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.
