Youth-GEMS: Understanding genetic and environmental interactions in youth mental health

ISRCTN	ISRCTN17131459
DOI	https://doi.org/10.1186/ISRCTN17131459
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	101057182
Sponsors	Hospital General Universitario Gregorio Marañón, University of Edinburgh, University of Split, Clinic for Neurology and Psychiatry for Children and Youth, Maastricht University, Tartu Ulikool
Funder	HORIZON EUROPE European Research Council: HORIZON-HLTH-2021-STAYHLTH-01 Grant Agreement number: 101057182

Submission date: 21/12/2023
Registration date: 30/01/2024
Last edited: 04/02/2026

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Mental and Behavioural Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
The first symptoms of mental illness usually begin during youth, the developmental stage between 12 and 24 years of age. The first manifestations of mental illness are often subtle and do not meet diagnostic criteria for specific diagnoses. This period is critical because early detection and treatment can maximize recovery and may even prevent the progression of illness. However, there is not enough knowledge about how early symptoms may predict later mental health, which poses difficulties in deciding treatment plans and assessing risk. The Youth-GEMs project aims to bridge this gap by studying young people who are in the first stages of mental illness during two years, with the objective of developing a model that will allow predicting the individual's risk and aid in prevention and treatment.

Who can participate?
People between 12 and 24 years of age who are attending specialised mental-health services for the first time.

What does the study involve?
Participants will fill in a questionnaire about their health, life experiences, symptoms and coping mechanisms every 3 months for 2 years. At baseline, they will also undergo a clinical interview with a mental health professional, a test on attention and memory (among other cognitive functions), and will give a blood or saliva sample.

What are the possible benefits and risks of participating?
This study is not testing any intervention or drug, therefore we do not expect any benefit of participating other than the experience of helping advance scientific knowledge. The risks are considered minimal. A common risk of blood extractions is a small bruise in the place where blood was taken, but it often resolves spontaneously in a few days. Another risk is a possible data breach. However, all scientists involved in this study have received training in data protection and are using the safest servers to store data to minimize this risk.

Where is the study run from?
The study is run from six sites in Europe: Madrid (Spain), Maastricht (The Netherlands), Oulu (Finland), Belgrade (Serbia), Split (Croatia) and Tartu (Estonia). All the sites will be coordinated from the leaders from Hospital General Universitario Gregorio Marañón (Spain) and Oulu University (Finland).

When is the study starting and how long is it expected to run for?
June 2021 to December 2026

Who is funding the study?
The European Union (EU)

Who is the main contact?
Dr Covadonga Martínez Díaz-Caneja, covadonga.martinez@iisgm.com

Contact information

Dr Covadonga Martínez-Díaz Caneja
Scientific, Principal investigator

Instituto de Psiquiatría y Salud Mental
Hospital General Universitario Gregorio Marañón
C. de Ibiza, 43
Madrid
28009
Spain

Phone	+34 (0)915 86 80 00
Email	covadonga.martinez@iisgm.com

Prof Ian Kelleher
Scientific, Principal investigator

Centre for Clinical Brain Sciences (CCBS)
University of Edinburgh
Kennedy Tower
Royal Edinburgh Hospital
Edinburgh
EH10 5HF
United Kingdom

ORCID ID	0000-0003-1484-651X
Phone	+44 (0)131 465 9585
Email	ian.kelleher@ed.ac.uk

Mr Renzo Abregú-Crespo
Public, Scientific

Instituto de Psiquiatría y Salud Mental
Hospital General Universitario Gregorio Marañón
C. de Ibiza, 43
Madrid
28009
Spain

