Depression in youth and adults : etiology, outcomes, and comorbidities

Depression is a common and debilitating mental disorder characterized by low mood, loss of interest in activities, and long-lasting functional impairment. It is a worldwide psychiatric illness with a wide range of ages of onset, and it occurs about twice as often in women than men. However, most large observational studies have focused on adult populations, leaving pediatric depression largely unexplored. Depressive disorder is linked to poorer physical health and increased comorbidity and mortality, particularly by suicide. This mental condition is the result of a complex interaction between environmental, social, genetic, physiological, and psychological influences, with many risk factors and underlying mechanisms still unknown. This thesis leverages epidemiological statistics and the availability of nationwide registers in Sweden to enhance the understanding of depression in children, adolescents, and adults, exploring adverse health outcomes, psychiatric and somatic comorbidities, potential risk factors, and melatonin treatment for sleep disturbances.

In Study I, we described the association of pediatric depression with a wide range of subsequent somatic conditions and premature death, while also exploring the potential role of psychiatric comorbidities. Compared to the general population, individuals diagnosed with depression during youth displayed higher risks for 66 of the 69 somatic diagnoses under investigation (including self-harm, endocrine and metabolic disorders, and sleep disturbances), as well as elevated risks for mortality, particularly for death by intentional self-harm. When adjusted for psychiatric comorbidity, associations were attenuated but persisted. This study provides new insights into the relationships between psychiatric and somatic disorders among a young population, increasing awareness about the burden of pediatric depression and providing a foundation for future research.

In Study II, we investigated the link between early-life infections and the risks of depression and self-harm during adolescence and early adulthood. Increased risks of the outcomes were observed among individuals exposed to childhood infections, compared to the rest of the population. When adjusting for familial influences, risks were considerably attenuated and no strong association persisted. Our findings show that childhood infections may not be involved in the etiology of later depression and self-harm, and highlight the importance of identifying these genetic and environmental risk factors shared between family members, which represent potential targets for interventions.

Study III explored the underlying factors contributing to the comorbidity of depression and endocrine-metabolic disorders. A family design was applied to investigate the familial co-aggregation of these medical conditions, while quantitative genetic modeling was used to quantify the relative contribution of genetic and environmental influences to the familial liability. We found evidence of shared etiology to the co-occurrence of depression and endocrine-metabolic conditions, which was primarily due to genetics for non-autoimmune conditions, and to unique environmental factors for autoimmune disorders, especially for type 1 diabetes. These findings expand current knowledge on the etiological sources of these comorbidities, which could guide future research aiming at identifying underlying pathophysiological mechanisms.

In Study IV, we examined whether melatonin use in children and adolescents with sleep disturbances was associated with a reduced risk of self-harm and unintentional injuries. Risks of the outcomes were assessed in periods before and after melatonin-treatment initiation, among youth with and without psychiatric disorders, and across sexes, injury types, psychiatric disorder diagnoses, and age groups. Melatonin-use initiation was associated with reduced risks of self-harm among adolescent females with depression and anxiety disorders, suggesting that sleep interventions may be an important component to reduce risk of self-injurious behavior in this pediatric population.

In conclusion, this thesis contributes to the understanding of depression in youth and adults, highlighting its extensive comorbidity and burden of disease, and posing quality-of-life and public health challenges. Our findings underscore an urgent need for screening, prevention, and early intervention of depression, particularly in young patients, as well as for adequate health care resources to treat this mental illness and its psychiatric and somatic comorbidities.

List of scientific papers

I. Leone M, Kuja-Halkola R, Leval A, D’Onofrio BM, Larsson H, Lichtenstein P, Bergen SE. Association of Youth Depression With Subsequent Somatic Diseases and Premature Death. JAMA Psychiatry. 2021 Mar 1;78(3):302-10.
https://doi.org/10.1001/jamapsychiatry.2020.3786

II. Leone M, Kuja-Halkola R, Leval A, D'Onofrio BM, Larsson H, Lichtenstein P, Bergen SE. Association of severe childhood infections with depression and intentional self-harm in adolescents and young adults. Brain, Behavior, and Immunity. 2022 Jan 1;99:247-55.
https://doi.org/10.1016/j.bbi.2021.10.004

III. Leone M, Kuja-Halkola R, Leval A, Butwicka A, Skov J, Zhang R, Liu S, Larsson H, Bergen SE. Genetic and Environmental Contribution to the Co-Occurrence of Endocrine-Metabolic Disorders and Depression: A Nationwide Swedish Study of Siblings. [Submitted]

IV. Leone M, Lagerberg T, Butwicka A, Kuja-Halkola R, Leval A, Larsson H, D’Onofrio BM, Bergen SE. Melatonin use and the risk of self-harm and unintentional injuries in youths with and without psychiatric disorders. [Manuscript]