Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CoCA (Comorbid Conditions of Attention deficit / hyperactivity disorder)

Teaser

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, affecting approx. more than 5% of all children. While 15% of affected cases continue into adulthood, another 50% suffer from subthreshold yet impairing symptoms, going along with...

Summary

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, affecting approx. more than 5% of all children. While 15% of affected cases continue into adulthood, another 50% suffer from subthreshold yet impairing symptoms, going along with decreased quality of life and underachievement. Most importantly, both in childhood as well as (and even more so) in adulthood, ADHD goes along with a considerable rate of comorbid disorders such as substance abuse (SUD), mood and anxiety disorders, and obesity, which have far-reaching consequences in terms of somatic and mental health morbidity. ADHD can thus be conceptualized as an entry point into a negative developmental trajectory. The high rate of comorbidity points towards joint disease mechanisms, but also opens a window of opportunity for prevention and early intervention. Improved understanding of pathophysiological mechanisms leading to ADHD with comorbid disorders therefore will greatly empower prevention and therapy. Given the high prevalence of the disorders studied, this has huge potential for improving public health throughout Europe. Our overarching goal is thus to deliver new knowledge and tools to prevent adolescent and young adult ADHD from escalating into detrimental comorbidities with mood and anxiety disorders, SUD, and obesity.

Work performed

To further establish the comorbidity between ADHD and the other disorders mentioned, large register-based databases are instrumental. Our project partners are in the privileged position that we can access population-based registers from Sweden, Norway, Demark, Estonia and The Netherlands. Also, we were granted access to a large dataset (>4 million insured persons) from a German healthcare insurance. During the first phase of the project, we arranged the framework to work on all datasets and obtained the respective regulatory approvals, so that all data could be prepared for further analyses. Initial results addressed gender aspects of comorbidity rates from three countries; also, we could address the cost of comorbidity in the German data showing that comorbidity significantly increases cost of disease. Also, the lifetime change of comorbidity patterns could be assessed. As it becomes apparent from family-based data, that ADHD and the mentioned comorbidities are co-inherited, a shared genetic basis seems conceivable. The underlying genetic basis can be addressed e.g. by genome-wide association studies (GWAS). Therefore, we requested (and were granted) access to all pertinent GWAS data available worldwide. A first cross disorder analysis showed that bipolar disorder and ADHD are highly significantly correlated on the genetic level; the same holds true for major depression. Further analyses addressing SUDs and obesity are under way, and gene by environment interaction studies are conducted in a candidate-driven approach. As we aim to target specific mechanisms by our clinical studies and our human experimental studies, namely, the circadian rhythm regulation and dopaminergic neurotransmission, we also defined gene sets, which are used as potential markers in all human experiments.

In these mechanism-based studies we have implemented two experimental approaches. First, the measurement of the human circadian system by actimetry and parallel hormone measurements; second, functional MRI neuroimaging also using a pharmacological challenge with both a dopamine agonist and antagonist. Protocols for all studies were established and approved and all sub-studies are actively recruiting and are under way. Blinding, however, does not permit to conduct any interim analysis other than those scheduled for safety reasons, so that the outcome of these experiments can only be assessed after completion of the studies.

A major part of our project is to test whether an easy-to-implement, non-pharmacological intervention that targets our proposed mechanisms can decrease the burden of comorbid symptoms. These interventions are Bright Light Therapy and Exercise. To this end we have manualized respective interventions and in parallel, we have set up a smartphone based monitoring and training system. This highly innovative approach (see Figure 1 for a screenshot) is meant to increase adherence to the study protocol and also to objectively assess a number of secondary outcomes; setting up and evaluating this system was therefore a major deliverable for the first reporting period. This could be successfully achieved, so that the clinical trial (for the study workflow, see Figure 2) could be initiated as planned in Frankfurt, London, and Barcelona; these sites are already actively recruiting patients in the study, while Nijmegen will follow soon after ethical clearance has been finally granted.

In parallel, we made substantial effort to disseminate our main concepts, ideas and data to the public along with respective recommendations for patients, professionals and policymakers. This resulted in both professional contributions to conferences and scientific journals, but also in a number of outlets aimed at the general public such as newspapers and social media. Our project has already gained wide visibility on all levels.

Final results

Using the largest available databases worldwide, our project will provide definite answers regarding the epidemiological comorbidity rates of ADHD with other mental and somatic disorders, as well as the role of gender and lifespan therein. By employing hypothesis-free approaches, we will uncover the genetic basis of these comorbidities. These genetic data will allow defining hitherto unknown disease mechanisms that can be used to refine diagnosis, but which can also potentially be used to define novel treatment avenues. As we are exploring and targeting two already hypothesized disease mechanisms by easy-to-implement non-pharmacological treatments, we strive to identify ecological means to reduce the suffering form comorbid diseases. A novel and innovative mHealth system using regular smartphones has been developed to implement these treatments, which could be easily scaled up if demonstrated to be efficacious.

As ADHD and comorbid conditions cause substantial burden of disease and are major cost drivers in society (which is also assessed in our project) our results will impact highly on mental healthcare and associated cost. As ca. 3% of the adult population suffer from adult ADHD, and as >50% of those patients are affected by a comorbid condition, a sizeable part of the population is a potential target for prevention and early interventions. As ADHD and its comorbidity lead to substantial impairment and as these patients often suffer from underachievement, our research will increase the quality of life of those patients and in parallel reduce long-term socioeconomic burden. As we also engage in societal outreach in order to educate lay audiences as well as professional healthcare providers, we also strive to reduce stigma and to raise awareness for this patient group: often ADHD is not considered in patients displaying by comorbid disorders, resulting in suboptimal treatment strategies, and transitional life stages are not adequately targeted thus missing a window of opportunity for preventive approaches. Especially our dissemination activities, but also our biomarker studies aim to overcome these shortcomings with overall improved early diagnosis and intervention.

Website & more info

More info: https://coca-project.eu/.