ORCID ID	0000-0001-5325-0992
Phone	+34 (0)914265095
Email	renzo.abregu@iisgm.com

Study information

Primary study design	Observational
Study design	Multicenter non-interventional observational study
Secondary study design	Cohort study
Study type	Participant information sheet
Scientific title	Gene-Environment interactions in Mental health trajectories of Youth (Youth-GEMs Cohort)
Study acronym	Youth-GEMs-Cohort
Study objectives	1. The researchers will be able to characterise multidimensional latent risk and resilience mental health trajectories in a trans-syndromal sample of help-seeking young people. 2. The quality of life trajectories will have genetic, environmental, biological, clinical, cognitive and digital predictors. 3. The researchers will be able to cross-validate clinical and digital predictors in help-seeking youth.
Ethics approval(s)	1. Approved 07/02/2024, Comité de Ética de la Investigación con Medicamentos (CEIm) Hospital General Universitario Gregorio Marañón / Ethics Committee in Research with Drugs Gregorio Marañón Hospital (C/ Dr. Esquerdo 46, Pabellón de Gobierno, Madrid, 28007, Spain; +34 (0)91 586 7007 - 91 426 9378; ceim.hgugm@salud.madrid.org), ref: 313/23 2. Approved 14/03/2024, Klinika za neurologiju i psihijatriju za decu i omladinu (Ethics Committee of the Clinic for Child and Adolescent Neurology and Psychiatry in Belgrade) (Dr Subotića starijeg 6, Belgrade, 11000, Serbia; +381 11 2658 355; ana.kesic.npk@gmail.com), ref: 193/3 3. Approved 29/04/2024, Etičko povjerenstvo Medicinskog fakulteta Sveučilišta u Splitu (Ethics Committee of the Faculty of Medicine, University of Split) (Šoltanska ul. 2A, Split, 21000, Croatia; +385 (0)21 557 929; uzz@mefst.hr), ref: 2181-198-03-04-24-0048 4. Approved 14/01/2025, University of Tartu Research Ethics Committee (Raekoja plats 9, Tartu, 51004, Estonia; +372 (0)737 6215; eetikakomitee@ut.ee), ref: 394/T-32 5. Approved 09/12/2024, Regional Medical Research Ethics Committee of the North Ostrobothnia Welfare Region (c/o OYS Tutkimuspalveluyksikkö N5, Research Service Unit N5 PO Box 10, OYS, 90029, Finland; +358 (0)50 448 4955; tutkimuspalvelut@pohde.fi), ref: OTE 11/2024 6. Approved 24/01/2025, Medisch-ethische toetsingscommissie (Medical Ethics Review Committee) (P. Debyelaan 25, Postbus 5800, Maastricht, 6202 AZ, Netherlands; +31 (0)43 387 6009; secretariaat.metc@mumc.nl), ref: METC 24-018
Health condition(s) or problem(s) studied	Non-chronic emerging mental health symptoms
Intervention	Current methodology as of 04/02/2026: Participants will be referred to the study by experienced mental health professionals. If they agree to participate, research staff will cite them in-site for informed consent procedures and baseline visit. During the baseline visit, participants will undergo a blood extraction, clinical interview and neurocognitive assessment with a trained psychologist or psychiatrist of the study. They will also download the app under their guidance and have the opportunity to ask questions. Finally, they will be asked to complete a self-report questionnaire in REDCAP. The follow-up visits will be conducted remotely through the REDCAP survey, although all participants will be able to contact their site project coordinator to ask questions, request a telephone call to guide them through the questionnaire or troubleshoot REDCAP issues. If participants prefer, follow-up visits will be conducted in person at the center. Participation will end after the 24-month follow-up assessment. Previous methodology: Participants will be referred to the study by experienced clinicians. If they agree to participate, research staff will cite them in-site for informed consent procedures and baseline visit. During the baseline visit, participants will undergo a blood extraction, clinical interview and neurocognitive assessment with a trained psychologist or psychiatrist of the study. They will also download the app under their guidance and have the opportunity to ask questions. Finally, they will be asked to complete a self-report questionnaire in REDCAP. The follow-up visits will be conducted remotely through the REDCAP survey, although all participants will be able to contact their site project coordinator to ask questions, request a telephone call to guide them through the questionnaire or troubleshoot REDCAP issues. Participation will end after the 24-month follow-up assessment.
Intervention type	Genetic
Primary outcome measure(s)	Quality of life, with general wellbeing, daily functioning, relationships with friends, relationships with family and coping as subdomains, measured with the MyLifeTracker outcome measure at baseline, 3, 6, 12, 18 and 24 months follow-up
Key secondary outcome measure(s)	Current secondary outcomes as of 04/02/2026: Clinical dimensions: 1. Anxiety and depression measured with the RCADS at baseline, and 3, 6, 12, 18 and 24 months follow-up 2. Distress tolerance measured with the DTS-short at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Current mania measured with the Altman Self-rating Mania Scale (ASRM) and Rapid Mood Screener (RMS) at baseline, and 3, 6, 12, 18 and 24 months follow-up 4. Psychotic-like symptoms measured with the Psychosis Experiences Inventory (PEI) at baseline, and 3, 6, 12, 18 and 24 months follow-up 5. Dissociative symptoms measured with the Dissociative Experiences Scale (DES) at baseline, and 6, 12, and 24 months follow-up 6. Suicidality measured with the Columbia Suicide Severity Rating scaleat baseline, and 24 months follow-up 7. Non-suicidal self-harm measured at baseline, and 24 months follow-up 8. General psychopathology measured with the Strengths and Difficulties Questionnaire (SDQ) at baseline, and 3, 6, 12, 18 and 24 months follow-up 9. Eating disorders measured with the Eating Disorder Screen for Primary Care at baseline, 12, and 24 months follow-up 10. Obsessions and intrusive thoughts measured with the Children’s Obsessional Compulsive Inventory Revised (ChOCI-R) at baseline, and 3, 6, 12, 18 and 24 months follow-up 11. Stressful life events measured with an ad-hoc questionnaire at baseline, 12, and 24 months follow-up 12. Childhood Trauma measured with the Childhood Trauma Questionnaire - Short version, Juvenile Victimization Questionnaire (JVQ), and Childhood Experience of Care and Abuse (CECA) at baseline 13. Bullying and cyberbullying measured with an ad-hoc questionnaire at baseline. 14. PTSD symptoms measured with the UCLA PTSD Reaction Index for DSM-5 Brief form at baseline. 15. Family and social environment measured with an ad-hoc questionnaire at baseline and 12 and 24-month follow-up. 16. Parental bonding measured with the Relationship Structures (ECR-RS) questionnaire and peer bonding measured with the Community and Youth Collaborative Institute (CAYCI) at baseline and 12 and 24-month follow-up. 17. Alcohol use and abuse measured with the AUDIT at baseline, and 3, 6, 12, 18 and 24 months follow-up 18. Drug use and abuse measured with the DUDIT at baseline, and 3, 6, 12, 18 and 24 months follow-up 19. Loneliness emotion with the Loneliness 3 item scale at baseline, 12 and 24 months follow-up. 20. Emotions and affect with Positive and Negative Affect Schedule (PANAS) at baseline, 3, 6, 12, 18 and 24 months follow-up. 21. Clinical impression measured with the Clinical Global Impressions Scale (CGI) at baseline, and 3, 6, 12, 18 and 24 months follow-up 22. Social and ocuppational measured with the Social and Occupational Functioning Assessment Scale (SOFAS) at baseline, and 3, 6, 12, 18 and 24 months follow-up 23. Mental health symptoms measured with DSM-5 Dimensional Cross-Cutting Symptom Assessment (DSM5-CC) at baseline, and 6, 12, 18 and 24 months. 