidence of child and adolescent schizophrenia spectrum disorders, 
emphasize the lack of trials to direct clinical practice. Hence, there is an urgent need for evidence-
based interventions that integrate psychosocial and pharmacological treatment while enforcing 
resilience factors in age-appropriate programs for psychosis with onset in individuals below age 18 
years. 
 
Aim 
The study aims to compare the efficacy and cost-effectiveness of an Early Intervention Service 
(EIS) versus treatment as usual (TAU) in children and adolescents aged 12-17 years with first-
episode psychosis.  
Hypotheses 
1. The EIS intervention (OPUS YOUNG) will be more effective than TAU in improving social 
functioning. 
2. The EIS intervention (OPUS YOUNG) will be more effective than TAU in reducing 
positive and negative psychosis symptoms and provide a higher client satisfaction and 
health related quality of life. 
3. The EIS intervention (OPUS YOUNG) will be more cost-effective than TAU. 
Method and procedures 
Design 
The design is an investigator-initiated pragmatic, open label, parallel group, superiority RCT with 
blinded outcome assessment. No commercial interests will be involved. The trial will seek approval 
by the Regional Ethical Committee and by the Knowledge Centre on Data Protection Compliance 
in The Capital Region of Denmark which assure that we comply with the General Data Protection 
Regulation according to guidelines of data collection in the Capital Region of Denmark and 
European Union standards. We will register the trial at clinicaltrials.gov. The trial procedures will 

 
 
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follow the Good Clinical Practice Guideline (GCP) [33] principles. 
 
Participants, patient selection 
Participants include children and adolescents (age 12-17 years, both inclusive) at the Child and 
Adolescent Mental Health Centre (CAMHC), Mental Health Services, Copenhagen University 
Hospitals, Capital Region of Denmark with a first-episode of psychosis fulfilling the ICD-10 [34] 
diagnostic criteria for schizophrenia or schizophrenia-like psychosis or depressive psychosis or 
substance induced psychosis.   
Patients who meet the inclusion criteria during the inclusion period between June 2021 and 
September 2023 will be invited to participate in the trial and then randomized to either OPUS 
YOUNG intervention or TAU intervention.  
Planned duration for study participation is two years from randomization to the treatment-endpoint 
at 24 months. We will perform an additional follow-up assessment 6 month after trial endpoint (see 
Figure 1 flow diagram and Table 2 study plan. 
 
 
Assessed for eligibility 
(n=550) 
Included and randomized 
(n=284-304) 
Excluded (n246) 
- Not meeting inclusion criteria (n=) 
- Declined to participate (n=) 
- Other reasons (n=) 
Allocated to intervention 
(n=142-152) 
Allocated to standard treatment 
(n=142-152) 
1-year follow-up assessment 
(n=)  
1-year follow-up assessment 
(n=)   
Treatment endpoint assessment 
(n=)  
Treatment endpoint assessment 
(n=)  
2.5-year follow-up assessment 
(n=)  
2.5-year follow-up assessment 
(n=)  
Figure 1 Flow of participants in OPUS YOUNG 

 
 
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Patient inclusion criteria 
1) Between 12 and 17 years of age (both inclusive) at trial inclusion. 
2) First-episode psychosis within F2 spectrum (F20 schizophrenia, F21 Schizotypal disorder, 
F22 delusional disorder, F23 acute and transient psychotic disorders, F25 schizoaffective 
disorders, F28/29 other or un-specified non-organic psychosis) or depression with psychotic 
symptoms (F32.3, F33.3) or substance-induced psychosis (F1X.5) according to ICD-10. 
3) Maximum 12 months since first prescription of antipsychotic treatment on the indication 
psychosis. 
4) Speak and understand Danish.  
5) Written informed consent from parents or legal caretakers. Participants who reach age 18 
years during the trial will be asked to give personal written informed consent to continue 
their study participation. 
 
Patient exclusion criteria 
1) A diagnosis of mental retardation of at least moderate severity defined as an IQ of 49 or below 
(F71, F72, F73 according to the ICD-10). 
2) Currently compulsory admission and/or treatment according to Danish legislation  
 
Eligible patients who do not wish to participate  
To be able to evaluate the external validity of the trial, we will register gender, age and diagnosis 
for the eligible patients who are not willing to sign informed consent and therefore not included 
despite fulfilling the inclusion criteria. We will register this information without the use of name or 
personal identification number and will only report this information on a group level. 
 
Participant withdrawal 
The informed consent to participate in the trial can be withdrawn by patients, parents, and legal 
caretakers at any time without any explanations.  
 
Standard referral and clinical assessment of patients prior to study recruitment.  
The Central Visitation Unit at Mental Health Services, Capital Region, and all in- and outpatient 
services at CAMHC refers all patients with suspected first-onset psychosis to a clinical assessment 
team within the CAMHC.  
As part of the standard psychiatric assessment in the in- and outpatients services, the health care 
professionals in the clinics will conduct a comprehensive multidimensional assessment, including a 

 
 
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structured psychiatric diagnostic interview (K-SADS-PL and SCAN 2.1 (section 17, 18, 19)), with 
all referred patients with first-onset psychosis prior to the patients being invited to participate in the 
OPUS YOUNG-study.  
In the CAMHS, there is a close collaboration between clinic and research. This means that health 
care professionals involved in the OPUS YOUNG-study are also engaged in the clinic. They assist 
with parts of the standard clinical assessments as clinicians in collaboration with the clinic. The 
results of the standard clinical assessment are reported to the patients’ medical journal. Only the 
health care professionals involved in the standard psychiatric assessments and treatment in the 
clinics will have access to the patients’ medical journal.  
After standard clinical assessment has been conducted, the clinics as a standard have a clinical 
diagnostic conference in which the results of the assessments are concluded upon. If the consultant 
psychiatrist or specialized psychologist in the clinic find the patient eligible for the OPUS YOUNG- 
study according to the in- and exclusion criteria, the patient and parents/legal caretakers are 
informed that the OPUS YOUNG-trial is taking place at the CAMHS, and the family is asked 
whether they are interested in being informed about the trial.  
 
Eligible participants, information about the trial, recruitment, informed consent, and 
screening. 
If the eligible patient and the family is interested in receiving information about the trial, they will 
be invited to be informed about the OPUS YOUNG study by the OPUS YOUNG research team. If 
the patient and family upon receiving information are interested in trial participation, written 
informed consent will be obtained (including permission to access information from the patients’ 
medical journal). The OPUS YOUNG research team will then, based on information from the 
standard clinical assessment in the medical journal, screen the participants for in- and exclusion 
criteria. If the patient fulfils the inclusion criteria 1-5 and none of the exclusion criteria, the patient 
will be included in the study. 
Importantly, no research activities or data collection for research will be initiated prior to written 
informed consent has been obtained.  
In some cases, it is more convenient for the patient and clinic to invite the patient to be informed 
about the OPUS YOUNG trial and invited to participate in the trial before the full standard clinical 
assessment (including K-SADS-PL and SCAN 2.1 (section 17, 18, 19)) has been completed in the 
clinic. Based on the clinical evaluation in the clinic, a patient with suspected or verified psychosis 

 
 
13 
can be asked by the clinic if they are interested in information about the OPUS YOUNG trial. If so, 
the clinic will facilitate an appointment with the OPUS YOUNG research team to meet the patient 
and family to inform about the study. If the patient and family wish to enter the study, the informed 
consent procedures described above will be conducted. In these cases, the standard clinical 
assessment performed in the clinic may not contain K-SADS-PL (full) and SCAN 2.1 (section 17, 
18, 19), i.e. these assessments will then be performed after patient consent to participate in the trial 
(in that case, the data from K-SADS-PL and SCAN 2.1 (section 17, 18, 19) will be categorized as 
research data and will not be documented in the patients’ medical journal). In these cases, the K-
SADS-PL and SCAN 2.1 (section 17, 18, 19) functions as screening instruments, i.e., if the patient 
does not show psychotic symptoms or does not fulfil the inclusion diagnostic criteria for a psychotic 
disorder, the patient will not continue participation in the trial. Overall, the OPUS YOUNG research 
team will screen the participants for in- and exclusion criteria. If the patient fulfils the inclusion 
criteria 1-5 and none of the exclusion criteria, the patient will be included in the study. 
 
Study assessments of included participants, parents/legal caretakers, clinicians, and municipal 
collaborators. 
All included patients and their parents/legal caretakers participate in a baseline assessment. Some of 
the baseline data will be assessed by interviews or questionnaires, while others, such as the standard 
clinical interview, will be obtained from the patients’ medical journal.  
Table 1 shows the assessment schedule for the research baseline and follow-up assessments for 
patients and parents/legal caretaker. In total, outcome assessments will be conducted four times 
during the study period; at baseline (entry into the study), after 12 months, after 24 months 
(treatment endpoint), and after 30 months (follow-up assessment 6 months after treatment 
endpoint). Parents/legal caretakers will be assessed and included in the overall data collection. The 
research appointments (baseline, 12, 24 and 30 months) will be registered in the participant’s 
medical journal, but no research data will be registered in the medical journal.  
Clinician-rated working alliance will be assessed at 24 months. Clinicians and municipal 
collaborators will additionally be invited to participate in semi-structured interviews around the 
same timepoint. The interviews will focus on trans-sectorial collaboration and activities and will 
include demographic information such as professional background, age, sex and current 
employment and function.  
 

