Long-term mental and physical health consequences of COVID-19 (long COVID) are a persistent public health concern. Little is still known about the long-term mental health of non-hospitalised patients with COVID-19 with varying illness severities. Our aim was to assess the prevalence of adverse mental health symptoms among individuals diagnosed with COVID-19 in the general population by acute infection severity up to 16 months after diagnosis.
This observational follow-up study included seven prospectively planned cohorts across six countries (Denmark, Estonia, Iceland, Norway, Sweden, and the UK). Participants were recruited from March 27, 2020, to Aug 13, 2021. Individuals aged 18 years or older were eligible to participate. In a cross-sectional analysis, we contrasted symptom prevalence of depression, anxiety, COVID-19-related distress, and poor sleep quality (screened with validated mental health instruments) among individuals with and without a diagnosis of COVID-19 at entry, 0–16 months from diagnosis. In a cohort analysis, we further used repeated measures to estimate the change in mental health symptoms before and after COVID-19 diagnosis.
The analytical cohort consisted of 247 249 individuals, 9979 (4·0%) of whom were diagnosed with COVID-19 during the study period. Mean follow-up was 5·65 months (SD 4·26). Participants diagnosed with COVID-19 presented overall with a higher prevalence of symptoms of depression (prevalence ratio [PR] 1·18 [95% CI 1·03–1·36]) and poorer sleep quality (1·13 [1·03–1·24]) but not symptoms of anxiety (0·97 [0·91–1·03]) or COVID-19-related distress (1·05 [0·93–1·20]) compared with individuals without a COVID-19 diagnosis. Although the prevalence of depression and COVID-19-related distress attenuated with time, individuals diagnosed with COVID-19 but never bedridden due to their illness were consistently at lower risk of depression (PR 0·83 [95% CI 0·75–0·91]) and anxiety (0·77 [0·63–0·94]) than those not diagnosed with COVID-19, whereas patients who were bedridden for more than 7 days were persistently at higher risk of symptoms of depression (PR 1·61 [95% CI 1·27–2·05]) and anxiety (1·43 [1·26–1·63]) than those not diagnosed throughout the study period.
Severe acute COVID-19 illness—indicated by extended time bedridden—is associated with long-term mental morbidity among recovering individuals in the general population. These findings call for increased vigilance of adverse mental health development among patients with a severe acute disease phase of COVID-19.
Nordforsk, Horizon2020, Wellcome Trust, and Estonian Research Council.
and comorbid psychiatric disorders
among patients with COVID-19 have been documented up to 6 months after hospital discharge.
Yet, in addition to the reported methodological shortcomings of the existing literature on this topic (ie, inpatient samples and absence of comparison groups),
little is still known about the long-term mental health of non-hospitalised patients with COVID-19 with varying illness severities.
worries of having infected others,
and extensive media coverage of long-term effects of the disease
might contribute to a transient rise in mental health symptoms. Second, the exacerbation of the COVID-19 illness resulting in severe influenza-like symptoms and associated pro-inflammatory processes
might contribute to the development of mental health symptoms among patients with a severe disease course
for, as yet, an unknown duration. Finally, several vulnerability factors, such as history of psychiatric disorders, might both be associated with the risk of a severe acute COVID-19 illness
and subsequent risks of adverse mental health symptoms.
Evidence before this study
There remain persistent concerns for long-term physical and mental health effects of SARS-CoV-2 infection (referred to as long or chronic COVID) among patients recovering from COVID-19. We searched PubMed on Dec 14, 2021, for publications in English on the mental health of those diagnosed with COVID-19, using the terms “COVID-19” AND (“mental health” OR “depression” OR “anxiety”) with no restrictions on publication date. We excluded studies that did not report specifically on the mental health of those diagnosed with COVID-19. High symptom levels of depression and anxiety among patients with COVID-19 have been reported, mostly based on patients admitted to hospital due to COVID-19 within 6 months of diagnosis. We found no studies focusing on non-hospitalised patients with COVID-19 with varying illness severity beyond 6 months of diagnosis.
Added value of this study
To our knowledge, this is the first study on non-hospitalised patients with COVID-19 in the general population up to 16 months after diagnosis. Leveraging multiple cohorts from six north-European countries of 247 249 adult individuals, our findings suggest that acute COVID-19 illness severity is associated with long-term adverse mental health symptoms among patients in the general population. During the up to 16-month observation period of the study, 9979 individuals were diagnosed with COVID-19 (mostly outpatients) and although overall symptoms of depression and COVID-19-related distress attenuated over time from diagnosis, individuals who were bedridden for 7 days or more in the acute illness phase—representing 22·3% of the patient population—showed persistently high symptom levels of depression and anxiety throughout the observation period. By contrast, individuals who were never bedridden due to COVID-19 presented with lower risks of mental morbidities than non-infected individuals throughout the observation period.
