Major Depressive Disorder is the third largest contributor to life-years lost due to ill health, disability, or early death – and is looking to be ranked first by 2030 (WHO, 2008).
As I know too well from personal experience, depression is characterised by a dampened mood, reduced interest in everything that matters, a lack of energy, and an increased risk of suicide. Given that medical conditions also lower a person’s ability to function in every realm of life, and impair one’s ability to cope with other physical and mental health issues, there is a surprising paucity of evidence on any associations between medical conditions and developing a major depressive disorder.
Although there have been previous studies looking backwards from a diagnosis of depression to background histories of chronic illness, this study by Sigvarden et al. (2025) is the first to consider a large cohort of patients, none of whom had already been diagnosed with either a medical condition or a major depressive disorder, t0 examine whether any associations exist.
A serious medical condition can trigger major depression, leaving people feeling overwhelmed and hopeless.
Methods
This was nationwide, population-based, and retrospective study, of the likelihood of a person experiencing a major depressive disorder, subsequent to a medical condition diagnosis.
The research design allowed for a huge sample of subjects. The researchers obtained data on everyone who lived in Denmark from January 1, 1995, to December 31, 2022. The Danish National Patient Registry was used to investigate the connection between medical conditions and depression on 6,528,353 individuals for a total of 100,770,621 person-years.
The researchers generated hazard ratios for major depressive disorders for people experiencing one or more of nine different categories of medical conditions:
- Circulatory
- Endocrine
- Pulmonary
- Gastrointestinal
- Urogenital
- Musculoskeletal
- Haematological
- Cancers
- Neurological.
Hazard ratios (HRs) were estimated with adjusted Cox regression models. Absolute risks were estimated with competing-risk survival analysis.
Results
Almost a third of the sample (32·4%; 2,114,575 individuals) were diagnosed with a medical condition during the period covered in the study. A smaller proportion of the population (17·0%; 1,112,043) were diagnosed with major depressive disorder.
As hypothesized, those with medical conditions were more likely than others to experience depression in addition to their medical condition(s) (hazard ratio 2·26, 95% CI 2·25 to 2·28), but there were considerable differences in hazard ratio (HR) across several of the sub-analyses.
The first month after onset of a medical condition held the highest likelihood of developing depression (HR 4·62, 95% CI 4·50 to 4·74), with the likelihood declining after that for all conditions other than cancers, where the peak was in the second and third months after diagnosis. By ten years after the onset of a medical condition, the hazard ratio for depression across all medical conditions declined to 1·84 (95% CI 1·82 to 1·86).
There were also differences by age: the older the cohort, the higher the hazard ratio. The top group, those aged 60+, were most likely to experience depression following diagnosis with a medical condition (HR 9·04, 95% CI 8·63 to 9·47).
Those who’d been hospitalised for a medical condition were more likely to experience depression than those who were being treated for their condition in the community (HR 11·83, 95% CI 11·25 to 12·45).
People who were diagnosed with more than one medical condition during the period under consideration were more likely to be diagnosed with depression than those diagnosed with only one medical condition during that period (HR 8·92, 95% CI 8·74 to 9·11). At the same time, however, even for those experiencing five or more conditions, the risk of depression diminished over time after the diagnosis.
The researchers found differences in depression likelihood across all of the nine conditions they considered. People with musculoskeletal conditions were most likely to experience major depressive disorder (HR 2·50, 95% CI 2·49 to 2·51), whereas those with endocrine conditions were least likely (HR 1·35, 95% CI 1·34 to 1·36).
Finally, women were more likely than men to experience depression after the onset of a medical condition. The researchers reported:
The absolute risk for major depressive disorder 20 years after onset of a medical condition was 18·9% (18·8 to 19·0) in men and 24·4% (24·3 to 24·5) in women compared with 6·9% (6·8 to 7·0%) in matched men without a medical condition and 10·7% (10·6 to 10·8%) in matched women without a medical condition.
A new medical diagnosis can hit hard; raising the risk of depression, especially in the early days and for certain groups of people.
Conclusions
This research generated several major findings. To begin with, being diagnosed with a medical condition substantially elevates the risk of experiencing a major depressive disorder. Twenty years after the onset of a medical condition, those who were diagnosed with (one or more of the nine) medical conditions under consideration were more than twice as likely to have developed major depressive disorder when compared with matched individuals without a medical condition.
Another important finding is that the risk of depression is highest immediately after the onset of a medical condition, especially in those aged 60 or older, women, people who are hospitalised for their medical condition, and those who have more than one medical condition.