 
 
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Table 1 study assessment schedule 
 
Patient assessment 
Assessment time, 
months 
Topic: 
Instrument/measure: 
Adm* A* 0 
12 24 30 
Demographics 
Demographic information 
I 
 
X 
X 
X 
X 
Duration of untreated 
psychosis 
Interview based on IRAOS 
I 
 
X 
 
 
 
Primary and comorbid 
diagnoses 
K-SADS-PL (full) 
SCAN 2.1 (section 17, 18, 19) 
I 
X 
 
X 
X 
 
Positive and negative 
symptoms 
SAPS, SANS 
I 
 
X 
X 
X 
X 
Affective symptoms 
YMRS 
HAM-D (6 items)  
I 
 
X 
X 
X 
X 
Global psychopathology   CGI-S,  
CGI-I 
IR 
IR 
 
X 
X 
X 
X 
X 
X 
X 
Social function 
PSP 
I 
 
X 
X 
X 
X 
Intelligence 
WISC-V (<16 years), WAIS-IV (≥16 years) 
T  
X 
 
 
 
 
Cognitive function  
BACS 
T 
 
X 
 
X 
 
Social cognition 
Hinting Task + EIMT 
T 
 
X 
 
X 
 
Quality of life 
KIDSCREEN-10  
Q 
 
X 
X 
X 
X 
Quality-adjusted life year CHU9D + EQ5D 
Q 
 
X 
 
X 
X 
Self-efficacy (general) 
GSE 
Q 
 
X 
X 
X 
X 
Working alliance 
WAI 
Q 
 
 
X 
X 
X 
Client satisfaction 
CSQ 
Q 
 
 
X 
X 
 
Negative effects of psych. 
treatment 
NEQ 
Q 
 
 
 
X 
 
Trauma  
Self-reported stressful life-events 
Q 
 
X 
 
 
 
Suicidal behaviour 
Self-reported suicidal ideation and behaviour 
I 
 
X 
X 
X 
X 
School adherence 
Days in school/education/employment (%) 
R/I 
 
X 
X 
X 
X 
Substance abuse 
TEM 
I 
 
X 
X 
X 
X 
Somatic Health  
Clinical assessment1, laboratory tests2, ECG 
ME 
 
X 
X 
X 
X 
Medication side-effects 
UKU 
I 
 
X 
X 
X 
X 
Medication compliance  
Self-reported use of antipsychotic medication 
I 
 
X 
X 
X 
X 
User perspectives on 
trans-sectorial activities  
Semi-structured interview 
I 
 
 
 
X 
 
Assessment of parents or legal caretakers 
Assessment time, 
months 
Topic: 
Instrument/measure: 
Adm* A* 0 
12 24 30 
Parent information on child:  
Primary and comorbid 
diagnoses 
K-SADS-PL (full) 
I 
X 
 
X 
X 
 
Executive functioning  
BRIEF-2 
Q 
 
X 
 
X 
 

 
 
15 
 
 
Negative effects of 
psychological treatment 
NEQ 
Q 
 
 
 
X 
 
School adherence 
Days in school/education/employment (%) 
Q 
 
X 
X 
X 
X 
Duration of untreated 
psychosis 
Duration of untreated psychosis (incl. patient 
referral process)  
Q 
 
X 
 
 
 
Genetic predispositions 
Genetic predispositions 
Q 
 
X 
 
 
 
Information on parents/family: 
Demographics 
Demographic information 
Q 
 
X 
X 
X 
X 
Parental Stress Scale 
PSS 
Q 
 
X 
X 
X 
X 
Family Function 
FAD 
Q 
 
X 
 
X 
X 
Self-efficacy 
GSE 
Q 
 
X 
X 
X 
X 
Client satisfaction 
CSQ 
Q 
 
 
X 
X 
 
User perspectives on 
trans-sectorial activities 
Semi-structured interview 
I 
 
 
 
X 
 
Clinician assessment 
Assessment time, 
months 
Topic: 
Instrument/measure: 
Adm* A* 0 
12 24 30 
Working alliance 
WAI 
 
 
 
 
X 
 
User perspectives on 
trans-sectorial activities 
Semi-structured interview 
I 
 
 
 
X 
 
Municipal collaborators 
Assessment time, 
months 
Topic: 
Instrument/measure: 
Adm* A* 0 
12 24 30 
User perspectives on 
trans-sectorial activities 
Semi-structured interview 
I 
 
 
 
X 
 
Notes: A* = Diagnostic and cognitive assessment prior to enrolment in the study conducted in the clinics. The results of these 
assessments will be obtained from the medical journal of the patients who consent to participate in the study and will be included as 
research data if informed consent is obtained.   
ADM* = Administration modus: I=interview, Q=questionnaire, R=registration, ME=will be obtained from the medical journal, IR= 
Interviewer-Rated. 
Abbreviations = IRAOS: Instrument for the Assessment of Onset and Early Course of Schizophrenia [35]; K-SADS: Kiddie-
Schedule for Affective Disorders and Schizophrenia[36]; SCAN 2.1: Schedules for Clinical Assessment in Neuropsychiatry  
[ref]; SAPS: Scale for Assessing Positive Symptoms[37]; SANS: Scale for Assessing Negative Symptoms[38]; YMRS: Young 
Mania Rating Scale; HAM-D (6 items): Hamilton Depression Scale[37, [40]]; CGI-S: The Clinical Global Impression Scale-
severity[41]; CGI-I: The Clinical Global Impression Scale- improvement[42]; PSP: Personal and social performance scale[43]; 
WISC-V: Wechsler Intelligence Scale for Children, fifth edition  or WAIS-IV: Wechsler Adult Intelligence Scale, fourth 
edition[44]; BACS: Brief Assessment of Cognition in Schizophrenia[45]; Hinting Task [46]; EIMT: Emotional Intensity Morphing 
Task[47,48]; KIDSCREEN-10: Health-related Quality of Life Screening Instrument for Children and Adolescents[49] ; CHU9D: 
Child Health Utility 9 Dimension[50]; EQ5D:  European Quality of life - 5 Dimensions[51]; GSE: General Self – efficacy 
Scale[52]; WAI: Working Alliance Inventory scale[53]; CSQ: Client Satisfaction Questionnaire[54]; NEQ: Negative effects 
Questionnaire[55]; TEM:  Trivsels- og Effekt Monitorerings-skemaet[56]; PSS: Parental Stress Scale [57]; FAD: The McMaster 
Family Assessment Device[58]; UKU: The UKU side effect rating scale [59]; BRIEF-2: Behaviour Rating Inventory of Executive 
Function, Second edition [60].  
1Standard clinical somatic health examination includes blood pressure, pulse, weight, height, BMI, and abdominal circumference. 
2Laboratory tests: Blood tests (fasting): triglycerides; total cholesterol; high-density and low-density lipoproteins; glucose; insulin; 
prolactin; haemoglobin; leukocyte cell and differential count; thrombocyte cell count; sodium; potassium; creatinine; aspartate 
amino transferase; alkaline phosphatases; thyroid stimulating hormone; vitamin D. Blood samples to analyse serum values of 
antipsychotics are drawn when needed. Urine tests: pregnancy test (at baseline and at follow-up if suspicion of pregnancy), 
screening for medication and substance abuse (at baseline and at follow-up if suspicion of substance use). ECG: electrocardiogram 
(standard leads). 

 
 
16 
Video and audio recording 
Some of the research assessments (Hinting Task, PSP, and follow-up K-SADS with adolescents and 
parents) will be video or audio taped in order to secure and evaluate the data quality. Recordings 
will only be initiated if the participant and parents/legal caretaker have given permission to the 
recordings, and participation in the study is possible without having consented to video or audio 
recordings.  
 
Registration of medication and use of health care during study 
The use of antipsychotics and any other medication (drug, daily dosage, duration) and use of health 
care and social services (type and intensity) will be carefully recorded in both the experimental 
group and the TAU group. Information on medication use will be obtained through the participant’s 
medical journal and by self-reported information at the assessment interviews. Information on 
service use will be obtained through the participant’s medical journal as well as from the Danish 
Registers (see below). 
 
Register-based information  
Data on the patients will be extracted at 30 months (6 months follow-up after end-of-trial) from the 
following registers from Statistics Denmark: The Danish Population Register, the Danish 
Psychiatric Central Register, the Danish Education Register, the Danish Register of Special 
Education, the Danish Institution Register, the Danish Register of School Grades, the Danish 
Patient Register, the Danish Prescription Register, and the Danish Migration Register. We will 
assess socio-demographic information including school attendance, school grades and exams, 
labour market affiliation, civil status, cohabitation status, data on complications to the pregnancy 
and birth of the participant, education, living in an institution (and type of institution), use of any 
health care and social services and, in the unlikely event: cause of death. 
 
Compensations 
All participants, including parents/legal caretakers, will be offered the opportunity to be 
compensated for their transport cost.  
 
Randomization 
After baseline assessment the participants will be randomized 1:1 to either the experimental 
treatment (OPUS YOUNG intervention) or standard treatment (TAU). Randomization of the 

 
 
17 
participant will be centralised and computerised with concealed randomization sequence carried out 
by the database system used in the Capital Region of Denmark (REDCap) [61]. The randomization 
concealment mechanism is performed by a computer algorithm saved in REDCap [61]. 
Randomization cannot be influenced by persons, and block size will be unknown for investigators 
and clinicians. To optimize the comparability between treatment groups, randomization will be 
stratified by the two factors: age (12-14 years and 15-17 years) and for the main outcome, PSP 
(score 1-44 and score 45-100).  
 
Blinding 
A trial coordinator will inform the randomisation unit on the participants’ data (age and 
identification) and will inform the patient and their family about which intervention programme 
he/she has been allocated to. The study is not blinded to patients, relatives, the OPUS YOUNG 
intervention team or staff members in TAU. The blinding applies to assessors (researchers) engaged 
with the outcome assessments and evaluation. In the follow-up outcome assessments, the patient is 
instructed in advance not to reveal what type of treatment he/she has received. If patients, despite 
instructions, reveal their treatment allocation to the researcher performing assessments, another 
person in the research group, who then will be kept blinded, will carry out the evaluation. The 
randomized intervention allocation is concealed until the statistical analyses of resulting data have 
been completed and conclusions drawn. 
 