Implications of all the available evidence
These findings have great implications for our understanding of long-term mental health symptom development in COVID-19, namely that the severity of acute COVID-19 illness modifies this risk. These results call for increased vigilance of adverse mental health among the substantial proportion of patients with a severe acute disease phase of COVID-19.
Indeed, one study has provided evidence for elevated risks of psychiatric disorders up to 6 months following COVID-19 regardless of whether patients were admitted to hospital or not.
However, few studies have explored mental health symptom development beyond 6 months after diagnosis of COVID-19 in the general population as well as to what extent varying acute infection severity in COVID-19 predicts long-term mental health symptomology. To this end, we leveraged the multinational and population-based COVIDMENT cohorts
to explore the mental health symptom trajectories up to 16 months after COVID-19 diagnosis. In line with the proposed underlying mechanisms summarised above, we hypothesised that mental health symptoms would generally decline with time from COVID-19 diagnosis (from when physical symptoms and uncertain prognosis could be expected to have resolved), whereas severe COVID-19 acute infection (indicated by number of days confined to bed [bedridden] due to COVID-19 symptoms) would be associated with persistent adverse mental health symptoms.
Study design and participants
The cohorts used different strategies for recruitment, most recruiting from already established cohorts, whereas some also opened for self-recruitment through social media. The cohorts were: The Danish Blood Donor Study (DBDS, n=71 562), The Estonian Biobank COVID-19 Cohort (EstBB-C19, n=14 452), The Icelandic COVID-19 National Resilience Cohort (C19-Resilience, n=23 962), The Norwegian COVID-19, Mental Health and Adherence Project (MAP-19, n=10 061), The Norwegian Mother, Father and Child Cohort Study (MoBa, n=132 486), The Swedish Omtanke2020 (n=28 293), and the UK-based CovidLife (n=18 518).
Individuals aged 18 years and older were eligible to participate. All cohorts had ethical approvals from respective national or regional ethics committees (see appendix p 2) with varying numbers of waves of data collections from March 27, 2020, to Aug 13, 2021. All participants provided written or electronic informed consent.
We excluded individuals from the analyses if they did not have complete information on COVID-19 diagnosis and at least one of the four outcome variables.
and Emotional State Questionnaire Depression subscale [EST-Q2] with the recommended cutoff of >11),
anxiety (Angst-Symptom-Spørgeskemaet, EST-Q2 Anxiety subscale
with the recommended cutoff of >11, and General Anxiety Disorder with the recommended cutoff of ≥10),
COVID-19-related distress (The Primary Care PTSD Screen for DSM-5 with the recommended cutoff of ≥4,
and the PTSD checklist for DSM-5),
and sleep quality (EST-Q2 Insomnia subscale
with the recommended cutoff of >5 and Pittsburgh Sleep Quality Index)
were included in all cohorts (see appendix p 2 for further information). All the screening measures for post-traumatic stress were modified to refer specifically to COVID-19 (eg, “Had nightmares about COVID-19?”) and are therefore hereafter referred to as COVID-19-related distress.
and mental morbidities,
we also included body-mass index (30 kg/m2) and smoking (never, former, or current) in all our models.
First, we explored the distribution of sociodemographic and health-related factors between individuals with and without a COVID-19 diagnosis for each cohort, individually and combined, along with symptom severity for individuals with a COVID-19 diagnosis. We then did a cross-sectional analysis contrasting the prevalence of mental health indicators among individuals with and without a diagnosis of COVID-19, overall and in subgroup analyses by illness severity and time from diagnosis.
The exponential of the effect size can be interpreted as a relative risk or a PR.
This approach can be extended to repeated measures data.
We used classical sandwich estimator with exchangeable working correlation structure to control for intra-individual correlation when repeated measures were available.
We adjusted the estimates for age and gender in the first model, and in the second model additionally for education, relationship status, smoking, body-mass index, previous psychiatric diagnosis, number of chronic medical conditions, and response period. Cohorts that did not measure specific covariates excluded them from their models (appendix p 2). MoBa and MAP-19 had a high proportion of missing body-mass index and smoking data and used a missing indicator on these covariates to avoid dropping large numbers of participants from the analysis.
