Work Packages

To facilitate the organisation and management, CoCA is structured into 11 Work packages (WPs) and each of these WPs has a leader, who supervises and adjusts the process flow and works closely with the project office. Varying numbers of parties are further involved in contributing to the WPs.

Please click on the name of the Work Package for a more detailed description:

WP 01 Research: Epidemiology and Socioeconomic Impact

While all of the disorders studied are common, precise estimates of their comorbid prevalence and their socioeconomic impact are needed. In addition, patterns of comorbidity across the lifespan and their stability across generations are not well documented. Nor have gender effects on impact and persistence been described. WP1 will use very large population samples and datasets from German health insurances (n=8,000,000) to study these issues. WP1 will A) determine medical costs and work loss by performing health-economic analyses and document the pattern of costs stratified by comorbidity type and sex, B) investigate patterns of comorbidity across the lifespan, C) describe sex-specific patterns of comorbidity, and D) document multigenerational transmission patterns of comorbidity.

Conclusions of the action:

WP 1 has shown that ADHD frequently co-occurs with anxiety, depression, substance use and abuse, and obesity. This holds throughout the lifespan and among men and women alike, although subtle differences are discernible. In addition, ADHD and comorbidities spread through generations. Medical costs of ADHD are considerable in part through the onset of comorbidities.

Overview of the results and their exploitation and dissemination:

  • WP1 main result 1: ADHD frequently co-occurs with anxiety, depression, substance use and abuse, and obesity
  • WP1 main result 2: ADHD and comorbidities spread from one generation to the next
  • WP1 main result 3: Medical costs of ADHD are considerable in part through the onset of comorbities.

Partners in this workpackage have provided many lectures at National and International conferences, and lay public events. They have written blogs, interviews and webinars in their own language and in English. They have also disseminated the WP1 findings through ADHD Europe (e.g. the ADHD awareness event).

Socio-economic impact and the wider societal implications of the project so far:

We have strongly contributed to the awareness of the impact of ADHD in adulthood, its risk with regard to onset of comorbidities and impairments in daily life. We have not only pointed out the costs, but also the treatment gaps in health care that may reduce costs. Finally, we have raised the awareness that comorbid conditions may in part be prevented. WP1’s  dissemination efforts will be continued given that the content of WP1 is our mainstream area of research.

WP lead: UMCG (Catharina Hartmann)

WP members: GUF-PPP, KI, UT, UiB, AU, HGC

WP 02 Genetic and Environmental Risk Factors for ADHD and its Comorbidities

WP2 will use well-characterized pre-existing samples to identify genetic and environmental risk factors for the overlap of ADHD, mood/anxiety disorders, SUD, and obesity, and to test whether genetic subgroups with potential prognostic implications can be defined. WP2 also uses all publicly available GWAS data to assess polygenic overlap among the disorders – accompanying work in WP1 –, and to test the role of biological pathways defined by the DA and CIRCA mechanisms. Hypothesis-free approaches using polygenic scores and pathway analysis will discover additional pathways. Using machine-learning, WP2 explores causal relationship between DA, CIRCA and ADHD/comorbidities.

Conclusions of the action:

WP2 has contributed to a better understanding of the genetic basis of ADHD and its comorbidities, i.e. disorders or traits that co-occur frequently with ADHD in the same individual. We have shown that there are shared genetic risk factors between ADHD and several psychiatric disorders, like cannabis or cocaine use disorders, alcohol or smoking-related phenotypes, depression, disruptive behavior disorder or autism, but also with personality or cognitive traits, like risk taking, neuroticism, emotional lability, aggressive behaviour or educational attainment, or with somatic conditions, such as obesity. All these results, reported in more than 50 scientific publications, support our initial hypothesis that certain genetic factors cut across psychiatric disorders and explain, at least in part, the comorbidity that we observe between ADHD and many other conditions.