Table 2 Study Plan 
 
Preparation  Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Start of study year 
December  
2019 
June 
2021 
June 
2022 
June 
2023 
June 
2024 
June 
2025 
End of study year  
May 2021  
May 2022 May 2023 May 2024 May 2025 July 2026 
Trial preparation 
(Fundraising, manuals) 
From January 
2019 
 
 
 
 
 
Recruitment of staff 
From October 
2019 
 
 
 
 
 
Preparation of OPUS 
YOUNG treatment 
including piloting the 
OY intervention 
From 
December 
2019 
 
 
 
 
 

 
 
18 
 
The OPUS YOUNG intervention and Treatment as Usual 
The trial is pragmatic, comparing two years of EIS (OPUS YOUNG) to TAU. All the participants 
included in the trial are offered illness and age-appropriate treatment for two years. The 
OPUSYOUNG treatment and the TAU (described below) will be provided at three different 
geographical locations (OPUS YOUNG in a community environment, first in Brønshøj, later from 
fall 2023 in Glostrup) and TAU in a hospital setting) in order to prevent spill over effects between 
interventions, and to meet the EIS demand of a minimally stigmatizing community environment. 
The OPUS YOUNG treatment program will be manualized in order to function as a standard 
operational procedure for the intervention. The TAU follows the general recommendations and 
guidelines according to the clinical practice in the CAMHC. 
Experimental intervention, OPUS YOUNG  
The specialized coordinated OPUS YOUNG treatment is EIS based on a multidisciplinary team 
with a low caseload of a maximum of 1 staff: 10 patients in average, and assertive outreach and 
tailored case management. In OPUS YOUNG, Cognitive Behavioural Therapy (CBT) is a part of 
Inclusion and 
randomization of 
participants to trial 
 
First 
participant 
randomize
d July 
2021 
 
 
Last 
participant 
randomize
d 
September 
2023 
 
 
Trial intervention 
 
X 
X 
X 
X 
 
Trial endpoint 
assessment (24- months 
follow-up) 
 
 
 
First 
participant 
end of 
treatment 
July 
2023 
 
Last 
participant 
end of 
treatment 
September 
2025 
Follow-up assessment 
6 months after trial 
endpoint (30 months 
follow-up) 
 
 
 
First 
participant 
6 months 
follow-up 
December 
2023 
 
Last 
participant 
6 months 
follow-up 
March 
2026 
Data analysis, 
manuscript writing and 
publications 
 
 
 
 
 
X 

 
 
19 
the therapeutic framework of cognitive behavioural case management (CBCM). In CBCM, the case 
manager both takes care of general aspects of the patient needs and care and provide cognitive 
psychotherapy [62]. OPUS YOUNG treatment focuses on enhancing the patient’s strengths and 
resilience, coping skills and resources, and will be tailored to meet the individual patient’s needs. 
The approach of the OPUS YOUNG team and CBCM include sharing best available evidence when 
facing the task of making decisions, supporting the patients and their relatives in decision-making 
and considering their options and resources, and to help patients achieve personal preferences and 
maximize resilience by following the principles of shared decision-making [63]. “Experts by 
experiences” will be integrated in psychoeducation for patients, relatives, and as a regular part of 
the introduction program for new OPUS YOUNG staff members. 
The OPUS YOUNG treatment consists of the following elements: modified assertive community 
treatment [64], cognitive-behavioural case management (CBCM) [62], psycho-educational family 
treatment including multiple family groups (MFG) [65] and psychoeducational siblings groups 
[66,67], Social Cognition and Interaction Training (SCIT) [68,69], possible individual Cognitive 
Behavioural Therapy (CBT) [62,70] in addition to CBCM, and manual based psychopharmacologic 
treatment building on (but not restricted to) the RAISE-ETP principles [71] and national guidelines 
[72]. 
 
To further meet known and common challenges for this age group, the OPUS YOUNG treatment 
has extra focus on components that strengthens resilience and are sensitive for achieving and 
maintaining positive benefits from the treatment: Special transition support, individual 
school/employment support, and prevention and treatment of substance abuse (further description 
of each element below). 
 
The OPUS YOUNG team 
Each OPUS YOUNG team is staffed by 1-2 specialist consultants in child- and adolescent 
psychiatry (one of the medical doctors may be a senior resident) and four to eight trained case 
managers (number of staff depends on number of patients included, however with a minimum of 
five staff members per team), who represent at least four different relevant professions (e.g. nurse, 
psychologist (preferably specialized in child- and adolescent psychiatry), pedagogue, vocational 
therapist, social worker).  

 
 
20 
All members of the OPUS YOUNG staff will be well educated, have profound experience with FEP 
and will be continuously trained and supervised in the core elements of the OPUS YOUNG 
treatment to provide the specialised assertive intervention. Team members must be trained in 
cognitive behavioural case management (CBCM) [62,73] and shared-decision making.  
 
Cognitive Behavioural Case Management (CBCM)  
All patients are designated to a primary staff member, a cognitive behavioural case manager 
(CBCM) (hereafter referred to as the case manager), who is responsible for the contact and alliance 
with both patient and parents/legal care takers and siblings throughout the two years of the OPUS 
YOUNG treatment. All staff members work as a case manager (except for the senior child- and 
adolescent psychiatrist consultant). In cooperation with a colleague, each staff member will be 
responsible for at least one of the group psychosocial programmes to support recovery (SCIT, 
psychoeducation to patients and parents/legal caretaker in MFGs, and sibling’s psychoeducation 
groups).  
CBCM comprises several components such as psychoeducation, case formulation, stress 
management, crisis management, challenging and behavioural strategies, and family work. CBCM 
offers patients a cognitive therapeutic approach with the aim to support autonomy, reduce stigma 
and to empower the individual in working towards personal recovery goals and illness self-
management. All staff members are initially and on-going trained and supervised in CBCM [74] 
securing that all team members get a basic understanding of the cognitive principles, able them to 
include the basic cognitive therapeutic principles in their collaboration and working alliance with 
the patient and to strengthening their ability to complement and support patients participating in 
SCIT and individual CBT. 
The case manager will give high priority to establishing and maintaining a strong and trustworthy 
alliance with the patient and his/her family, also when the patient is hesitant and/or reluctant 
towards the intervention and collaboration. The intensity of contact is flexible and phase specific. 
Typically, the patient and case-manager will initially be in contact weekly, however, the rate can be 
increased if needed and decreased if considered appropriate for the patients. The relationship 
between patient and case manager works consciously towards a strong working alliance [75,76], 
with confidence and transparency. It is essential for the case manager to be able to respond quickly, 
if changes in the patient’s condition occur, which require increased support. Once a sustainable and 
trusting connection has been established, it is much easier for patient and his/her relatives to ask for 

 
 
21 
help and support in times of greater need. Appointments should match the patient’s needs in 
general; meaning that the team offers a possibility for late afternoon appointments, the team is 
accessible in working hours and a possibility for patients and relatives to leave voice- or text 
messages outside working hours. The patient and his/her relatives can make direct contact with the 
case manager by cell phone. The patient and family should in advance be provided with a crisis 
plan comprising sufficient information to handle emergency situations and ability to access 
immediate help in the health care system when needed. This standard procedure will be developed 
as early as possible in cooperation with patients and relatives. Furthermore, the case manager is 
responsible for coordinating the treatment within the team, and for coordinating across school, 
social services, and other institutions involved in the treatment. The treatment is assertive, meaning 
that the team is responsible for maintaining contact with the patient and legal caretakers at all times. 
Meetings can be held in the patient’s home or in other places in their community or at his/her case 
manager’s office, according to the patient’s preferences. The OPUS YOUNG intervention does not 
include a formal inpatient component. However, the case manager and team will ensure continuity 
of care by facilitating referral to inpatient units and may work with inpatient staff and directly with 
the patient if hospitalization is required. 
 
Psychoeducational family-based intervention 
Parents/legal care takers are usually the patient’s closest relation and are thus very important 
collaborative partners as they have a unique knowledge of the patient and the family history. 
Psychoeducational family based intervention covers a program that provides families with 
education about psychotic disorders and related difficulties, and how to manage psychotic 
disorders, including strategies for problem-solving skills and how to improve communication 
within the family [77]. It has been demonstrated in several studies that family psychoeducation is 
associated with reduced rates of relapses [78,79]. The team invites the parents/legal caretakers to 
individual meetings from the very start of the treatment, to review the present situation and to create 
a working alliance, both for those who want to participate in psycho-educational Multi Family 
Groups (MFG) and for those who will not be able to join an MFG or refuse. Also, the team will 
invite and motivate all for participating in psychoeducational workshops. The parents/legal 
caretakers are offered on-going cooperation with the case manager and are invited to psycho-
educational workshops, in which they are given formal information about the illness and how to 
manage it. Psychoeducation involves active interaction between the OPUS YOUNG team providing 

 
 
22 
the education and the family/relatives. In addition to individual psychoeducation, the team focuses 
on inviting and motivating patients and legal caretakers to participate in MFG [80,81], see below.  
Psycho-educational multifamily groups (MFG) 
Based on McFarlane’s psycho-educational MFG [65], OPUS YOUNG will invite all patients and 
their parents/legal caretakers to participate in an MFG during a period of 12 months.  
The MFG includes six to seven patients with their parents/legal caretakers and two trained group 
leaders. They will meet every second week for one and a half hour (a total of 20 sessions will thus 
be offered to each family). The groups will be scheduled in the afternoons, enabling participants to 
participate after school/work hours [65,81]. 
MFG address many of the complex and difficult every-day problems that families with an 
adolescent may face, in addition to more illness specific issues that most of the patients with 
psychosis are dealing with. MFG use principles of problem-solving techniques, which include all 
participants actively in the problem-solving process. In OPUS YOUNG the McFarlane’s model of 
MFG will be age-adjusted to meet a younger population, by addressing questions and topics of 
relevance for this age group, e.g., how to manage school and peer relations or how to deal with 
misuse. 
 