24. Premorbid Adjustment measured with the Premorbid Adjustment Scale (PAS) at baseline. 25. Pregnancy and early development measured with the APGAR measure and ad hoc questions at baseline 26. Obstetric complications measured with the Scale of Obstetric Complications by Lewis at baseline 27. Development milestones with ad hoc questions at baseline Lifestyle and behavioural factors: 1. Internet and social media use measured with the Social Media Disorder Scale (SMDS-9) at baseline, and 3, 6, 12, 18 and 24 months follow-up 2. History of crime and violent behaviour measured with an ad hoc questionnaire at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Reward response measured with Behavioral Inhibition and Behavioral Activation System (BIS/BAS) Scales at baseline, and 3, 6, 12 and 24 months follow-up Physical health: 1. General health measured with the EQ-5D-Y at baseline, and 3, 6, 12, 18 and 24 months follow up 2. Disability measured using 12-item Self-Report World Health Organization Disability Assessment Schedule (WHODAS) at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Sleep and circadian alterations measured with the REACH study at baseline, and 3, 6, 12, 18 and 24 months follow-up 4. Physical activity measured with the REACH study at baseline, and 3, 6, 12, 18 and 24 months follow-up 5. Menstrual cycle measured with the Menstrual Distress Questionnaire (MDQ) at baseline, and 3, 6, 12, 18 and 24 months follow-up Psychological mechanisms, subjective experience and existential dimensions: 1. Coping mechanisms measured with Coping Orientation to Problems Experienced Inventory (Brief-COPE) at baseline, and 3, 6, 12, 18 and 24 months follow-up. 2. Resilience measured with the Brief Resilient Coping Scale (BRCS) at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Self-esteem measured with the Multidimensional Wellbeing in Youth Scale – self-confidence dimension at baseline, and 3, 6, 12, 18 and 24 months follow-up 4. Well-being measured with the EPOCH measure of adolescent well-being at baseline, and 3, 6, 12, 18 and 24 months follow up 5. Callous/unemotional traits measured with the Inventory of Callous-Unemotional Traits and Antisocial Behavior (INCA) for Young People at baseline, and 3, 6, 12, 18 and 24 months follow-up 6. Reward responsiveness measured with the BAS Reward Responsiveness & Frustrative Nonreward Responsiveness Subscale at baseline, and 3, 6, 12, 18 and 24 months follow-up 7. Irritability measured with the Affective Reactivity Index (ARI) at baseline, and 3, 6, 12, 18 and 24 months follow-up 8. Reflective functioning measured with the Reflective Functioning Questionnaire (RFQ) at baseline, and 3, 6, 12, 18 and 24 months follow-up. Neurocognitive functioning 1. Estimated IQ, assessed using the Wechsler Intelligence Scales (WAIS and WISC) at baseline. 2. Sustained attention, cognitive flexibility, working memory, visual memory, sensorimotor ability, and motor speed, assessed using an ad hoc neuropsychological battery at baseline. Previous secondary outcomes: Clinical dimensions: 1. Anxiety and depression measured with the RCADS at baseline, and 3, 6, 12, 18 and 24 months follow-up 2. Distress tolerance measured with the DTS-short at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Current mania measured with the Altman Self-rating Mania Scale at baseline, and 3, 6, 12, 18 and 24 months follow-up 4. Psychotic-like symptoms measured with the Prodromal Questionnaire (PQ-16) and the PEI at baseline, and 3, 6, 12, 18 and 24 months follow-up 5. Dissociative symptoms measured with the DES-B at baseline, and 3, 6, 12, 18 and 24 months follow-up 6. Suicidality measured with the Columbia Suicide Severity Rating scaleat baseline, and 3, 6, 12, 18 and 24 months follow-up 7. Non-suicidal self-harm measured at baseline, and 3, 6, 12, 18 and 24 months follow-up 8. General psychopathology measured with the Strenghts and Difficulties Questionnaire (SDQ) at baseline, and 3, 6, 12, 18 and 24 months follow-up 9. Eating disorders measured with the Eating Disorder Screen for Primary Care at baseline, and 3, 6, 12, 18 and 24 months follow-up 10. Obsessions and intrusive thoughts measured with the Obsessional Compulsive Inventory - Child self report at baseline, and 3, 6, 12, 18 and 24 months follow-up 11. Childhood Trauma measured with the Childhood Trauma Questionnaire - brief at baseline 12. Stressful life events measured with an ad-hoc questionnaire at baseline, and 3, 6, 12, 18 and 24 months follow-up 1. Bullying and cyberbullying measured with an ad-hoc questionnaire at baseline and 3, 6, 9 and 12 months follow-up 2. PTSD symptoms measured with the UCLA PTSD Reaction Index for DSM-5 Brief form at baseline and 12 months follow-up 3. Family and social environment measured with an ad-hoc questionnaire at baseline 4. Parental bonding measured with the Relationship Structures (ECR-RS) questionnaire and peer bonding measured with the Attachment Questionnaire for Children (AQC) at baseline and 12 and 24-month follow-up. 5. Alcohol use and abuse measured with the AUDIT at baseline, and 3, 6, 12, 18 and 24 months follow-up 6. Drug use and abuse measured with the DUDIT at baseline, and 3, 6, 12, 18 and 24 months follow-up Lifestyle and behavioural factors: 1. Internet and social media use measured with the Social Media Disorder Scale at baseline, and 3, 6, 12, 18 and 24 months follow-up 2. Gaming disorder measured with the Nine-Item Internet Gaming Disorder Scale at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. History of crime and violent behaviour measured with an ad hoc questionnaire at baseline, and 3, 6, 12, 18 and 24 months follow-up Physical health: 1. General health measured with the EQ-5D-Y at baseline, and 3, 6, 12, 18 and 24 months follow up 2. Disability measured using 12-item Self-Report World Health Organization Disability Assessment Schedule (WHODAS) at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Sleep and circadian alterations measured with the PROMIS Sleep Disturbance and Sleep-Related Impairment in Adolescents at baseline, and 3, 6, 12, 18 and 24 months follow-up Psychological mechanisms, subjective experience and existential dimensions: 1. Coping mechanisms measured with the Brief COPE at baseline, and 3, 6, 12, 18 and 24 months follow-up 2. Resilience measured with the Brief Resilient Coping Scale at baseline, and 3, 6, 12, 18 and 24 months follow-up 3. Self-esteem measured with the Multidimensional Wellbeing in Youth Scale – self-confidence dimension at baseline, and 3, 6, 12, 18 and 24 months follow-up 4. Well-being measured with the EPOCH measure of adolescent well-being at baseline, and 3, 6, 12, 18 and 24 months follow up 5. Callous/unemotional traits measured with the INventory of Callous-Unemotional Traits and Antisocial Behavior (INCA) for Young People at baseline, and 3, 6, 12, 18 and 24 months follow-up 6. Reward responsiveness measured with the BAS Reward Responsiveness & Frustrative Nonreward Responsiveness Subscale at baseline, and 3, 6, 12, 18 and 24 months follow-up 7. Irritability measured with the Affective Reactivity Index at baseline, and 3, 6, 12, 18 and 24 months follow-up
Completion date	31/12/2026

