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Comorbid Conditions of Attention deficit / hyperactivity disorder

Periodic Reporting for period 3 - CoCA (Comorbid Conditions of Attention deficit / hyperactivity disorder)

Reporting period: 2019-01-01 to 2020-06-30

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, affecting more than 5% of all children. While 15% of the affected cases develop the full syndrome in adulthood, another 50% suffer from subthreshold, yet impairing symptoms, along with decreased quality of life and underachievement. Most importantly, both in childhood and adulthood, ADHD is accompanied by 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 poor somatic and mental health, impaired social and occupational functioning as well as quality of life. ADHD can thus be conceptualized as an entry point into a negative developmental trajectory. The high rate of comorbidity points towards common disease mechanisms, but also opens a window of opportunity for prevention and early intervention. Therefore, enhanced understanding of pathophysiological mechanisms leading to ADHD with comorbid disorders will greatly empower prevention and therapy. 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.
To establish the comorbidity between ADHD and other disorders and their relation to age and gender, large register-based databases are instrumental. The CoCA partners are in the privileged position to have access to population-based registers from Sweden, Norway, Denmark, Estonia, The Netherlands, and a large dataset from a German healthcare insurance. Using these large datasets from almost 20 million people, we charted and quantified the high rate of ADHD comorbidity with mood disorders, substance use, obesity and other mental disorders across the lifespan and in relation to gender. Also, the cost of comorbidity was estimated and shown to be huge. Data are converging to similar numbers in the different countries, and are summarized in a scholarly review which we currently prepare.
Interestingly, family-based data shows that ADHD and its comorbidities are co-inherited, pointing to a shared genetic basis. By examining the largest samples world-wide, we confirmed this hypothesis and quantified the shared heritability between these disorders. In terms of gender differences, we found that female individuals with ADHD are at an increased risk for certain comorbid conditions (e.g. ASD).
GWAS studies can further help to uncover disease mechanisms. In one of the largest GWAS summary statistics, we found a link between dopaminergic gene sets with obesity and ADHD, pointing to an important shared aetiology in the ADHD/obesity comorbidity, as hypothesized in our proposal. We also investigated the contribution of dopaminergic versus serotonergic gene sets to ADHD and comorbid disorders, showing more associations of the dopaminergic than the serotonergic gene set. Thus, several of our genetic studies suggest a convergence of genetic and neurobiological pathways for ADHD and comorbidities.
To further elucidate the mechanisms underlying comorbidity, we implemented two experimental approaches in healthy individuals and ADHD patients with comorbid disorders; First, the measuring the human circadian system by actimetry and parallel hormone measurements; Second, functional neuroimaging (fMRI) using a pharmacological challenge (dopamine agonist and antagonist). Analyses of our pharmaco-fMRI study in healthy participants shows that brain connectivity and activation are indeed changed by modifications of the dopaminergic system. Further, we have completed the recruitment of ADHD patients suffering from various comorbid disorders for our pharmaco-fMRI study; The data is currently being analysed. The same holds true for the circadian study, where recruitment has almost been finished.
A major part of our project is to test whether an easy-to-implement, non-pharmacological intervention can decrease the burden of comorbid symptoms. These interventions are Bright Light Therapy and Exercise, thus targeting our proposed mechanisms. The recruitment for the clinical study has been completed and the last patients are now completing the last time points of the study. The study protocol was published in an open access journal (Mayer et al., 2018), and results are expected soon after unblinding.
In parallel, we continued to make substantial effort to disseminate our main concepts, ideas and data to the public including recommendations for patients, professionals and policymakers. This resulted in multiple contributions to scientific conferences and journals, but also in a number of outlets aimed at the general public such as newspapers and social media. Especially our social media strategy was further implemented, and we ensured to outreach to patients by organising patient in events.
Using the largest available epidemiological and genetic databases worldwide, our project provides definite answers regarding the comorbidity rates of ADHD with other mental and somatic disorders, including the role of gender and lifespan therein. By employing hypothesis-free approaches, we can uncover and quantify the genetic basis of these comorbidities. Our consortium has already published several high-impact studies on these data, which will allow us to define hitherto unknown disease mechanisms that can be used to refine diagnosis; With our hypothesis-driven approach, we recently demonstrated a role for dopaminergic genes in ADHD, while circadian system genes do not seem to play a role. Such studies have the potential to lead the way to novel treatment avenues. As we are exploring and targeting two previously hypothesized disease mechanisms by easy-to-implement non-pharmacological treatments in a randomized clinical trial, we strive to identify ecological means to reduce the suffering from 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 proven efficacious. The system demonstrated feasibility and acceptance and we are eagerly awaiting the outcome of the clinical study.
As ADHD and comorbid conditions cause substantial burden of disease and are major cost drivers in society (which has been also assessed in our project and put together in a fact sheet), our results will impact highly on mental healthcare practice. As an approximate 3% of the adult population suffer from adult ADHD, with >50% of those patients being affected by a comorbid condition, a sizeable part of the population represents a potential target for prevention and early interventions, which should be underscored in the respective clinical guidelines. Because ADHD and its comorbidities 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. By engaging in societal outreach activities aimed at educating lay and professional healthcare providers, we strive to reduce stigma and raise awareness for this patient group: This is of great importance, because ADHD is frequently overlooked as a diagnosis in patients who display a comorbid condition, resulting in suboptimal treatment strategies. In addition, transitional life stages are not adequately targeted, thus missing a window of opportunity for preventive approaches.
Figure_1_mHealth-System
Figure_2_Study-Workflow