Overview of the results and their exploitation and dissemination

  • WP2 main result 1: Following a candidate-gene approach, we have shown that the dopaminergic system, crucial for the transmission of signals across neurons in the brain, is a biological link between ADHD and obesity, two disorders that co-occur frequently in patients
  • WP2 main result 2: Through a genome-wide study of ADHD and lifetime cannabis use we showed that these conditions share genetic risk factors (genetic correlation of 29%), identifying four specific genomic regions that cut across disorders. We also demonstrated that ADHD genetics is causal for cannabis use
  • WP2 main result 3: A genome-wide study of ADHD and disruptive behaviour disorder revealed that when the two conditions coincide in patients, genetics is more important as a risk contributor than in ADHD alone. This increased genetic load is due in part to risk variants related to aggressive behaviour

These main results have been published already in top scientific journals (all first decile): Mota et al. Neuropsychopharmacology 2020;45:1188; Soler Artigas et al. Mol Psychiatry 2020;25:2493; Demontis et al. Nat Commun. 2021;12:576. They have also been disseminated to the general public through traditional media (press, radio, TV) and via internet blog (https://mind-the-gap.live/) or podcast (https://gotohealthmedia.com/anxiety-depression-substance-use-obesity-adhd-prof-dr-andreas-reif-catharina-hartman-phd-video/). The knowledge generated by this project will serve as a basis for prediction of comorbid conditions that may arise in ADHD patients.

Socio-economic impact and the wider societal implications of the project so far:

Many ADHD patients suffer more from comorbid conditions that arise as a consequence of the primary diagnosis (e.g. substance use disorders or depression) than from ADHD as such. Therefore, having genetic tools that allow to predict (always probabilistically) possible complications along the lifespan can be very useful to take preventive measures or to avoid certain environmental risk factors.

WP lead: UB (Bru Cormand)

WP members: GUF-PPP, RUMC, UMCG,VHIR-BCN, UMR,UT, SUNY

WP 03 Role of Circadian Rhytms in ADHD and its Comorbidities (CIRCA)

This studies the mediating role of the circadian system and sleep in the link between ADHD and its comorbidities. WP3 will use epidemiologic data, which is linked to genotypes to study the mediating role of the circadian system, and will assess the impact of genetic variation therein on brain structural/functional connectivity. WP3 will also study the role of circadian parameters on behavioural, endocrinological, and molecular levels by gene expression studies, hormone measurements and by assessing circadian preference, sleep behaviour and quality using m-Health approaches. WP3 will perform the same non-invasive biorhythm assessments in a sub-set of participants from the clinical trial (WP6) with phenotyping done before and after the intervention to assess suitable biomarkers.

This study will be conducted in Rostock, Germany. To participate please contact the Clinic and Policlinic for Psychiatry and Psychotherapy (UMR).

Conclusions of the action:

The main objectives of WP3 included to assess circadian parameters on a behavioral, endocrinological and molecular level (e.g. actimetry, salivary melatonin/cortisol level analysis, circadian genotype analysis, circadian gene expression analysis) between healthy controls and participants with an ADHD diagnosis as well as between ADHD comorbidities. Statistical significant differences in mid-sleep on work days as well as on free days are shown between HC and ADHD groups, particularly in ADHD comorbidity groups. Statistical significant differences in saliva ghrelin levels between ADHD and ADHD+obesity as well as in cortisol levels in the ADHD+affective group compared to all other groups (HC, ADHD, ADHD+other comorbidities) are observed. Melatonin and cortisol levels in Clock rs1801260, Per3 rs57875989, Cry rs2287161 and CK1 rs135745 genotypes showed statistical significant differences in HC and ADHD groups, particularly in ADHD comorbidity groups.

Overview of the results and their exploitation and dissemination:

  • WP3 main result 1: Statistical significant differences in saliva ghrelin levels between ADHD group without comorbidities and ADHD+obesity group as well as in cortisol levels in the ADHD+affective group compared to all other groups (HC, ADHD, ADHD+other comorbidities).
  • WP3 main result 2: Statistical significant differences in melatonin and cortisol levels in Clock rs1801260, Per3 rs57875989, Cry rs2287161 and CK1 rs135745 genotypes in HC and ADHD groups, particularly in ADHD comorbidity groups.
  • WP3 main result 3: Alterations in circadian gene expression between HC and ADHD groups.

The main results will end up in 3 publications.

Socio-economic impact and the wider societal implications of the project so far:

The immediate benefits of this work will be to establish the link between changes in molecular circadian rhythm and physiological parameters. Using biomarkers will be facilitate diagnosis in adult ADHD, particularly in comorbidities.