Sibling psycho-educational groups 
As most of the adolescents experiencing FEP live and share their everyday life with their parents 
and siblings, siblings may experience increased levels of stress during the prodrome and onset of 
illness in their sister or brother, a burden affecting the whole family [82]. An explorative study of 
the experiences and needs of siblings of young adults with FEP treated in early intervention teams, 
found that siblings are greatly affected by the onset of the psychosis in their brother or sister, and  
although siblings did not identify themselves as caregivers, most of the siblings played a significant 
role in their brothers or sisters life [82]. The study conclude that the siblings desired a dynamic, 
robust and accessible service, e.g., information and support from peer siblings, to meet their needs 
[82]. Education and support for siblings will become increasingly important as they are both natural 
agents as caregivers now and in the future, also due to the familiar-high-risk for psychosis and 
mental illness it is important to reduce the level of stress in their everyday life [83]. A Cochrane 
review of psychoeducation for siblings of people with severe mental illness, find that siblings most 
often were recruited together with other family members, and that the overall proportion of siblings 
were low [66]. None of the studies in the review reported outcomes exclusively for siblings and the 

 
 
23 
authors were only able to include data from one small study in the review and thus, not able to 
conclude which type of psychoeducation were most effective in meeting siblings’ needs [66].  
In OPUS YOUNG all siblings from age 7 years (may be adjusted according to siblings needs and 
abilities) are offered participation in a siblings’ psycho-education group matching their age or if this 
is not possible, individual psychoeducation will be offered. The psychoeducation will be dynamic 
and based on dialogue, include information on symptoms and how to cope and manages in their 
daily life as a sibling to a relative with a FEP. The siblings together with the OPUS YOUNG team 
and the family will determine whether the sibling’s age-appropriate needs are best met by joining a 
siblings psycho-educational group or the psycho-educational family workshop [84] . 
 
Social Cognition and Interaction Training (SCIT) 
It is important for all people to be able to function socially, and the adolescent years are crucial for 
the development of independent social skills. A core characteristic in schizophrenia is impaired 
ability to function socially [85,86]. Impaired social functioning is obviously a problem that may 
stigmatize and marginalize children and adolescents with psychotic disorders, and in turn increase 
risk of social isolation and loneliness.  
Furthermore, social functioning strongly predict poor long-term recovery [87–89]. Hence, 
implementing best practices for improving social cognition and functioning is an important clinical 
goal in EIS. 
Social cognition is conceptualized as “the mental operations underlying social interactions, which 
include the human ability and capacity to perceive the intentions and dispositions of others” [90].  
The impairments of social cognition in schizophrenia involve at least three broad domains: emotion 
perception, attributional style, and theory of mind (ToM) [68].  
The SCIT program is the first coherent and comprehensive, stand-alone intervention targeting all 
three domains of social cognition. The SCIT program also targets underlying processes, such as 
cognitive rigidity, jumping to conclusions, and intolerance of ambiguity. 
The SCIT has proven effective in adults with schizophrenia by improving patients’ performances in 
key social cognitive abilities targeted by the program (emotion perception, social perception, ToM 
and attributional style) and by improving social relationships and overall social functioning [68,69]. 
In a feasibility study, the EPPIC group in Melbourne applied SCIT to early intervention treatment. 
The participants were aged between 16 and 26 years. SCIT was well tolerated, and retention was 

 
 
24 
good. The participants improved significantly on measures of emotion recognition and social and 
occupational functioning. As a result of the study’s findings, the EPPIC group suggests applying 
SCIT early in the course of illness. The group argues that SCIT would prove especially efficacious 
if applied as early as possible in the course of illness due to greater brain plasticity in the adolescent 
brain development. Also, the SCIT appeared acceptable for a young population [91]. 
SCIT is a manual based group intervention including 20 sessions, 1 session/week, with each session 
lasting 60 min. SCIT is comprised of three phases:  
(1) emotion recognition training while considering social context (defining emotions, emotion 
mimicry training, understanding paranoia) 
(2) recognizing attributional styles and ‘figuring out situations’ (distinguishing facts from guesses, 
jumping to conclusions, understanding bad events)  
(3) integration of these skills into real-life situations [68,92,93]  
 
The SCIT program uses a variety of supporting materials and activities like games and videos to 
teach the pitfalls of jumping to conclusions, improve cognitive flexibility in social situations, and 
help participants distinguish between social “facts” and “guesses”. The activities are engaging as 
they resemble youths’ leisure activities.  The original SCIT materials will be adapted to fit Danish 
children and adolescents. In the third phase, integration, the participants are helped to put into 
practice what they have learned. To prepare for real-life situations, new understandings and skills 
are rehearsed through role-playing sessions together with the therapist or with other participants in 
the group.  
 
Cognitive Behavioural Therapy (CBT) 
Individual cognitive behavioural therapy (CBT) is recommended for first-episode psychosis  as well 
as for patients with schizophrenia [93], even though the evidence is questionable. Two recent meta-
analyses of CBT for adults with psychosis or schizophrenia found effects “in the small range” on 
overall symptoms [94] and functioning [95]. However, the benefits were not sustained after end-of-
trial, and no robust effects were found with regard to psychotic symptoms, distress or quality of life. 
This was particularly the case when adjusting for lack of masking and other potential biases.  
A systematic review of psychological interventions in psychosis for children and adolescents 
identified only one small study of CBT (a feasibility RCT, n=20) providing some indications that 
psychological interventions might be effective in early onset psychosis [96].  

 
 
25 
Still, CBT was offered in 7 out of 10 EIS programs recently reviewed [6], typically with the aim to 
support autonomy, reduce stigma and empower the individual to work towards personal recovery 
goals and illness self-management [97]. In OPUS YOUNG these aims are targeted by the core 
components, particularly the cognitive-behavioural case management (CBCM) and the SCIT in 
combination.  
In order to avoid stacking of psychosocial treatment elements with the risk of overwhelming the 
participant, we will reserve the possibility of standard individual CBT to those patients in need of 
intensified psychological treatment. CBT would aim to 1) reduce the burden of non-psychotic 
symptoms (anxiety, depressive symptoms, reactions to trauma, substance abuse); and to 2) improve 
social relationships, enhance positive activities and feelings, and thereby improve self-esteem and 
install hope for the future.  
The CBT will be provided by the team psychologist (or psychiatrist), who will have formal training 
in CBT and a thorough clinical experience with CBT for youths. 
 
Pharmacological treatments 
The pharmacological treatments are manualized and based on international and Danish guidelines 
[72,98,99], which recommend a low-dose strategy for patients with FEP. This recommendation is 
supported be recent findings of increased risk of death (with a 4.3-fold increased risk of death from 
cardiovascular or metabolic causes) in children and youth treated with antipsychotic doses above 50 
mg chlorpromazine equivalents compared to children and youth treated with antipsychotic doses 
below 50 mg chlorpromazine equivalents (for which there was no significantly increased risk) [99]. 
Guidelines furthermore include restriction to indications for which there is good evidence of 
efficacy, adequate trial of alternatives including psychosocial interventions, when possible, 
cardiometabolic assessment before treatment and monitoring after treatment, and limiting therapy to 
the lowest dose and shortest duration possible. The pharmacological treatment in OPUS YOUNG 
will adhere to evidenced based use of second-generation antipsychotic drugs as the first choice and 
will at all times strive to avoid off-label use as much as possible. Due to the overall equality in 
efficacy among antipsychotic drugs used in adolescent FEP, the choice between available 
antipsychotics should be guided according to evidence base, approval status and side effect profiles, 
which differ [100,101]. An algorithm for selecting an appropriate antipsychotic agent will be 

 
 
26 
provided in the manual (see Appendix 1). The manual based psychopharmacologic treatment will 
build on the RAISE-ETP principles [71]. Systematic and close monitoring of side effects such as 
sedation, extrapyramidal symptoms, prolactin increase, QT prolongation, and weight gain, 
increased waist circumference, lipid and blood glucose abnormalities indicating risk factors for 
cardiovascular diseases and diabetes with validated scales [59]; are mandatory, as well as actions to 
manage side effects individually. The treatment follows a shared decision-making model involving 
the legal caretakers when appropriate and the patient must see the prescriber on a regular basis 
according to individual needs. 
The pharmacological treatment in OPUS YOUNG is described in a separate manual and algorithm 
which together with the OPUS YOUNG protocol [Protocol version 2, dated September 9, 2020] has 
been presented to the Danish Medicines Agency (DMA), case number 2020091477. The Danish 
Medicines Agency has concluded (September 18, 2020), that the OPUS YOUNG trial is not 
covered by the definition of a clinical (medicinal) trial, since the aim of the study is not to 
investigate the pharmacological effect of each of the drugs, but rather to test the effect of the 
algorithm. The DMA therefore concluded that the study should not seek approval in DMA but 
should seek approval in the Scientific Ethical Committee. The DMA furthermore recommends 
contacting the Danish Data Protection Agency concerning registration and further handling of 
personal information in the study. Finally, the DMA asks the study group to be vigilant concerning 
reporting to the DMA of spontaneous side effects to medications (see guidelines, 
https://laegemiddelstyrelsen.dk/en/sideeffects/side-effects-of-medicines/report-a-side-
effect/humans/report-an-adverse-drug-reaction-from-medicines-for-healthcare-professionals-e-
form/). We will promote side effect reporting to the DMA according to these guidelines.  
  
Special components of OPUS YOUNG 
The OPUS YOUNG team has special focus on areas particularly critical for this group of 
adolescents:  
1) Special transition support will bridge the gap between child and adolescent psychiatry and 
adult psychiatry, or social care, by securing the patients a safe transfer from OPUS YOUNG 
treatment to continued standard treatment in child and adolescent or adult mental health 
services (depending on age at end of the two years OPUS YOUNG treatment). In contrast to 
standard care, patients in OPUS YOUNG will not be terminated from the intervention and 
transferred to adult psychiatry if they turn 18 years of age during the two years intervention 

 
 
27 
period. The OPUS YOUNG team will follow the principles of the “NICE guidelines for 
supporting young people in their transition to adult services” [31] . Principles in the NICE 
guidance, emphasizes to allocate a named worker (in OPUS YOUNG; the case manager) to 
oversee, coordinate and delivery transition support and advocate for the young person if 
needed, and further, to ensure that the overall plan for supporting is revised if the young person 
is not in contact with services after transfer [31]. The transition to standard care will be 
scheduled approximately half a year in advance.  
 
