CME Author: Vicki Brower
Study Authors: Oleguer Plana-Ripoli, Karsten Bøcker Pedersen, et al.; Steven E. Hyman
Target Audience and Goal Statement:
Psychiatrists, psychologists, internists, family medicine specialists, epidemiologists, and geneticists
The goal was to study comorbidity within mental disorders in a large population, and develop an interactive website to visualize all results and guide future research and clinical practice.
After an individual receives a diagnosis of a specific mental disorder, does the risk of developing other mental disorders increase, and if so, by how much?
Study Synopsis and Perspective:
Danish researchers found that the risk of a second mental disorder increased sharply in the 6 months following an individual’s initial diagnosis, and this risk, which the investigators called “pervasive,” continued beyond 15 years.
“For some disorders (e.g., mood disorders) the absolute risks of developing specific later disorders (e.g., anxiety disorders) was substantial — i.e., 30-40% over 5 years.
This new population-based cohort study of nearly six million people found that for patients with mood disorders, for example, the risk of a subsequent neurotic disorder diagnosis was highest in the first 6 months from initial diagnosis (HR 77.8, 95% CI 76.5-79.2), and was still increased at 15 years (HR 4.3, 95% CI 4.1-4.4).
The study by John McGrath, MD, PhD, of Aarhus University in Denmark, and colleagues, published in JAMA Psychiatry, found that overall, each mental disorder they considered — including schizophrenia, substance use, intellectual disabilities, eating disorders, and organic, mood, and behavioral disorders — was associated with an increased risk for all the others, with the level of increased risk differing across pairs.
Hazard ratios ranged from 2.0 for the risk of eating disorders in individuals initially diagnosed with intellectual disabilities (95% CI 1.7-2.4) to 48.6 for the risk of intellectual disabilities in those with prior developmental disorders (95% CI 46.6-50.7) after adjusting for age, calendar time, and sex. Further adjustments for previous disorders demonstrated a similar pattern, but with weaker associations, the researchers stated.
They noted that certain pairs of disorders were accompanied by substantial absolute risks. For example, among those who developed a mood disorder before age 20, approximately 40% of men and 50% of women subsequently developed an incident neurotic disorder within the next 15 years. The associations between disorders were also bidirectional — i.e., linked disorders remained related regardless of which was diagnosed first.
“The data suggest that some disorders share common (upstream) risk factors,” McGrath told MedPage Today via email. “These could be genetic or environmental factors.”
For the study, McGrath and colleagues collected sociodemographic data from the Danish Civil Registration System for patients born from 1900 to 2015, and matched data on mental disease from the Danish Psychiatric Central Research Register. The team used ICD-8 (1969-1993) and ICD-10 (1994 onward) codes to classify diagnoses.
In total, 5,940,778 individuals were included (evenly split between men and women) and followed for 83.9 million person-years. Patients were a mean 32.1 years old at initial diagnosis. Across the study period, 882,730 patients died, and 85,356 emigrated from Denmark and were lost to follow-up.
Notably, patients were more likely to present with subsequent disorders if they received the index diagnosis at a younger age, McGrath noted.
The absolute risk was also time-dependent, the researchers found. For example, about 11% of men and 10% of women diagnosed with a mood disorder were diagnosed with neurotic disorders within a month. At 5 years, 22.9% of the men and 24.1% of the women had been diagnosed with a neurotic disorder. By 10 years, these rates had increased to 27.2% and 28.9%, respectively.
The researchers said they hope the findings can be used proactively — “if clinicians and individuals with mental disorders had ready access to diagnosis-, age-, and sex-specific absolute risks of potential future morbidity, this information could permit more tailored interventions and better education about self-management (i.e., personalized medicine).”
Source References: JAMA Psychiatry, online Jan. 16, 2019; DOI: 10.1001/jamapsychiatry.2018.3658
Editorial: JAMA Psychiatry, online Jan. 16, 2019; DOI: 10.1001/jamapsychiatry.2018.4269
Study Highlights: Explanation of Findings
The researchers conducted a comprehensive study of comorbidity within treated mental disorders by using Danish population registers encompassing nearly 6 million individuals, examining the association between 90 possible pairs of disorders and estimating the association in both directions. Overall, the team found, receiving a diagnosis of one disorder increased the risk of a subsequent diagnosis with each of the other disorders.
McGrath and co-authors emphasized that an increased risk of comorbidity between mental disorders was the rule, not the exception. The study may be unique in its examination of comorbidities within mental disorders and the finding of absolute risks associated with comorbid mental disorders, the team added.
“The findings related to bi-directionality and persistence of elevated HRs over time support the hypotheses that certain mental disorders share risk architectures,” the researchers wrote, adding that a growing body of genetic evidence indicates that different mental disorders share common gene variants.
Steven Hyman, MD, of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, who wrote an accompanying editorial, told MedPage Today that the study findings speak to the complicated nature of diagnosing mental disorders and provide evidence that the risk of developing one of these disorders is “highly polygenic.”
“The DSM [Diagnostic and Statistical Manual of Mental Disorders] has divided up the landscape into many discrete categorical disorders so that you have ‘disorder x’ or you don’t — sort of like you have smallpox or your don’t, or you have Ebola or you don’t,” Hyman explained. “The trouble in psychology is that then people get a second discreet diagnosis and a third discreet diagnosis. Looking at this analysis and genetics, this may not be a very good way of thinking about it.”
Hyman said that the study authors’ choice to use the ICD-10 — referring to the 10th revision of the World Health Organization’s International Statistical Classification of Diseases and Related Health Problems was deliberate, since it classifies mental disorders into 10 high-level groupings, rather than individual disorder diagnoses.
He noted that previous research certainly suggests that psychiatric disorders are related, particularly those often clustered together, such as depression and anxiety. What is striking about this study, however, is that the observed increases in risk were seen across clusters of disorders that are thought to have very different risk factors. Genetic studies also indicate significant pairwise sharing of risk across mental disorders and across many cognitive and behavioral phenotypes, he said.
“It’s premature to say what this sharing consists of, or that it’s only one factor — and a factor here might mean a cluster of shared risk genes,” Hyman continued. “But it’s a really interesting and important problem that is very different from neurologic disorders, which do not share [risk] with each other.”
At this time, there is a convergence between population studies of comorbidity with family, twin, and molecular genetic studies that are leading to new ways to classify mental disorders, but the field “still has a long way to go to be able to translate them into actionable biology or cognitive frameworks for prevention and treatment,” Hyman wrote.
Still, the study has implications now for how diagnoses are made; how clinicians, patients, and health systems might plan longitudinal care; and how new symptoms might be interpreted as they arise over a lifetime, Hyman observed.
The health contribution comes not only from the analysis of the large data set, but also from the website the authors created, and with which clinicians and patients “can gain insight into risk of comorbid disorders based on initial diagnosis, age, and sex,” he added.
McGrath and co-authors said that in future studies they would expect to concentrate on more complex forms of comorbidity, such as individuals with at least three types of disorders, and look to estimate risks for specific types of disorders rather than clusters of disorders.
Among the study limitations, the researchers said, were the fact that patients with less severe disorders who were treated by general practitioners might have been excluded from the data set. Lastly, since the study was strictly a Danish population, the findings may not be generalizable across other countries.
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco