Oleguer Plana-Ripoll1, Carsten Bøcker Pedersen1,2,3, Yan Holtz4, Michael E Benros2,5, Søren Dalsgaard1,2, Peter de Jonge6,7, Chun Chieh Fan8,9, Louisa Degenhardt10, Andrea Ganna11,12,13, Aja Neergaard Greve2,14, Jane Gunn15, Kim Moesgaard Iburg16, Lars Vedel Kessing17,18, Brian K Lee19, Carmen C W Lim4,20, Ole Mors2,21, Merete Nordentoft2,5, Anders Prior22, Annelieke M Roest6,7, Sukanta Saha4,20, Andrew Schork2,23, James G Scott20,24,25, Kate M Scott26, Terry Stedman27, Holger J Sørensen2,28,29, Thomas Werge2,30,31, Harvey A Whiteford20,32, Thomas Munk Laursen1,2, Esben Agerbo1,2,3, Ronald C Kessler33, Preben Bo Mortensen1,2,3, John J McGrath1,4,20. 1. National Centre for Register-based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark. 2. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark. 3. Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark. 4. Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia. 5. Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. 6. Developmental Psychology, Department of Psychology, Rijksuniversiteit Groningen, Groningen, the Netherlands. 7. Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, Groningen, the Netherlands. 8. Department of Cognitive Science, University of California San Diego, La Jolla. 9. Center for Multimodal Imaging and Genetics, School of Medicine, University of California San Diego, La Jolla. 10. National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia. 11. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 12. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts. 13. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston. 14. Psychosis Research Unit, Aarhus University Hospital Risskov, Risskov, Denmark. 15. Department of General Practice, Melbourne Medical School, The University of Melbourne, Parkville, Victoria, Australia. 16. Department of Public Health, Aarhus University, Aarhus, Denmark. 17. Copenhagen Affective Disorder Research Centre, Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 18. Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 19. Department of Epidemiology and Biostatistics, School of Public Health, Drexel University, Philadelphia, Pennsylvania. 20. Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Queensland, Australia. 21. Psychosis Research Unit, Psychiatry, Aarhus University Hospital, Aarhus, Denmark. 22. Research Unit for General Practice, Aarhus, Denmark. 23. Institute of Biological Psychiatry, Copenhagen Mental Health Services, Copenhagen, Denmark. 24. Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia. 25. Metro North Mental Health, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. 26. Department of Psychological Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. 27. West Moreton Division of Mental Health and Specialised Services, Archerfield, Queensland, Australia. 28. Mental Health Centre Copenhagen, Hellerup, Denmark. 29. Faculty of Health Sciences, Copenhagen University Hospital, Copenhagen, Denmark. 30. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. 31. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 32. School of Public Health, University of Queensland, St Lucia, Queensland, Australia. 33. Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.
Abstract
Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.
Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5 940 778 persons were included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.
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