2) Individual school/employment support. In cooperation with the patients’ school or 
educational/vocational institution, the case manager will support and encourage educational 
and vocational goals among all adolescents, including those who have dropped out of school or 
are at risk of doing so. To ensure that relevant education/vocation is provided, we will liaise 
with the patients’ school and educational authority and with their parents. Mutual agreement 
determines whether a special educational needs’ assessment is necessary. The case manager 
and the team will, in corporation with extern agents provide supported employment programs 
for those above compulsory school age who wish to find employment [102]. Case manager and 
the team will consider and motivate for other work‑related activities or supported work when 
individuals are unable to attain a regular job or are unsuccessful in their attempts to find 
employment. To enable the patients’ access to employment and educational opportunities, these 
efforts will be sensitive to the young person's needs and skill level and will be worked out in 
partnership with local stakeholders. OPUS YOUNG will follow the principles of the NICE 
guidelines for education, employment and occupational activities for children and young 
people with psychosis and schizophrenia [103]. 
 
3) Prevention and treatment of substance abuse are integrated in the OPUS YOUNG intervention 
and carried out by the case manager in collaboration with, and supervised by, consulting 
experts. A Cochrane review of psychosocial interventions for cannabis use disorder suggested 
that improvements in cannabis use, frequency and severity of dependence were most likely 
when the treatment offered were a combination of cognitive behavioral therapy (CBT) and 
motivational enhancement therapy (MET) [104]. This combination of CBT and MET as well as 
the use of gift cards and follow up sessions, have in a Danish randomized study shown to be 
very effectful in reducing and cessation of cannabis use among young people [105,106]. In 

 
 
28 
OPUS YOUNG we integrate this combination of CBT and MET as add on of 12 manualized 
sessions for those patients who have a misuse and who are motivated for treatment, with use 
the MOVE manual [107]. 
 
In general, and to ensure confidence and the opportunity to collaborate with the patient on 
minimization or cessation of misuse, the case manager will exercise a non-judgmental approach 
towards use of substances.  OPUS YOUNG will follow the principles of NICE “Coexisting 
severe mental illness and substance misuse: assessment and management in healthcare settings” 
and consider the expected NICE guideline “Drug misuse prevention” [108].  
We will also actively intervene to prevent initiation of smoking and promote smoking 
cessation, as this poses an additional severe threat to health [109]. From our prior studies 
including youth with psychosis, we know that tobacco use is high among these patients. In the 
TEA trial, 40% of 12-17 year old patients with early onset psychosis compared to 1% of 
healthy controls were smokers (p<0.001) [110].  
Experts by experience  
In OPUS YOUNG the use of “experts by experiences” also known as peer support, will be 
integrated as an independent and permanent part in psychoeducation for both patients, caregivers, 
and siblings. Furthermore, experts by experiences will contribute to the introduction of new team 
members and act as an expert panel like the OPUS panel. The OPUS panel was founded in 2009 by 
a group of young people who had been in treatment in EIS teams (OPUS) in Denmark and their 
relatives. The purpose of the panel is that the members with their personal history and through 
dissemination about living with an invisible disease helps to broaden the knowledge about the 
diagnosis of schizophrenia, and reduce the stigmatization experienced by both patients and 
therapists in the field. In addition, experts by experiences will increase the hope for current patients 
treated in EIS and affect the treatment culture in a positive direction. An early intervention youth 
mental health service in Melbourne uses families as partners in mental health care in close 
collaboration with clinical teams to provide new family members with a range of interventions to 
assist recovery, their experience that new families asked for contact with peer-families very early in 
the course of treatment [111]. 
 
A phase-specific individual tailored treatments course in OPUS YOUNG 

 
 
29 
OPUS YOUNG treatment is a complex intervention that allows to be tailored to the individual 
patient. Therefore, many different courses of treatment can take form. Table 3 shows an example of 
how the two years intervention could proceed. 
 
Table 3 Example of OPUS YOUNG treatment for two years 
Example of 2-years OPUS YOUNG treatment 
Year 
1 
1 
1 
1 
2 
2 
2 
2 
Cognitive Behavioural Case Management (CBCM) 
 
 
 
 
 
 
 
 
Collaboration with relatives 
 
 
 
 
 
 
 
 
Social Cognition and Interaction Training (SCIT) 
 
 
 
 
 
 
 
 
Multi Family Groups (MFG) 
 
 
 
 
 
 
 
 
Individual Cognitive Behavioural Therapy (CBT) 
 
 
 
 
 
 
 
 
Pharmacological treatment 
 
 
 
 
 
 
 
 
Individual school/employment support 
 
 
 
 
 
 
 
 
Prevention and treatment of substance abuse 
 
 
 
 
 
 
 
 
Transition support 
 
 
 
 
 
 
 
 
 
 
Mandatory for all patients 
 
When motivated and able, flexible start time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A motivated option 
 
According to individual needs 
 
Treatment as usual (TAU)  
Participants allocated to the standard treatment will be offered the existing treatment in CAMHS. 
According to the Specialty Plan for child and adolescent psychiatry by the Danish Health 
Authorities, 2019 [112] children and adolescents with psychosis will be referred to a predefined 
level of care in the Danish health care system according to the severity and complexity of their 
psychotic illness. In essence, the individual patient will be referred to the unit in CAMHC that best 
fits the level of care indicated. In Denmark, three levels of care may be provided: Main function, 
regional function, or highly specialized function. If the needs of a patient change during the course 
of illness, the patient will be transferred to a higher or lower level of care. The treatment follows 
national Danish guidelines and local guidelines but is not manualized. None of the levels of care in 
TAU are currently assertive as a standard. The unit for highly specialized function for children and 
adolescents with schizophrenia in CAMHC manages the patients with the most severe psychotic 
illness. In addition to standard treatment, this unit is specialized by providing a multidisciplinary 
team, case-management (no defined upper case-load), family support and psychoeducation, in 
addition to psychopharmacological treatment. In some cases, social skills training and CBT may be 
offered. In general, office visits take place in outpatient clinics. The main and regional functions are 

 
 
30 
both at a less intensive level of care than the highly specialized function, and standard treatment 
usually offers psychoeducation, antipsychotic treatment, and some support to the families. The 
outpatient units proving the TAU plans to implement an adjusted and transdiagnostic version of 
flexible assertive community treatment (F-ACT) building on reports from Danish adult mental 
health services [113] and models from Dutch youth mental health services [114]. The establishment 
of F-ACT teams in TAU are expected to be initiated in September 2021. 
 
Fidelity monitoring 
We will assess the fidelity of the OPUS YOUNG treatment and structure during the trial period, 
using an special OPUS YOUNG modified version (Appendix 2) of The Danish Fidelity Scale for 
Specialized Early Intervention Team [115–117]. To lower the possibility of idiosyncratic 
judgement, two assessors will independently conduct the fidelity assessment once a year, and their 
interrater reliability will be measured. Further we will assess fidelity of core parts of the treatment; 
CBCM, SCIT and Family intervention to guide and maintain adherence to the OY intervention 
throughout the trial period. Furthermore, meetings and co-rating will be arranged to ensure program 
fidelity and interrater reliability. 
 
Recruitment of staff, training, and preparation of OPUS YOUNG treatment 
Since January 2019 an OPUS YOUNG manual including all treatment elements suiting the target 
group has been developed. The first OPUS YOUNG team has been established, and they have 
tested the OPUS YOUNG intervention since January 2020. The team has participated in the final 
preparations of materials and are qualified and educated in the manual-based OPUS YOUNG 
treatment, and ready for including patients by June 2021. The first team will be on-going 
throughout the entire trial period and will get an important status as a critical mass that can help 
with the introduction of the new team members and guide their education in the manual-based 
treatment. Recruitment of additional multidisciplinary staff will take place gradually relative to the 
number of patients included in the experimental treatment (see figure 2).  
The OPUS YOUNG staff will in addition to their clinical profession be educated and trained in 
cognitive behavioural therapy as well as the core elements of the OPUS YOUNG treatment: 
CBCM, MFG, SCIT, MOVE, and the psychoeducational family-based involvement. Moreover, 
training of staff will include: the overall program principles of early intervention services, 
psychopathology and how to work together as a team of health professionals with different and 

 
 
31 
overlapping roles. Ongoing training and supervision will ensure that the staff is qualified to perform 
the core elements of the treatment. The OPUS YOUNG team will develop material and videos for 
use in the SCIT-treatment. 
 
Cooperation with the OPUS organization for adults   
The OPUS YOUNG team will have close collaboration with the Danish OPUS teams for adults 
aged 18-35 years and benefit from their 20 years of experience and competence in EIS.  
Experts from the OPUS team together with experts in cognitive behavioural therapy, will initially 
and on-going, train, teach and supervise the OPUS YOUNG staff in the function as CBCM. 
Likewise, experienced multifamily group-therapists from the OPUS team will teach and supervise 
OPUS YOUNG staff in how to lead and facilitate a multifamily-group. OPUS YOUNG team 
leaders will attend the OPUS-leader meetings, which again will facilitate cooperation, increase the 
possibility for knowledge to be shared and developed between teams and bridge the age spread. The 
OPUS YOUNG staff will participate in the annual national OPUS conferences. A close 
collaborating will strengthen the overall specialized early intervention efforts for young people with 
the first episode of psychosis in Denmark.  
 
Figure 2 Expected number of patients in OPUS YOUNG intervention during the 26 months of 
recruitment. OPUS treatment team 1 will be engaged from June 2021 to September 2025. OPUS 
treatment team 2 will be engaged in the expected two-year period when the patient volume is above 
71 patients. 
 

