Attention-deficit/hyperactivity disorder and adverse health outcomes : from association to prevention

Sammanfattning: Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurodevelopmental disorder, characterized by persistent inattention and/or hyperactivity-impulsivity that are inappropriate for one’s developmental stage. Individuals with ADHD suffer from adverse outcomes including somatic and psychiatric comorbidities. ADHD is also associated with increased risk of factors that may impose higher mortality risks. However, evidence has been limited on the association between ADHD and somatic diseases such as asthma. Also, the association between ADHD and premature death, as well as the potential effects of ADHD medication treatment is largely unknown. The overarching aim of this thesis is to investigate the associations between ADHD and specific adverse outcomes including asthma and premature death. Individual studies were conducted to clarify the magnitude and etiology of the associations, as well as potential effects from medication treatment that may prevent poor prognosis. In Study I, we combined a meta-analysis of existing studies and a Swedish national population-based analysis to investigate the population-level association between asthma and ADHD. In the meta-analysis, we found a significant cross-sectional association between asthma and ADHD when considering both unadjusted and adjusted odds ratios. The sub-group and meta-regression analyses showed consistently robust results across study settings. Estimates of the association from the Swedish population analysis were similar with the pooled results from the meta-analysis, and the association remained statistically significant after adjustment of potential confounders in the population-based analysis. In Study II, we investigated the familial liability to the comorbidity between asthma and ADHD. In the familial co-aggregation analysis, relatives of individuals with asthma had an increased risk of ADHD compared to relatives of individuals without asthma. The association was strongest in monozygotic twins and attenuated with decreasing degree of genetic relatedness. Results from the twin modelling analysis supported that a substantial part of the association between asthma and ADHD was explained by genetic factors. Estimates for contributions from shared and non-shared environment factors were not statistically significant. In Study III, we investigated the all-cause and cause-specific mortality risks in ADHD and the role of psychiatric comorbidity. We found that ADHD was associated with significantly increased all-cause and cause-specific mortality risks, with suicide and unintentional injuries being the leading causes of death. Psychiatric comorbidity largely mediated the elevated mortality risks in ADHD, as the mortality risks increased substantially with the number of comorbid psychiatric disorders. Early-onset disorders such as conduct disorders contributed substantially to the association for natural deaths, while later-onset disorders such as substance use disorders may have mediated most of the risk for unnatural deaths in ADHD. In Study IV, we investigated how ADHD medication initiation and continuation associated with mortality risks among individuals with ADHD. During follow-up to a maximum of 2 years, the mortality rates due to any cause and unnatural causes were significantly lower among those who initiated medication treatment compared to those who had not initiated medication. Among individuals who had been on ADHD medication for up to 6 months after diagnosis, continuation of medication treatment was significantly associated with substantially lower all-cause and unnatural cause-specific mortality risks including suicide and unintentional injuries compared to discontinuation. In summary, results of Study I and II together support the significant association between asthma and ADHD. The comorbidity may largely be explained by shared etiology, with substantial influences from shared genetic factors. The findings also point out shared genetic factors as an important direction to understand the mechanisms of adverse conditions related to ADHD other than asthma. Study III and IV together reveal that ADHD is associated with significantly increased all-cause and cause-specific mortality risks, and ADHD medication treatment may help to reduce the risks. The findings point out medication treatment as a promising way to prevent extremely severe adverse outcomes among individuals with ADHD. In conclusion, findings from this thesis work support that individuals with ADHD are at increased risk of adverse outcomes including somatic conditions such as asthma and severe adversities such as premature death. Shared genetic factors largely explained the association between asthma and ADHD, indicating the significance of detecting within-individual and family history of either disorder for preventing delayed diagnosis of the other condition. Moreover, psychiatric comorbidities and medication treatment play crucial roles in understanding the mechanisms of ADHD associated mortality risks and in preventing premature deaths among individuals with ADHD.