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	12 Years
Upper age limit	24 Years
Sex	All
Target sample size at registration	1000
Key inclusion criteria	Current inclusion criteria as of 04/02/2026: 1. Age between 12-24 years 2. New appointment with a mental health service within the past 2 months 3. Good command of the languages used in the study, as most of the clinical assessment will be based on self-reported questionnaires 4. Written informed consent by the participant, their parents if minors, or legal representatives if appropriate Previous inclusion criteria: 1. Aged 12-24 years 2. Less than 1 month from the first contact with mental health services 3. Good command of the languages used in the study 4. Written informed consent by the participant and their parents and legal representatives, when appropriate
Key exclusion criteria	Current exclusion criteria as of 04/02/2026: 1. Previous contact with a mental health service at the same level of care (primary, secondary, tertiary, quaternary) within the past 12 months 2. Intellectual disability with associated functional impairment 3. Severe neurological or medical condition 4. Genetically confirmed neurobehavioral syndromes 5. Significant difficulties in completing the self-reported questionnaires Previous exclusion criteria: 1. Intellectual disability with associated functional impairment 2. Severe neurological or medical condition 3. Genetically confirmed neurobehavioral syndromes 4. Significant difficulties in completing the self-reported questionnaires
Date of first enrolment	02/03/2024
Date of final enrolment	31/12/2026