WP lead: UMR (Johannes Thome)

WP members: GUF-PPP, UMCG, KI, UB, VHIR-BCN, KCL, UT, AU

WP 04 Dopaminergic Neurotransimission and the Reward System (DA)

WP4 focuses on a multi-level analysis of the dopamine mechanism and will analyse epidemiologic studies to test whether reward processing moderates the outcome of ADHD and comorbid disorders. The interplay between genetic/environmental factors, ADHD diagnosis, comorbidity and the dopamine system is studied together with WP1/2 and experimentally validated in healthy volunteers undergoing pharmacoMRI with dopamine agonists/antagonists. A sub-sample of participants of the clinical trial (PROUD; WP6) is studied with these paradigms to probe whether DA is a useful biomarker to stratify patients regarding their risk for comorbidity and therapy response.

This study will be conducted in Frankfurt am Main / Rhine-Main region, Germany and Nijmegen, Netherlands. To participate please contact the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy (GUF-PPP).

Conclusions of the action:

On a genetic and epidemiological level, risk genes (e.g. dopaminergic gene sets) and ADHD diagnosis predispose patients to suffer from comorbid disorders which have a major impact on patient’s life’s (e.g. depression or substance use disorder). The reward system is a heterogenous entity as exposed via pharmacological neuroimaging, but some markers were identified (functional connectivity of the ventral striatum) which not only distinguish between number of comorbid diagnosis in ADHD but predict therapeutic response in the clinical PROUD trial.

Overview of the results and their exploitation and dissemination:

  • WP4 main result 1: Dopaminergic genes mediate comorbidities in a cross-disorder analysis in ADHD and obesity
  • WP4 main result 2: Dopaminergic modulation affects major hubs of the reward systems measured via fMRI in healthy volunteers
  • WP4 main result 3: Changes in the connectivity between the ventral striatum and the prefrontal cortex mediate therapeutic responsiveness in a clinical study

Socio-economic impact and the wider societal implications of the project so far: 

Not only did we show that the neurotransmitter dopamine affects the reward system but the reward system mediates to some degree ADHD and its subsequent negative trajectory (like comorbid disorders). Dopamine and the reward system are not only targets for drug treatment but psychological and social interventions might alter the reward system too. The neuroimaging markers of the reward system should not only be used to develop new treatments – especially psychological interventions – but to predict therapeutic response. Future studies are needed to implement this on a larger scale.

WP lead: GUF-PPP (Andreas Reif)
WP members: RUMC, UMCG, UB, VHIR-BCN, KCL, UT, SUNY, AU

WP 05 m-Health Approaches for Monitoring and Coaching Chronobiology and Physical Activity in ADHD and Comorbid Conditions

A m-Health monitoring and feedback system to be used in WP6 is developed using modern smartphone-based systems to 1) cost-effectively, objectively, and reliably measure real-life behaviour; 2) analyse behaviour in real-time and provide encouraging feedback to participants to reinforce functional behaviour. All participants in the trial conducted in WP6 will be monitored by a contracted smartphone with this pre-installed app, monitoring physical activity and circadian pattern. In addition, we will assess physical fitness components that are strong predictors of future obesity and mental diseases.

Conclusions of the action: 

In WP 5, we successfully developed, implemented, and tested the feasibility and validity of the mHealth- and feedback-system for monitoring physical activity and chronobiological rhythm in daily life. In addition, we could solve technical and application-specific problems concerning the mHealth-system during the recruitment period with continuous troubleshooting and technical support for the clinical sites.

Overview of the results and their exploitation and dissemination:

  • WP5 main result 1: “Cross-sectional study” on mHealth data: In comparison to patients with ADD and healthy individuals, patients with ADHD profits the most from physical activity in improving their mood.
  • WP5 main result 2: Review on e-diaries in ADHD: Investigating ADHD symptoms and comorbidities using the Ambulatory Assessment method can help to understand underlying mechanisms of ADHD and capture dynamic patterns of behavior that cannot be investigated in physicians’ office, laboratory or clinical settings.
  • WP5 main result 3: Validation study: The various research-grade activity monitors investigated (i.e., Movisens Move 4, ActiGraph GT3X+, GENEActiv, and Axivity AX3) can provide very close estimations of the daily time spent in sedentary time, light, moderate, and vigorous PA, as well as sleep, WASO and sleep efficiency when their raw data are processed in an identical manner.