In a subpopulation with repeated symptom measures, we did a cohort analysis testing for potential change in symptom burden over time, from before and until after COVID-19 diagnosis. Among the Icelandic C19-Resilience, Norwegian MoBa, Swedish Omtanke2020, and the UK-based CovidLife cohorts, we did a pair-wise comparison of repeated measures of mental health outcomes at two timepoints among individuals with a COVID-19 diagnosis. Baseline measurements were the first response to a questionnaire after reporting a positive COVID-19 diagnosis, and the follow-up measurement was the last available response to a questionnaire. The aforementioned extension of the modified Poisson regression models was done to test the difference of the mental health outcomes between the two timepoints, while adjusting for response period. We did a similar comparison of mental health measures at two timepoints for individuals who answered at least one questionnaire before being diagnosed with COVID-19 and at least one questionnaire after being diagnosed. The baseline measurement was the last questionnaire before a COVID-19 diagnosis and the follow-up measurement was the first questionnaire in which a COVID-19 diagnosis was reported.
Heterogeneity for each overall mental health outcome was examined using the I2 statistic.
Statistical analyses were done in R (version 4.1.1), SAS (version 9.4), and Stata (version 17.0). Our study is reported according to the Strengthening the Reporting of Observational studies in Epidemiology checklist (appendix pp 25–27).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Data are n (%) or mean (SD). C19-Resilience=The Icelandic COVID-19 National Resilience Cohort. DBDS=The Danish Blood Donor Study. EstBB-C19=The Estonian Biobank COVID-19 Cohort. MAP-19=The Norwegian COVID-19, Mental Health and Adherence Project. MoBa=The Norwegian Mother, Father and Child Cohort Study.
In this multicohort study including almost 250 000 individuals across six countries, we found that acute COVID-19 illness severity was associated with mental morbidities up to 16 months after diagnosis. Although individuals who were never bedridden due to COVID-19 had lower risks of adverse mental health symptoms compared with those not diagnosed with COVID-19, individuals who were bedridden for 7 days or longer—representing 22·3% of the participants with a COVID-19 diagnosis—persistently showed 50–60% higher prevalence of depression and anxiety symptoms throughout the observation period.
However, the longest follow-up in these studies was 6 months, except for one recent study with 1-year follow-up involving only patients admitted to hospital. In that study, 331 (26%) of 1271 patients with COVID-19 had anxiety or depression at 12-month follow-up,
which is similar to the results of our study. In previous outbreaks of other infectious diseases, a high prevalence of post-traumatic stress disorder and depressive disorders have been observed after diagnosis. For example, a high prevalence of these symptoms was observed up to 4 years after diagnosis of severe acute respiratory syndrome in 2003
and these symptoms were also reported following the 2015 outbreak of Middle East respiratory syndrome up to 12 months after diagnosis.
However, disease severity was generally not addressed in these studies, which also were limited to patients admitted to hospital.
Collectively, the existing literature suggests that the elevated relative risks of mental morbidities are not limited to COVID-19 but have also been reported after other previous pandemic infections.
Our study participants were diagnosed with COVID-19 from February, 2020, to August, 2021; therefore, with the advent of vaccinations and new, reportedly weaker SARS-CoV-2 variants,
the proportion of patients with COVID-19 with a severe course of acute illness might be lower in more recently infected individuals.
and the unpredictable prognosis of COVID-19 (eg, worrying about long-term health effects, or even death
). However, such psychological mechanisms might be expected to lead to transient mental health symptoms that attenuate with time (ie, with recovery of physical symptoms of the illness). Indeed, the observed increase in symptoms of COVID-19-related distress in this group of patients might be indicative of such psychological mechanisms as the symptoms attenuated quickly after 2 months of diagnosis. By contrast, the persistent symptoms of depression and anxiety among individuals who were bedridden for 7 days or longer might be due to continued physical long COVID symptoms where functional limitations, perhaps limiting social contact, might cause worry and a sense of helplessness.
Alternatively, the inflammatory processes among patients with severe acute illness could also affect the risk of persistent mental health symptoms.
Indeed, inflammation associated with chronic
diseases have previously been linked with development of mental morbidities, particularly depression. Such mental morbidities have also been reported to persist after reduction in inflammation.
Hospital admission represents another severity indicator of acute COVID-19 illness in our study; whether the high prevalence of depression in this group is mediated by aforementioned inflammatory processes, social isolation, or both, remains to be further elucidated.
In the current study, the prevalence of psychiatric disorders was slightly higher among individuals with COVID-19 than those without a diagnosis; thus we included this variable in all our regression models, and when considering the association between time bedridden during the acute illness and symptoms of long-term mental morbidities. Nevertheless, we cannot exclude the possibility of residual confounding—ie, that previous psychiatric vulnerabilities lead to more severe acute COVID-19, yielding the observed associations in our data. This potentially bidirectional association between psychiatric morbidity and COVID-19 requires further study through prospective designs.
