Periodic Reporting for period 4 - CoCA (Comorbid Conditions of Attention deficit / hyperactivity disorder)
Periodo di rendicontazione: 2020-07-01 al 2021-06-30
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, affecting 2-3% of all adults and leading to many consequences, e.g. poor physical and mental health. Using data sets of about 20 Mio. individuals, we found a substantial co-occurrence (i.e. comorbidity) of ADHD with anxiety, depression, substance use and abuse, and obesity, throughout the lifespan and across generations. We identified shared genetic risk factors for ADHD and its comorbidities, especially genes that have a role for the dopamine system, suggesting that genetic factors cut across psychiatric disorders. Strikingly, our machine learning algorithms predicted comorbidities from clinical data and also showed predictive roles of the dopaminergic and circadian systems. In addition, variables of the dopamine-based reward system also predicted therapeutic response in a clinical trial (called PROUD), in which we assessed the feasibility of two lifestyle interventions, i.e. physical exercise and bright light therapy, in a group of young people with ADHD. To do so, we successfully developed, implemented, and tested a first of its kind smartphone-based feedback-system for monitoring physical activity and chronobiological rhythms in daily life. Enhanced understanding of the underlying mechanisms also led to the discovery of novel, unexplored drug targets leading to several new drug candidates that modify the brain neurotransmitter levels and can be potentially used in these disorders. These findings were communicated to scientific and non-scientific communities, also involving patient organisations such as ADHD Europe. We provided an extensive training program to young researchers to educate a new generation of researchers.
We accessed databases that include data from whole populations of several countries (~20 Mio people) and demonstrated that ADHD frequently co-occurs with anxiety, depression, substance use and abuse, and obesity. This enabled us to chart the development of comorbidity over the lifespan in a sex-specific manner. Medical costs of ADHD were substantial, partly through the onset of comorbidities. As ADHD comorbidities are co-inherited, a shared genetic basis is likely. We showed that the dopamine neurotransmitter system is a biological link between ADHD and obesity. We further showed that genetic factors underlying ADHD are causal for cannabis use. When we studied genetic variants across the whole genome, we found that in co-occurring ADHD and disruptive behaviour disorder, genetics are more important than in ADHD alone. Thus, several of our genetic studies point to a convergence of genetic and neurobiological pathways for ADHD and comorbidities. Machine learning models, also using genetics, were able to predict comorbidity in ADHD youth as early as 2-years old. We incorporated these new genetic findings in our machine learning algorithms and further improved risk predictions for ADHD comorbidities. Further, we used genetic data to identify novel drug targets for ADHD comorbidities and nominated five drug targets (the genes TPH1, TPH2, PTPRF, CSAD, YWHA/14-3-3) that we investigated further. We then developed a new chemical class of tryptophane hydroxylases (TPH1 and TPH2, important enzymes in the metabolism of serotonin) inhibitors. We also found that clinically approved drugs have potent inhibitory and stimulatory effects against these and other target proteins, opening up new therapeutic avenues.
To further elucidate the mechanisms of comorbidity, we a) measured the human circadian system by actimetry (i.e. the objective measurement of movements over the day) and parallel hormone measurements, and b) performed neuroimaging (fMRI) using a pharmacological dopamine challenge to modulate the reward system. We found significant differences in saliva circadian hormone levels (hunger hormone ghrelin, stress hormone cortisol) in ADHD comorbidity groups. Modulation of the dopamine system changed the communication between several brain reward centers, which had a role in treatment response in a clinical study.
Importantly, we aimed to test whether lifestyle interventions (Bright Light Therapy and Exercise) that target our proposed mechanisms can decrease the burden of comorbid symptoms. Measurement was done using a novel smartphone based system which was validated and further investigated, showing that e.g. ADHD patients benefit more from physical activity in improving their mood than healthy controls. The clinical trial on the interventions, the so-called PROUD trial, is currently being analysed. The findings from this pilot study will be used to judge whether future research is warranted to assess efficacy of these lifestyle interventions in a larger trial.
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 for the general public such as newspapers and social media. Our social media strategy was further expanded and outreach to patients was ensured by organising patient events.
To further elucidate the mechanisms of comorbidity, we a) measured the human circadian system by actimetry (i.e. the objective measurement of movements over the day) and parallel hormone measurements, and b) performed neuroimaging (fMRI) using a pharmacological dopamine challenge to modulate the reward system. We found significant differences in saliva circadian hormone levels (hunger hormone ghrelin, stress hormone cortisol) in ADHD comorbidity groups. Modulation of the dopamine system changed the communication between several brain reward centers, which had a role in treatment response in a clinical study.
Importantly, we aimed to test whether lifestyle interventions (Bright Light Therapy and Exercise) that target our proposed mechanisms can decrease the burden of comorbid symptoms. Measurement was done using a novel smartphone based system which was validated and further investigated, showing that e.g. ADHD patients benefit more from physical activity in improving their mood than healthy controls. The clinical trial on the interventions, the so-called PROUD trial, is currently being analysed. The findings from this pilot study will be used to judge whether future research is warranted to assess efficacy of these lifestyle interventions in a larger trial.
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 for the general public such as newspapers and social media. Our social media strategy was further expanded and outreach to patients was ensured by organising patient events.
Using the largest available databases worldwide, our project provides definite answers to the epidemiological comorbidity rates of ADHD. We have strongly contributed to the awareness of the impact of ADHD in adulthood, its risk regarding 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. We have developed genetic tools that (probabilistically) predict possible complications along the lifespan, which can be very useful to take preventive measures or to avoid certain environmental risk factors. We have engineered machine learning approaches to make better prediction on the course of disease. Beyond that, genetic findings paved the way to develop novel drug therapies that can be clinically tested; drug targets were pinpointed by investigating two mechanisms that are involved in the pathogenesis of ADHD comorbidity, i.e. circadian and dopamine systems. A novel and innovative electronic health system using regular smartphones has been developed to allow clinical monitoring (also in the context of randomized controlled trials). We have used this tool in a phase IIa trial on prevention of depression and obesity in young adults with ADHD to provide recommendations to clinicians, public health authorities, and patients.
As ADHD and comorbid conditions cause substantial burden of disease and are major cost drivers in society, our results impact highly on mental healthcare and associated cost. As ca. 3% of the adult population suffer from ADHD, with >50% of those patients having a comorbid condition, a large part of the population is a potential target for prevention and early interventions. We also strived to raise awareness for this patient group by engaging in societal outreach to educate lay audiences and professional healthcare providers.
As ADHD and comorbid conditions cause substantial burden of disease and are major cost drivers in society, our results impact highly on mental healthcare and associated cost. As ca. 3% of the adult population suffer from ADHD, with >50% of those patients having a comorbid condition, a large part of the population is a potential target for prevention and early interventions. We also strived to raise awareness for this patient group by engaging in societal outreach to educate lay audiences and professional healthcare providers.