The main results are/will be published in peer-reviewed journals with open access, blog posts, newsletters and presented in conferences.

Socio-economic impact and the wider societal implications of the project so far:

The basic research we made can help to better understand dynamic processes in ADHD. Our findings and lessons learned are a further step to improve research methods to set up new trials and interventions to improve ADHD symptomatology and comorbidities.

WP lead: KIT (Ulrich Ebner-Priemer)
WP members: GUF-PPP, RUMC, VHIR-BCN, UMR, KCL, UGR

WP 06 Pilot Randomized-Controlled Phase IIa trial on Prevention of Comorbid Depression and Obesity in ADHD (PROUD)

In WP6, the randomized, single-blinded, controlled PROUD study in 14-30 year old adolescents and young adults with ADHD will be performed. The aim of the study is to prevent the development of major comorbid disorders in ADHD, such as depression and obesity, and to improve general health. Two active interventions are compared to guideline based treatment as usual. One intervention is an exercise-based intervention, the other intervention is bright light therapy. Interventions will be supported by an Health App application developed in WP5. All outpatients with ADHD are invited to participate in the trial. Four study centers take part: Barcelona, Frankfurt, London, and Nijmegen.

Conclusions of the action:

The study protocol of our multi-centre, pilot randomized controlled trial was appropriate to assess – in a group of young people with ADHD across Europe – the feasibility of two lifestyle interventions through a smartphone app, i.e. physical exercise and bright light therapy, and their potential efficacy in preventing the development of co-morbid depression and obesity. The findings from this pilot and feasibility study will be used to judge whether future research is warranted to assess efficacy of these lifestyle interventions in young people with ADHD in a larger scale confirmatory randomized controlled phase III trial.

Overview of the results and their exploitation and dissemination:

  • WP6 main result 1: Between March 2017 and March 2020, 207 patients from four clinical sites were enrolled (treatment as usual group, N = 68; exercise intervention group, N = 69; bright light therapy group, N = 70)
  • WP6 main result 2: Recruitment goals (N=51 per group) were reached. 174 patients (treatment as usual group, N = 61; exercise intervention group, N = 54; bright light therapy group, N = 59) were included in the main analysis set (modified intention-to-treat analysis) to assess feasibility of the interventions in young people with ADHD and treatment effects on depression and obesity.
  • WP6 main result 3: Feasibility and effect sizes of the interventions have been analysed according to the statistical analysis plan, and are currently prepared for publication.

We published three blogs with general information about the trials, and three blogs that consisted of interviews with PROUD participants. We created a newsletter for participants in the study that will be sent in four languages (English, German, Dutch and Spanish) by the end of June 2021. This newsletter will summarize the main objectives of the PROUD study and share some ‘fun facts’ about the trial. We have written an article in the ADDIS ADHD magazine about the CoCA study, highlighting the main messages from the project and explaining the PROUD trial. This article will be published in July 2021. We organised a course for clinicians about recognising and treating comorbidities of ADHD across the lifespan that included information about non-pharmacological interventions. This course was taught in April 2021 at the annual meeting of the European Psychiatry Association. Dissemination will continue when results on feasibility and effects sizes are published.

Socio-economic impact and the wider societal implications of the project so far:

Based on the results of the feasibility, phase IIa trial on prevention of depression and obesity in young adults with ADHD, recommendation to clinicians, public health authorities, and patients will be developed. These will be included in national clinical, evidence based guidelines on diagnosis and treatment of ADHD, such as the AWMF-S3-Guidelines on ADHD or the NICE-guidelines, because the study meets the high quality inclusion criteria of these guidelines. This will help to provide cost-effective interventions for ADHD.

WP lead: GUF-CAPPP (Christine Freitag)
WP members: GUF-PPP, RUMC, VHIR-BCN, UMR, KCLUKL-HD KKS, UKL- HD IMBIKIT, UGR

WP 07 Research and Piloting: Classification and Prediction

WP7 will generate predictive biomarkers for disease and response to treatments. WP7 will use methods from machine learning and diagnostic accuracy analysis to predict outcomes in datasets from WP1 & 2 using our candidate mechanisms as starting points. WP7 will then use the resulting classifiers in real life patients from WP3 & 6 as a proof of concept. WP7 will also assess the relevance of these classifiers with respect to the specific mechanisms tested in WP3 & 4. WP7 will assess the degree to which results from other WPs have significant degrees of predictive utility which can be useful for health care planning and allocating scarce resources for prevention and treatment.