 
 
32 
 
 
Hierarchy of outcome measures 
Primary outcome 
The primary outcome is change in the estimate of the adolescent’s social function, measured with 
Personal and Social Performance Scale (PSP) [43]. PSP provides a global score on a scale from 1-
100, with lower scores indicating lower social functioning, as well as scores on four subdomains 
(Socially useful activities, Personal and social relationships, Self-care, and Disturbing and 
aggressive behaviour) on a scale 6-point Likert scale. The scoring of PSP is based on all available 
information and concerns the patient’s daily level of functioning in the family, in school, and during 
leisure time during the past month. Researchers will interview the participants prior to the scoring 
of PSP using a semi structured interview guide suitable for children and adolescents, developed by 
the OPUS YOUNG research team. The final PSP-score will be determined using consensus rating, 
by which the rater will discuss the PSP score with an experienced user of PSP (the co-PI of the 
OPUS YOUNG study) and/or a senior consultant and other researchers from the research team.    
Prior to the initiating the OPUS YOUNG study, we will conduct a pilot-study to ensure that the 
assessors have a high level of inter-rater reliability with ICC values for the primary outcome 
measure of at least 0.70, prior to working as assessors in the trial (ICC is calculated in SPSS using 
two-way mixed models for absolute agreement on single measures). Assessors at entry and at the 
follow-up interviews will be independent and blind to treatment allocation. Patients will be 
instructed to maximize efforts to keep their treatment allocation unknown for the investigator.  
0
25
50
75
100
125
150
Number of patients in OY intervention
June 2022 
september 
2024
september 
2023 
June 2021 
September 2025 

 
 
33 
 
Secondary outcome measures: Positive symptoms, negative symptoms, and disorganized symptoms 
(SAPS and SANS); client satisfaction (CSQ); and quality of life (KIDSCREEN-10).  
 
Exploratory outcomes:  
Affective symptoms (YMRS, HAM-6); global psychopathology (CGI-S, CGI-I); duration of 
untreated psychosis (IRAOS); global cognitive functioning (BACS total score); social cognition 
(Hinting Task and EIMT); general self-efficacy (GSE); patient and clinician rated treatment alliance 
(WAI); negative effects of psychological treatment (NEQ); school adherence; parental stress (PSS); 
family function (FAD); quality-adjusted life year (CHU9D and EQ5D); executive functioning 
(BRIEF); socially useful activities, personal and social relationships, self-care, disturbing and 
aggressive behaviours (PSP subscales); use of psychopharmacological treatment; substance abuse; 
and the use of psychiatric and social services. 
 
Sample size calculation  
Based on the literature concerning the level of psychosocial dysfunction measured with PSP in 
early onset psychosis (EOP) [118–121] we expect a Standard Deviation (SD) on PSP around 
SD=13. Concerning the expectations on relevant group difference in improvement during two years 
of EIS [6,122] we have evaluated the minimal relevant difference (MIREDIF). MIREDIF should 
represent a meaningful minimal group difference in response in the sense that it would justify a 
choice between two interventions in a clinical setting. The total PSP scale score range from 1 to 
100. The metanalysis [6] on EIS interventions found, for functional outcome measured with Global 
Assessment of Functioning (GAF, scaled 1-100) including n=1005 participants in 7 studies, a 
standardized mean difference (difference in mean outcome between groups/standard deviation in 
outcome among participants) of 0.21 (in the individual 7 studies included ranging from 0.02 to 
0.56). With a SD of 13, this equals an expected difference in PSP scores between groups of around 
2.73, ranging from 0.26 to 7.28. Based on these findings and the evaluation of what is clinically 
meaningful when regarding the PSP 10-point ranges of functioning we have decided that it would 
be clinically relevant to be able to detect a difference of 5 points in outcome score on the total PSP 
scale between the two interventions. Using a power of 90% and a two-sided alpha of 5%, and 
expecting a SD of 13 on PSP, the required sample size necessary to detect or reject a difference of 
at least 5 points between the OPUS YOUNG and TAU group on PSP at endpoint is 284, why we 

 
 
34 
plan to enrol a minimum of 142 patients in each group. However, to account for drop-outs and due 
to our relatively long recruitment procedure time, where patients are referred from the clinic and 
may wait during the assessment period being offered participation, we will include up to 152 
patients in each group if necessary, within the recruitment period. This will ensure that patients who 
are in the recruitment process will still be offered participation in the study even if the minimum of 
284 participants has already been enrolled. This is ethically more proper, as patients in the centre 
entering the recruitment procedure are informed about the potential possibility to be offered 
inclusion in the study. The last patients will be assessed and included by September 1st, 2023. After 
this, no more patients will be included. 
The required sample size was estimated as follows (N=total sample size, SD=standard deviation of 
the outcome measure, α=type 1 error, β=type 2 error, MIREDIF=minimal relevant difference of 
outcome measure, z = fractiles in normal distribution), when assuming equal sample sizes, equal 
SDs for the two interventions, and α=0.05 and β=0.10:  
𝑁= 4 × (𝑧1−𝛼/2 + 𝑧1−𝛽)2 × (
𝑆𝐷1
𝑀𝐼𝑅𝐸𝐷𝐼𝐹)2 
The required sample size with an estimated SD of 13 and a MIREDIF of 5: 
𝑁= 42 × (13
5 )2 = 284 
 
Handling of study drop-out: 
Based on data from a prior study (the TEA trial) of 113 patients with first-episode psychosis aged 
12-17 years conducted in our CAMHS in the period 2010-2014 we have evaluated the expected 
study drop-out in the OPUS YOUNG trial. The TEA trial compared the beneficial and harmful 
effects of two antipsychotics, aripiprazole versus quetiapine, in a 12-week study. The drop-out rate 
(lost to follow-up assessments at week-2, week-4 or week-12) was 14% and 10%, respectively. In 
the TEA trial missing data was handled by intention-to-treat-analysis and multiple imputations 
[123]. In the OPUS YOUNG study, including an identical group of participants, we expect a drop-
out rate of approximately 10%. We expect that the combination of pharmacological and 
psychosocial treatment in both intervention arms will motivate the patient and family to adhere to 
treatment. Furthermore, even though the drop-out rate for the two-year adult OPUS study was 
approximately 30%, our experience from the clinic is that parents intensively support young 
patients to adhere to treatment and support continued participation in clinical trials. 

 
 
35 
As we scientifically and ethically find it important to strive to include the most exact needed 
number of participants possible, not too few (risk of loss of statistical power), not to many (risk of 
burdening too many patients with engagement in a RCT) we will handle missing data as a result of 
study drop-out by performing intention-to-treat analysis with multiple imputation of missing data 
[124]. See also section on statistical analysis below. 
 
Power calculation for secondary outcome measures  
For secondary outcomes, we have performed power calculations on the most relevant secondary 
outcome measures. Based on the results of the power calculations the measures SAPS, SANS, CSQ, 
and KIDSCREEN-10, were selected as secondary outcomes.  
 
SAPS, SANS 
We are planning a trial with a minimum of 284 participants randomized 1:1. In a previous study, the 
response within each intervention group was normally distributed with a SD of 1.4 (SAPS) and 1.2 
(SANS) points. If the true difference in the experimental group (OPUS YOUNG) and control group 
(TAU) for both SAPS and SANS is a mean of 0.4 points [125] with a standard deviation of 1.4/1.2 
points, we will be able to reject the null hypothesis that the population means of the experimental 
and control groups are equal with probability (power) of 80%. The type I error probability 
associated with this test of this null hypothesis is 5%. 
 
CSQ 
We are planning a trial with a minimum of 284 participants randomised 1:1. In a previous study the 
response within each intervention group was normally distributed with an SD of 4.45 points. If the 
true difference in the experimental group (OPUS YOUNG) and control group (TAU) is a mean of 
3.09 points [125] with a standard deviation of 4.45 points, we will be able to reject the null 
hypothesis that the population means of the experimental and control groups are equal with 
probability (power) of 99%. The type I error probability associated with this test of this null 
hypothesis is 5%. 
 
KIDSCREEN-10 
We are planning a trial with a minimum of 284 participants randomised 1:1. If the true difference in 
the experimental group (OPUS YOUNG) and control group (TAU) is a mean of 5 points and with 

 
 
36 
an expected standard deviation of 10 points [126], we will be able to reject the null hypothesis that 
the population means of the experimental and control groups are equal with probability (power) of 
99%. The type I error probability associated with this test of this null hypothesis is 5%. 
 
Table 4 Power calculation 
OUTCOME 
MIREDIF 
SD 
N 
Power 
Primary 
 
 
 
 
PSP 
5.0 
13 
2*142 
90% 
Secondary 
 
 
 
 
SAPS 
0.4 
1.2 
2*142 
80% 
SANS 
0.4 
1.2 
2*142 
80% 
CSQ 
3.09 
4.45 
2*142 
99% 
KIDSCREEN-10 
5 
10 
2*142 
99% 
Notes: Minimal relevant difference of outcome measure (MIREDIF), Standard Derivation (SD), Number 
of cases (N) 
 
Evaluation of cost-effectiveness of OPUS YOUNG 
The majority of first episodes of psychosis occur in adolescence or young adulthood, and it is 
important to detect and treat these early as delayed treatments can lead to poor clinical and social 
outcomes, with potential consequences over the lifetime for the individual and the society. Despite 
increased implementation costs, investments in EIS for young adults have shown to be cost-
effective in OPUS due to lower psychiatric health care costs and better outcome [30]. To assess the 
cost-effectiveness of the OPUS YOUNG intervention, we will conduct an economic evaluation of 
the trial adopting a public-sector perspective. The cost-effectiveness analysis compares differences 
in costs and outcome between the intervention group and standard treatment by calculating the 
incremental cost-effectiveness ratio [127]. The time horizon of the economic evaluation will be 2.5 
years. Outcome measures and cost data will be based on  collected research and clinical data 
combined with register data [30].  
 
Evaluation of psycho-educative siblings’ groups 
In a qualitative-design we will explore siblings’ perceptions of being a sibling to a brother or sister 
with a FEP and identify factors important for siblings to benefit from the psycho-educative siblings’ 
group. We will invite siblings to participate in an individual, semi-structured interview exploring 

 
 
37 
their experiences of being siblings to a brother or sister with FEP using a descriptive 
phenomenological approach to gain an in-depth understanding of the lived experiences of siblings. 
 
Data-management  
The assessors will enter data directly into a database REDCap via an online Case Report Form 
(CRF). A data manager will ensure that all variables are properly defined with variable and value 
labels. Algorithms will be kept in special files. Data will be exported to relevant software packages: 
(SPSS, SAS, Stata, R.). All data will be examined carefully in order to identify errors in data entry. 
 