In conclusion, in this study we found that severe COVID-19 acute illness was associated with long-term mental health symptomology among recovered patients. Although patients with mild acute COVID-19 illness are unlikely to have long-term mental health morbidities, more than a fifth of the included patients with COVID-19 had a severe acute illness course (the large majority at home, although some in hospital), which was associated with persistent risks of depressive and anxiety symptoms up to 16 months after diagnosis. These findings motivate continued clinical vigilance and follow-up studies beyond the first year among individuals with the most severe symptomology after COVID-19 infections.
Ingibjörg Magnúsdóttir, Anikó Lovik, Anna Bára Unnarsdóttir, Daniel McCartney, Helga Ask, Kadri Kõiv, Lea Arregui Nordahl Christoffersen, Sverre Urnes Johnson, Andrew McIntosh, Anna K Kähler, Archie Campbell, Arna Hauksdóttir, Chloe Fawns-Ritchie, Christian Erikstrup, Dorte Helenius, Drew Altschul, Edda Bjork Thordardottir, Elías Eyþórsson, Emma M Frans, Gunnar Tómasson, Harpa Lind Jónsdóttir, Harpa Rúnarsdóttir, Henrik Hjalgrim, Hrönn Harðardóttir, Juan González-Hijón, Karina Banasik, Khoa Manh Dinh, Li Lu, Lili Milani, Lill Trogstad, Maria Didriksen, Omid V Ebrahimi, Patrick F Sullivan, Per Minor Magnus, Qing Shen, Ragnar Nesvåg, Reedik Mägi, Runólfur Pálsson, Sisse Rye Ostrowski, Thomas Werge, Asle Hoffart, David J Porteous, Fang Fang, Jóhanna Jakobsdóttir, Kelli Lehto, Ole A Andreassen, Ole B V Pedersen, Thor Aspelund, Unnur Anna Valdimarsdóttir
The COVIDMENT cohorts and their data collections were designed by IM, AL, ABU, CF-R, HA, KK, LANC, SUJ, OVE, AHo, DJP, FF, JJ, KL, OAA, OBVP, TA, UAV, and their respective teams. UAV, IM, and TA directed the combined effort of this study implementation. UAV, IM, JJ, and TA designed the analytical strategy in close collaboration with all team members and all authors helped to interpret the findings. IM, AL, ABU, DM, HA, KK, LANC, and SUJ conducted the literature review and drafted the manuscript under the supervision of UAV. All authors revised the manuscript for critical content and approved the final version of the manuscript. IM and TA had access to and verified all the data and all authors could access the data on request.
The individual-level data underlying this article were subject to ethical approval and cannot be shared publicly due to data protection laws in each participating country.
Declaration of interests
OAA has received a grant to their institution from Nordforsk and Research Council of Norway for the present manuscript. OAA has also received a grant to the institution for an entity other than the present manuscript from South East Norway Health Authority, KG Jebsen Stiftelsen, and National Institutes of Health, EU. OAA has received royalties for a textbook in psychiatry, consulting fees from HealthLytix and Milken Institute, payment for lectures from Sunovion and Lundbeck, and payment for expert testimony from the Norwegian Court. Outside of this work, OAA has a patent for a devise for nasal delivery. OAA has participated at his institution on boards for local principal investigator Clinical Trial Janssen, local principal investigator Clinical Trial MAPS, and local principal investigator Clinical Trial Boehringer. UAV has received grants for the current work from Nordforsk and Horizon2020 as well as grants outside the current work from the Icelandic Research Fund, Swedish Research Council, Swedish Cancer Society, and the European Research Council. All other authors declare no competing interests.
This work was primarily supported with grants from Nordforsk (CovidMent, 105668) and Horizon2020 (CoMorMent, 847776). HA was supported by the Research Council of Norway (RCN 324 620), the MoBa COVID-19 data collection was supported by RCN (312 721), and OAA was supported by RCN (273 291, 223 273). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006) and is currently supported by the Wellcome Trust (216767/Z/19/Z). Recruitment to the CovidLife study was facilitated by SHARE—the Scottish Health Research Register and Biobank. DBDS data collection was funded by the Independent Research Fund Denmark (0214-00127B). SHARE is supported by NHS Research Scotland, the Universities of Scotland and the Chief Scientist Office of the Scottish Government. The research in the Estonian Biobank was supported by the EU through the European Regional Development Fund (project number 2014-2020.4.01.15-0012), and the Estonian Research Council through grant number PSG615, the programme Mobilitas Pluss (MOBTP142), funding of Estonian subproject of NordForsk project number 105668, and National Programme for Addressing Socio-Economic Challenges through Research and Development (RITA), supported by the Estonian Government and European Regional Development Fund (RITA1/02-112).
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Published: March 14, 2022
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