Conclusions of the action:

WP7 developed machine learning algorithms that successfully predicted the development of ADHD and comorbidities based on epidemiological, imaging, clinical and genetic data.  The analysis also found predictive roles of the CIRCA/DA systems in ADHD and comorbidities, albeit the it is overall difficult to differentiate subgroups of ADHD with various comorbidities.

Overview of the results and their exploitation and dissemination:

  • WP7 main result 1: In registry data, our machine learning models were able to predict substance use disorder in ADHD youth as early as 2-years old.
  • WP7 main result 2: Using genomic data, we incorporated novel gene set polygenetic risk score (gsPRS) to our machine learning algorithms and improved genetic risk predictions for ADHD and related disorders.
  • WP7 main result 3: In studies of several clinical cohorts, our machine learning prediction results found evidence that supports the CIRCA and dopamine mechanisms in the ADHD pathophysiology.

Results have been published in peer-review journals or in preparation for publications. We have also presented our results in scientific conferences, workshops and online blogs.

Socio-economic impact and the wider societal implications of the project so far:

WP7’s early risk prediction algorithms and methods to predict and understand treatment outcomes using advanced machine learning techniques will help to improve the effectiveness of early prevention strategies and personalized treatment plans, which will help to reduce the socioeconomic burden from both the direct medical costs as well as indirect societal costs associated from underdiagnosis, misdiagnosis and suboptimal management of children and adults with ADHD.

WP lead:  SUNY (Stephen Faraone)
WP members:  GUF-PPP, RUMC, UMCG, UB, VHIR-BCN, AU

WP 08 Novel Treatment targets in ADHD and its comorbid conditions

In WP8 Candidate proteins emerging from WP2 & 7 will be subjected to evaluation as potential novel treatment targets for ADHD and comorbid disorders using chemical libraries. Candidate proteins with known high-resolution 3D structures will be screened in silico with subsequent high-throughput in vitro assays. A major goal of WP8 is to produce new leads to “repurpose” existing treatments for ADHD and its comorbid conditions that also will generate hypotheses for future clinical trials.

Conclusions of the action:

Until now, medications that are used to treat ADHD and its comorbid conditions have been discovered by accident and are probably not targeting the underlying biology. We systematically explored the genetic finding of ADHD and 19 other related conditions and found several new, unexplored drug targets. Using computational and experimental methods we discovered several new drug candidates that modify the brain neurotransmitter levels and potentially can be used in these disorders.

Overview of the results and their exploitation and dissemination:

  • WP8 main result 1: We have developed a framework to assess the druggable genome ADHD and its comorbid conditions.
  • WP8 main result 2: Based on accumulated genetic evidence, access to structural information and experimental systems, we nominated five enzymes and regulatory proteins that were subject to in silico and experimental investigations (gene names: TPH1, TPH2, PTPRF, CSAD and YWHA/14-3-3).
  • WP8 main result 3: We discovered a new chemical class of TPH1 and TPH2 inhibitors. We also found that several clinically approved drugs have potent inhibitory and stimulatory effects against these enzymes and the other target protein. This provides a starting point for re-purposing of existing drugs for new indications, including ADHD and its comorbid conditions.

All findings have been published in peer-reviewed open access scientific journals and presented at international conferences. Several of the findings are being pursued in ongoing and future projects with separate funding. The potential for intellectual property protection and commercialization of the findings is currently being explored.

Socio-economic impact and the wider societal implications of the project so far: 

As drug development for neuropsychiatric disorders, such as ADHD, has been very slow, there is an urgent need for new treatment options. Our research show that we can use genetic data to explore future avenues for treatments in these conditions. This can include re-purposing of existing drug against new target and indications.