Statistical analyses 
The analyses will be according to intention-to-treat with two-sided tests. Missing data will be 
handled by multiple imputations. The primary outcome measure, as other continuous outcome 
measures, will be analysed with mixed model analysis with repeated measurements with 
unstructured variance matrix, using the mixed model command in SPSS. This approach assumes 
that the distribution of missing data can be estimated from the information from previous 
assessments and from information about other participant cases in the database. The condition for 
using this method is the assumption that data are missing at random or missing completely at 
random when taking into consideration the information extracted from baseline assessments and 
information about the other participants in the database. In this model, baseline values of the scales 
are included. All tests will be two-tailed. The threshold for the significance level will be set at 
p<0.05. For evaluation of the dichotomous outcome measures, we will use multiple multivariate 
imputations, using all other covariates to impute a distribution of missing values. The dichotomous 
outcomes will be analysed with logistic regression analyses. Variables included as covariates will 
be the same as those included in analyses of continuous measures. Similar to the repeated 
measurement, the condition for using multiple imputations requires that data are missing at random 
or missing completely at random, when taking into consideration the information extracted from 
baseline interviews and information about the other patients in the database. Analysis will be based 
on intention-to-treat principles. Data from all patients will be included in the group to which 
random assignment is made, regardless of intervention received. 
 
The specific hypotheses examined are:  

 
 
38 
• The primary hypothesis: 2 years OPUS YOUNG is superior to 2 years TAU (CAMHS or 
CAMHS+AMHS) examined in all patients aged 12.00 to 17.99 years at inclusion.  
• Planned sensitivity analysis 1: 1-year OPUS YOUNG vs. 1-year TAU CAMHS in patients 
ages 12.00 to 16.99 years at inclusion (hence, the patients in this study sample do not turn 
18 years during the trial and are solely treated in CAMHS).    
• Planned sensitivity analysis 2: 2-years OPUS YOUNG vs. 2-years TAU CAMHS in 
patients aged 12.00 to 15.99 years at inclusion (hence, the patients in this study sample do 
not turn 18 years during the trial and are solely treated in CAMHS for the entire intervention 
period of 2 years).    
• Planned sensitivity analysis 3: 2-years OPUS YOUNG vs. 2-years TAU CAMHS + AMHS 
in patients aged 17.00 to 17.99 years at inclusion (hence, all patients in the TAU group will 
have undergone transition from CAMHS to AMHS, while the patients in the OPUS 
YOUNG group will receive OPUS YOUNG treatment for the entire 2 years of intervention.    
Due to expected lower sample size in the three planned sensitivity analysis, we do not aim to show 
statistical superiority of OPUS YOUNG over TAU in these analyses but will examine possible 
differences by comparing effect sizes.   
 
Ethical considerations 
Both the patients and parents/caretaker may be in a state of psychological crisis at the time they are 
invited to participate in the trial, making it difficult for them to decide whether to participate in the 
study. There is a risk that they will consider OPUS YOUNG better than TAU, which may affect 
them when the outcome of randomization is revealed. Still, we do not expect anyone to be affected 
negatively from being involved in the trial. While OPUS YOUNG is geographically located in a 
civilian environment, there is still a risk that some participants will find being in OPUS YOUNG 
treatment associated with stigmatization.   
 
In general, the results of this trial can be of great importance for future health-care planning to 
benefit young people with a first-episode psychosis. OPUS YOUNG treatment is tailored to meet 
the patient’s individual needs and to support the patient’s empowerment and recovery process. 
 
Written informed consent 

 
 
39 
All participants are below 18 years of age when invited to participate in the trial, why signed 
informed consent will be obtained from parents/legal caretakers prior to entering the trial. The 
adolescents between 15 and 17 years of age will sign written informed consent in addition to the 
parental consent. Municipal collaborators and clinicians who wish to participate in the interviews 
regarding user perspectives on trans-sectorial activities will also sign written consent before the 
interview. 
 
Procedures regarding verbal and written information: 
Patients, who are deemed eligible to participate in the trial according to the in- and exclusion 
criteria, as well as their parents/legal caretaker, will be given verbal information about the trial by a 
health care professional involved in the trial. The verbal information will be provided during regular 
clinic visits at the CAMHS in the presence of parents/legal caretakers, and in the privacy of an 
examination room, together with the patient’s primary health care provider. The verbal information 
will be provided in an age-appropriate manner and parents/legal caretakers will be explained their 
right to have an assessor (e.g., friend or family member) present and in case the parent/legal 
caretaker should want that, a new appointment will be made for the information meeting. Written 
information brochures explaining the study background, procedures, aims, and (patient) rights will 
be provided both to the participant (age-adjusted language for the 12-14 years old and the 15-17 
years old, respectively) and the parents/legal caretakers. Both the verbal and written information 
will inform about participants’ rights to withdraw from the trial at any point without it affecting 
future treatment. 
Potential participants and their parents/legal caretakers will have a minimum of 24 hours to 
consider participation before being contacted by the health professional involved in the trial. The 
child and their parents/legal caretaker will be informed that the decision must be a shared decision, 
and both the child as well as their parents/legal caretakers should agree on the child’s participation 
prior to the parents/legal caretakers’ consent to the participation. If potential participants and their 
parents/legal caretakers approve to participate, parents/legal caretakers and the participating youth 
if 15 years of age or above will sign informed consent prior to initiating any research activities.  
 
Parental Power of Attorney: 

 
 
40 
A parent/legal caretaker will have the possibility of signing a power of attorney to the other 
parent/legal caretaker. Parents/legal caretakers will be informed that use of this form is voluntary 
and can be withdrawn at any time. 
 
If only one parent has custody: 
If one parent has sole custody, only this parent will give written informed consent to their child’s 
participation in the research project. In this case, the research team will obtain necessary 
documentation for the parent’s sole custody.  
 
When the participant turns 18 years of age: 
Participants who turn 18 years of age during the trial (within 2.5 years after inclusion) will receive 
new written and verbal information and be asked to give personal written informed consent in order 
to continue their study participation. 
 
Parental participation:  
Each parent/legal caretaker will receive their own written and verbal participant information and 
informed consent form regarding parental participation. If the parents do not give informed consent 
to be involved in the trial themselves, the adolescent patient with psychosis can still be included in 
the trial, if the above criteria for patient participation is fulfilled.  
 
Participation of relevant clinicians and municipal collaborators:  
At approx. 24 months (follow-up assessment) clinicians participating in the treatment in both the 
OPUS YOUNG intervention and in TAU will be invited to a semi-structured interview. Only a 
limited number will be invited from both treatments. Relevant municipal collaborators, taking part 
in the treatment and collaboration around the group of participants in the trial, will likewise be 
invited to participate in interviews. 
Clinicians and municipal collaborators invited to participate in interviews, will receive written 
information brochures explaining the study background, procedures and aims, alongside the 
invitation. Consent will be obtained prior to participation in the interviews. The written information 
will inform about participants’ rights to withdraw consent at any point. 
 
 

 
 
41 
Feasibility of the study  
Based on data from the Danish Psychiatric Central Register and from the CAMHC local register, 
we expect to be able to recruit a minimum of 284 patients for the trial in the two-year period from 
June 1, 2021, to September 2023. This is realistic as we expect approximately 200 patients per year 
to be eligible for participating in the trial in the Capital Region in Denmark. The intervention part of 
the trial lasts for two years, but due to follow-up assessment six months after end of treatment, 
participation in the study is 2,5 years, i.e., the last randomized participant will conclude the 
intervention and trial end-point assessment September 31, 2025, and the 6-month follow-up 
assessment February 1, 2026 (see study plan, Table 2). The present study is a collaboration between 
the CAMHC and the adult mental health services (AMHS). Research in child and adolescent mental 
health is a prioritized focus area in the Mental Health Services of the Capital Region of Denmark, 
which supports and hosts the present study. Furthermore, the Danish Regions, covering all public 
health services in Denmark prioritizes in their 2020 recommendations for health research studies 
focusing on transition from child and adolescent health services to adult health services [128].  
The CAMHC has ample experience in conducting clinical studies and trials on early onset 
psychosis [109,110] and the AMHS harbour the OPUS study [125,129,130], which has conducted 
trials and carried out a national implementation strategy of EIS in first-episode psychosis for 20 
years. We expect patients and relatives to adhere to the two-years duration of OPUS YOUNG 
treatment as we have 20 years of positive experiences from the adult OPUS treatment, where the 
case manager’s welcoming, assertive, competent, and cooperative approach have proven effectful 
for adherence. We expect this to be true for a younger age group as well, as the cooperation in 
CBCM is based on the same principles. Furthermore, as part of our preparations for the trial we 
have conducted a focus group interview with parents and patients who has been part of the piloting 
phase of the trial and who has received OPUS YOUNG treatment for periods of 1-6 months at the 
time of the interview. Both parents and patients expressed very positive evaluations of the OPUS 
YOUNG treatment, and provided helpful suggestions for adjustments of the program. 
We acknowledge the efforts needed to recruit and maintain contact with everyone participating in 
the study. In CAMHS we have conducted several studies recruiting and including a total of more 
than 200 youths with first-onset psychosis below age 18 years. We are confident that we can engage 
patients in the OPUS YOUNG study, based on experience from managing the Tolerability and 
Efficacy of Antipsychotics (TEA) [109,131] trial, as well as our abilities to include patients with 
early-onset psychosis in clinical prospective neurobiological and cognitive studies [132–138]. 

 
 
42 
Furthermore, we have vast experience from the OPUS I trial in which we succeed in an attrition of 
only 30% of all randomized patients at both 2, 5- and 10-years follow-up [125,129,139] as well as 
inclusion of 76,5% (90% in Aarhus and 63% in Copenhagen) of eligible patients [139]. 
 