Locations

Countries of recruitment

Croatia
Estonia
Finland
Netherlands
Serbia
Spain

Study participating centres

Fundacion para la Investigacion Biomedica del Hospital Gregorio Maranon

Doctor Esquerdo 46
Madrid
28007
Spain

Sveuciliste U Splitu Medicinski Fakultet

Šoltanska 2
Split
21000
Croatia

Clinic for Neurology and Psychiatry for Children and Youth

dr Subotića starijeg 6
Belgrade
112112
Serbia

Tartu Ulikool

Ravila 14a
Tartu
50411
Estonia

Universiteit Maastricht

Minderbroedersberg 4
Maastricht
6200 MD
Netherlands

University of Oulu

Pentti Kaiteran katu 1
Linnanmaa
Oulu
PO Box 8000
Finland

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon request from Dr Covadonga Martínez (covadonga.martinez@iisgm.com)

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

04/02/2026: The following changes were made to the study record:
1. The ethics approval, methodology, secondary outcomes, inclusion/exclusion criteria and contact details were updated.
2. The date of final enrolment was changed from 02/01/2026 to 31/12/2026.
3. The completion date was changed from 02/01/2026 to 31/12/2026.
12/02/2024: The recruitment start date was changed from 01/03/2024 to 02/03/2024.
09/02/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 02/01/2024 to 01/03/2024.
2. Trial's existence confirmed by Comité de Ética de la Investigación con Medicamentos (CEIm) Hospital General Universitario Gregorio Marañón / Ethics Committee in Research with Drugs Gregorio Marañón Hospital.
07/02/2024: The ethics approval was added.