The researchers also found that the risk of major depressive disorder varies across medical conditions. People with musculoskeletal conditions exhibited the highest risk of experiencing depression. The researchers hypothesize that this might be due to the chronic pain that can accompany these conditions.
Being diagnosed with a medical condition can double the risk of depression, and diagnoses of musculoskeletal conditions were associated with the highest risk.
Strengths and limitations
With more than 100 million person-years of cumulative follow-up (!), this population-based cohort study sheds new light on the risk of major depressive disorder after the onset of one or more medical conditions.
While the findings have limited utility in uncovering detailed mechanisms in play between the onset of a medical condition and the development of depression, the authors correctly identify based on their large scale dataset that:
The uniform time-dependent rates of major depressive disorder after all medical conditions support the notion that a common pathway could be involved.
The researchers point out the potential impact of changes in social roles contingent on medical conditions, including changes in lifestyle, increased dependency on others, reduced employment opportunities, and a decline in social interactions. Any and all of these changes can reduce a person’s coping resources, and lead to the feelings of helplessness and hopelessness that are symptomatic of depression.
In addition, they point out that:
Immune system dysregulation (including inflammation) entails an increased risk of cardiometabolic diseases and is implicated in the onset, symptom profile, and severity of major depressive disorder.
Finally, the researchers point out the shared gene-regulated hormonal and neurotransmitter pathways of many medical conditions as well as depression, and speculate that their findings support other evidence that the onset of medical conditions lowers an individual’s threshold for developing depression.
The authors highlight several limitations. First, this was an observational study, which means that causal inferences cannot be drawn. They also observe that their findings might not apply in populations with different sociodemographic and ethnic compositions. They state that ethnicity data were not available, but they don’t mention socioeconomic status, which might well be relevant here.
Of note, one key limitation of this study is incomplete analysis of available data – analyses of possible outcome differences by relationship status (living alone/cohabiting) and employment status. The researchers did have these data, but did not report any findings. Given the well-documented importance of social support to all mental and physical health outcomes, it would have been of interest to analyse connections in their data set, or at least have mentioned why these analyses were not done.
This study shows us who is more vulnerable to depression after a medical diagnosis, but the mediating networks and mechanisms are unclear.
Implications for practice
There are enormous personal and societal costs of untreated depression. By informing our understanding of who might be most vulnerable to depression, this study is invaluable to professionals across many different branches of medicine, psychology, psychiatry, social work, and public policy.
The most obvious implication of this study’s findings is that any time someone is diagnosed with a medical condition, attention should also be paid to their mental health, including the possibility of depression. Health-care professionals who integrate mental health assessments into physical healthcare improve their chances of diagnosing and intervening early in their patients’ risk of depression, thereby improving their patients’ chances for better outcomes.
This happens ideally when a patient is being seen by a multidisciplinary team. Medical practitioners across specialties should be alive to the greatly increased risk of major depressive disorder subsequent to the diagnosis of a medical condition, especially during the first month post-diagnosis, for those aged 60 years or older, those who are hospitalised for their medical condition, those with multiple medical conditions, and women.
These findings about the connection between major depressive disorder and medical conditions should be on the curriculum in all forms of medical and mental health education. This includes training for trainee psychologists, psychiatrists, counsellors, gerontologists, nurses, nurse practitioners, family doctors, cardiologists, internists, rheumatologists, and every other form of mental and medical care practitioner. In the meantime, until these findings are widely understood, they should also be shared in professional development seminars and workshops.
Because this study adds to the growing weight of evidence showing the importance of integrating mental health services into medical care settings, there are allied public health implications. While public awareness campaigns already focus on reducing the stigma of mental or physical health problems in isolation, more can be done on encouraging holistic approaches to physical and mental health, highlighting their comorbid risks.
Future research on this topic should consider that people with physical and mental health challenges still need to operate in society as a whole. It is valuable to examine the mediating impacts which social and financial supports, or cultural influences and employment, or their absence, can have on the risk of developing a major depressive disorder following a medical diagnosis.
What impact can social factors, like finances, public awareness, and culture, have on the risk of developing depression following a medical diagnosis?
Statement of interests
None
Links
Primary paper
Sigvardsen, Per E et al. (2025) Medical conditions and the risk of subsequent major depressive disorder: a nationwide, register-based, retrospective cohort study. The Lancet Public Health, Volume 10, Issue 6, e503 – e511 DOI: 10.1016/S2468-2667(25)00073-8
Other references
WHO. The global burden of disease: 2004 update. World Health Organization, 2008.