Strengths and limitations 
One of the main strengths of this trial is the use of a gold standard RCT design aiming to provide 
available evidence while minimizing bias. The use of a computer generated random sequence 
generation handled by an algorithm saved in REDCap [61] reduces the risk of selection bias. The 
use of blinded outcome assessors for outcomes and the use of intention-to-treat analysis aim to 
prevent biased effect estimates. All CAMHC patients in the catchment area who potentially meet 
inclusion criteria are offered to take part in the trial. Due to the very few exclusion criteria, the 
study will have high external validity.  
The study builds on an evidence-based coordinated specialized assertive care model that has been 
proven efficient in young adults [125,129,140]. The study will provide novel results, since no 
previous studies have focused on EIS in patients below age 18 years. The current trial is 
supplemented with innovative and age-appropriate components aiming to target modifiable 
complications of early psychosis.  
The fact that we are not able to blind the participants and staff might increase the risk of 
performance bias. The OPUS YOUNG treatment is a complex intervention, which makes it difficult 
to elucidate exactly which components are primarily responsible for the treatment effects. Due to 
the relatively few cases of psychosis in childhood and early adolescence, our sample will be small 
relative to adult samples. We have considered a multicentre trial but have weighted the strength of 
limiting the trial to one geography (short distance for group supervision and rating sessions, close 
cooperation with one clinic that provides a stable and uniform standard treatment). 
 
Perspectives 
A positive effect of specialized OPUS YOUNG treatment would be of great importance for future 
health-care planning to benefit young people with a first-episode psychosis. At the time being, we 
lack evidence to guide clinical practice for best treatment of this very severe mental disorder at a 
very important time of life. The present alternative is to extrapolate from EIS studies in adults, 
which cannot be considered evidenced based care, due to the specific needs of children and 
adolescents with psychosis. Youth have a right to access evidence-based treatment, which in this 

 
 
43 
case can only be addressed by conducting an RCT of EIS versus TAU. If this model proves to be 
more effective than TAU, it has an enormous potential for improving symptoms, function, recovery 
and adherence to treatment, adherence to school/education and thus to community and independent 
living, while at the same time reducing the need for hospitalization and society costs for this 
vulnerable patient group. Furthermore, we plan to assess follow-up at five years after end of trial. 
 
Project organization and management  
The trial will be carried out in the Capital Region of Denmark and will be co-ordinated by CAMHC 
and in collaboration with the adult mental health services (AMHS). Here, a series of interventional 
trials in different phases of schizophrenia spectrum disorders are already being conducted, ranging 
from high-risk and the early prodromal phase, and the early psychotic phase to later phases with 
specialized interventions for co-morbid substance abuse and neurocognitive deficits.  
The steering committee consists of researchers with massive expertise on early and first-onset 
psychosis and with profound trial experience. Importantly, experienced clinicians are represented in 
the steering committee to ensure a close collaboration between research and clinic throughout the 
process. The study group has extensive international networks on EIS and the treatment of 
psychosis in childhood and adolescence, and the advisory board for the present study will include 
experts on these areas and on transition and complex interventions. 
Principal investigator: Anne Katrine Pagsberg, professor, MD, PhD, senior consultant (child and 
adolescent psychiatry) and senior researcher, CAMHC.  
Co-investigator (until December 2021): Marianne Melau, MSc, PhD, senior researcher CAMHC. 
Steering committee: Anne Katrine Pagsberg, professor, MD, PhD, senior consultant (child and 
adolescent psychiatry) and senior researcher, CAMHC, area of expertise; PI for pharmacological 
and non-pharmacological clinical interventions; Marianne Melau, MSc, PhD, senior researcher 
CAMHC; area of expertise: Early intervention in psychosis (investigator in OPUS), CBCM, MFG, 
program fidelity; Merete Nordentoft, professor, MD, MSc, PhD, senior consultant (Psychiatry) 
AMHS, area of expertise: PI for several large RCT incl. OPUS; Pia Jeppesen, associate professor, 
MD, PhD, senior consultant (child and adolescent psychiatry) and senior researcher (CAMHC) area 
of expertise; PI  of RCT (Mind My Mind trial) and investigator in OPUS, MFG experience. Anne 
Amalie Elgaard Thorup, professor, MD, PhD, senior consultant (child and adolescent psychiatry)  
and senior researcher (CAMHC) area of expertise: RCT in high risk for psychosis, and investigator 
in OPUS; Jens Richardt Jepsen, psychologist, PhD, senior researcher, (AMHS and CAMHS), area 

 
 
44 
of expertise: neurocognition, early onset psychosis; Lene Halling Hastrup, Senior Researcher, 
Health Economist, PhD, Psychiatric Research Unit, Psychiatry Region Zealand, area of expertise: 
health economy. The centre management and clinicians will be represented by Elisabeth Bille 
Brahe, clinical quality manager (CAMHS); Lis Raabæk Olsen, senior consultant (CAMHS), MD, 
PhD; Jacob Rydkjær senior consultant, MD, PhD (CAMHS). 
 
Advisory board: Professor Max Birchwood, MSc psychology, Mental Health and Wellbeing,  
University of Warwick, Coventry, United Kingdoms; Professor of Youth Mental Health Patrick 
McGorry MD PhD, Executive Director, University of Melbourne; Professor of Child and 
adolescent psychiatry, Psychiatry and Molecular Medicine Christoph Correll, Professor of Child 
and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany and The Donald and 
Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, NY, USA; Professor Swaran 
P Singh, Head, Mental Health and Wellbeing Deputy Head, Division of Health Sciences Warwick 
Medical School, University of Warwick. Ditte Lammers Vernal, MSc psychology, PhD, Aalborg 
University Hospital, Denmark.    
  
Management of the project (co-ordinating investigator). The Ph.D.-students involved in the project 
will benefit from being involved with researchers who have worked with clinical and 
epidemiological research in schizophrenia spectrum disorders for many years and from the 
excellent opportunities for international collaboration. All assessments will be carried out by 
researchers and Ph.D.-students, trained in all instruments used in the study before study start.  
 
Sharing of depersonalized data  
We will share the depersonalized data at www.clinicaltrials.gov. 
 
Publications and dissemination policy 
The OPUS YOUNG treatment approach will be manualized. Comprising a manual for CBCM, 
SCIT and MFG as it is delivered in OPUS YOUNG. Furthermore, and inspired by The Raise 
program for Coordinated Specialty Care for First Episode Psychosis in USA [87], we will offer the 
OPUS YOUNG manual online designed to guide implementation of future OPUS YOUNG team 
together with education programs that cover core elements in OPUS YOUNG treatment. 

 
 
45 
Results from the analysis of data in OPUS YOUNG will be published in peer-reviewed 
international scientific journals.  
 
PhD projects 
The OY trial has planned five PhD studies (A-E): 
 
A. The characteristics of the study population and pathways to care, the use of health care, and 
social services prior to study inclusion based on baseline data from all included participants and 
data from the Danish National Registers. (2021-2023) 
 
B. Benefits and harms of OY vs. TAU: Analysis of the primary and secondary/exploratory 
outcomes of the RCT and testing the two main hypotheses, 1) that OY is more effective than TAU 
in improving social functioning, and 2) that OY will be more effective than TAU in reducing 
positive and negative psychosis symptoms and provide a higher client satisfaction and health related 
quality of life. Furthermore, the PhD will analyze self-efficacy, experience of service, treatment 
alliance and adherence, the use of pharmacotherapy, school adherence, family burden, siblings’ 
perceived stress, substance misuse, and adverse treatment effects. This PhD will also analyze the 
sustained effects at 6 months follow-up for OY vs. TAU. (2023-2026) 
 
C. User perspectives on trans-sectorial activities in OY vs. TAU: The primary focus in this PhD is 
to  investigate and describe the trans-sectorial activities (the collaborations of OY/TAU with 
municipal and school services) and analyze whether the amount and quality of trans-sectorial 
activities is an effect moderator for outcomes at 24 months (end of trial) and 30 months (follow-up). 
Drawing on semi-structured interviews at approx. 24 months (end of trial, follow-up), clinical, and 
register data the study includes perspectives from patients, parents/legal caretakers, clinicians, and 
municipal collaborators on trans-sectorial activities and the quality of the collaboration.(2024-2026) 
 
 
D. Clinical and cognitive Illness trajectories in OY vs TAU: To explore the detailed symptomatic 
and diagnostic illness trajectories as well as the cognitive and social cognitive trajectories during 
the first two years of early onset psychosis. Cluster analysis will be used to determine psychosis 
subgroups based on symptom/cognitive deficits heterogeneity and their course. Growth mixture 

 
 
46 
modeling (GMM) analysis will be used to identify distinct treatment response patterns for OY vs. 
TAU. The results will substantiate efforts to individualize future treatments based on patient 
subgroup profiles. Predictors of treatment effects will be evaluated using all available information 
from the examinations during the trial and the Danish National Registers. (2024-2026) 
 
E. Cost-effectiveness of OY vs. TAU: To investigate the cost-effectiveness of OY vs. TAU, in to 
inform decision makers concerning the cost and benefits of the OY intervention. Cost-utility 
analyses (CUA) will be carried out for the trial period. The CUAs will be conducted from an 
extended health sector perspective and include the costs of all interventions directed toward the 
individual youth’s mental health problems no matter the provider of services. Uncertainty about the 
long-term effects limits the possibilities of carrying out formal decision analytic modelling but can 
be handled by analyzing different possible scenarios in extrapolation scenarios of the development 
in health-related quality of life (HRQoL). Costs (of OY and TAU) will be estimated at the 
individual participant level. Youths are assessed for HRQoL using the Child Health Utility 9- 
Dimension (CHU-9D) and EQ-5D. CHU-9D is a generic preference-based HRQoL-measure 
constructed for use in children and youth while EQ-5D is a generic preference-based HRQoL-
measure constructed for use in youth and adults. We will measure the value of health outcomes in 
Quality-Adjusted Life Years (QALY). Health states will be defined using CHU-9D and EQ-5D. We 
will analyze the Incremental Cost-Effectiveness Ratio (ICER). (2024-2026) 
 
The PhD studies will benefit from the international collaboration with highly experienced 
researchers with expertise in clinical and epidemiological research in schizophrenia spectrum 
disorders. 
We will communicate all trial results, both positive, negative as well in-conclusive results, to 
health-care professionals, service users, policy makers and other relevant groups. 
 
 

 
 
47 
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