WP lead: UiB (Jan Haavik)
WP members: GUF-PPP, RUMC, SUNY

WP 09 Impact and Dissemination

The impact of our program will be substantial in the fields of prevention and health promotion, clinical/social management of disease, and therapy development. The dissemination of CoCA’s work will be tuned to the corresponding stakeholders, i.e. policy makers, academic and commercial parties interested in therapy development, and public and private health care providers. Importantly, as CoCA will emphasize the role of life-style modifications (sleep, exercise) in preventing and treating ADHD-related comorbidity, the general public and patients themselves are among the most important audience to be targeted also using social media and related approaches. Optimal tuning of dissemination to stakeholders for maximal impact will be achieved through a communication plan.

Conclusions of the action:

We have successfully made CoCA and the scientific finding from this project known to the scientific community and general public through our dissemination and education activities. To reach patients our close collaboration with ADHD Europe has proven very fruitful. Next steps for valorisation of intellectual property rights have been explored and initiated where possible.

Overview of the results and their exploitation and dissemination:

  • WP9 main result 1: Blogs and videos / webinars by CoCA partners
  • WP9 main result 2: Infographics summarizing findings from WP1 and WP6
  • WP9 main result 3: Open access publications of multiple scientific findings from the CoCA project

These dissemination products will remain online and thepublications will remain available in open access. The infographic from WP6 will be shared as soon as findings from the PROUD trial can be publicly disseminated. 

Socio-economic impact and the wider societal implications of the project so far:

Through our dissemination and education efforts we have reached a wide variety of stakeholders, including researchers, health care professionals, patients and other members of the general public, across the globe. Our dissemination materials, such a blog posts, videos, scientific publications, and infographics will have a lasting impact as they will remain online.

WP lead: RUMC (Barbara Franke)
WP members: GUF-PPP, UMG, UB, VHIR-BCN, UMR, KCL, UT, KIT, UiB, SUNY, AU, concentris

WP 10 Training and Ethics

Training within CWP10 incorporates three components. First, we will run specialized training courses on project topics; second, we will set up a mentoring programme, which aims to foster the career development of all early career and female researchers. Third, we will provide extensive ongoing training, ensuring standardization of data collection procedures and analyses. Project-wide ethical conduct will be monitored and supported by an internal ethics board. CoCA will comply with all legal regulations and recommendations of the EU, national legislation and local ethics committees.

Conclusions of the action:

We had an overall aim of training a new generation of PhD scientists and clinicians. We successfully achieved this aim and provided a wide range and extensive training program to the young researchers in our consortium. We conclude that training and fostering the skills of early career researchers (ECRs) is a key component of any large-scale project/consortium. We have learned that training must be relevant and fluid such that ECRs themselves decide the topics. Training should incorporate both academic and other skills. Collaborations within ECRs should be goal orientated, with a clear focus.

Overview of the results and their exploitation and dissemination:

Learnings from running this training work package and reflections on dissemination efforts are summarised in the following article:
We also produced 7 masterclasses and 11 webinars, the webinars can be found on the CoCA YouTube channel (link below).

Socio-economic impact and the wider societal implications of the project so far:

It is essential that young scientists are trained appropriately so that science they conduct in the future has the maximum impact on society. Hence, in CoCA, young scientists learned about effective dissemination, diversity and inclusion, neurodiversity as well as knowledge of neuroscience, genetics, ADHD and scientific topics directly related to ADHD and its comorbidities. These trainings will foster very important skills for young scientists. Additionally, webinars, some of which convey key scientific learnings from the CoCA project are available to the public via this link: https://www.youtube.com/channel/UCvu_75EM6tgWAMCGRKIP0Yw

WP lead: KCL ( Jonna Kuntsi)
WP members: GUF-PPP, RUMC

WP 11 Project Management

The management WP is by led by the coordinator – who is experienced in conducting EU projects – together with concentris, a SME with longstanding, hands-on expertise in the management of EU Framework projects (e.g. Aggressotype, MATRICS, IMAGEMEND, PRISM). Together they take care of the management of contractual, financial, legal, administrative and scientific issues. They ensure the proper functioning of the project in order to achieve the objectives, to complete the Milestones and Deiverables in time and make sure that the consortium’s contractual duties are carried out. In addition, it establishes a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project.

WP lead: GUF-PPP (Andreas Reif)
WP members: concentris

Gain insight into the mechanisms underlying this comorbidity triad with its huge burden for healthcare, economy, and society