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Perlis RH, Ognyanova K, Santillana M, et al. Association of Acute Symptoms of COVID-19 and Symptoms of Depression in Adults. JAMA Netw Open. 2021;4(3):e213223. doi:10.1001/jamanetworkopen.2021.3223
After acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a subset of individuals experience persistent symptoms involving mood, sleep, anxiety, and fatigue,1 which may contribute to markedly elevated rates of major depressive disorder observed in recent epidemiologic studies.2 In this study, we investigated whether acute coronavirus disease 2019 (COVID-19) symptoms are associated with the probability of subsequent depressive symptoms.
In this survey study, we included data from US adult participants in 8 waves of an internet-based nonprobability survey conducted by Qualtrics with multiple panels of respondents (PureSpectrum). Surveys were conducted approximately monthly between June 2020 and January 2021. Of 82 319 respondents who completed the Patient Health Questionnaire–9 (PHQ-9), a total of 3904 nonoverlapping individuals reported prior COVID-19 illness and completed the survey questions used in this analysis. The study was reviewed and approved by the institutional review board of Harvard University. All participants signed electronic informed consent. We followed the American Association for Public Opinion Research (AAPOR) reporting guideline for survey studies.
In addition to standard sociodemographic questions, including self-identified race and ethnicity in 5 prespecified categories based on the US Census, the survey asked participants whether they had been diagnosed with COVID-19 illness by a clinician or received a positive test result and in which month(s) they had been ill; these individuals were also asked to indicate the presence or absence of specific symptoms and overall perceived severity of COVID-19 illness (ie, not at all, not too, somewhat, or very). Participants also completed the PHQ-9, a screen for symptoms of depression,3 with each of the 9 items scored from 0 to 3, yielding a score between 0 and 27; a score of 10 or greater is considered moderate depression.
For the primary analysis, we incorporated indicator variables for each symptom as well as overall severity in a logistic regression model with PHQ-9 score of 10 or greater (ie, moderate or greater depression) as the dependent variable. We then adjusted for sociodemographic features including age, gender, race/ethnicity, geographic region, urban vs suburban or rural, and household income, using glm package in R version 3.6 (R Project for Statistical Computing). Statistical significance was set at α = .05, and all tests were 2-tailed.
There were 3904 individuals reporting prior COVID-19 illness (Table), with a mean (SD) age of 38.1 (12.4) years. Overall, 1730 (44.3%) were women; 416 (10.7%), Hispanic individuals; 439 (11.2%), Black individuals; and 142 (3.6%), Asian individuals. Mean (SD) time since initial COVID-19 symptoms was 4.2 (2.7) months. A total of 2046 participants (52.4%) met the criteria for symptoms of major depressive disorder. In fully adjusted models, presence of headache was associated with greater probability of moderate or greater depression symptoms (adjusted odds ratio [OR], 1.33; 95% CI, 1.10-1.62), as was greater overall severity (somewhat vs not at all severe: adjusted OR, 2.59; 95% CI, 2.04-3.30; very vs not at all severe: OR, 5.08; 95% CI, 3.93-6.59). Women were less likely to have symptoms than men (adjusted OR, 0.72; 95% CI, 0.61-0.84), and the likelihood of symptoms decreased with increasing age (adjusted OR by decade, 0.76; 95% CI, 0.72-0.81). The Figure illustrates ORs from regression models adjusted for sociodemographic features, omitting 288 individuals who lacked overall COVID-19 severity data.
Among more than 3900 individuals with prior COVID-19 illness surveyed between May 2020 and January 2021, 52.4% met criteria for moderate or greater symptoms of major depression. In regression models, these symptoms were more likely among younger respondents compared with older respondents and among men compared with women as well as among those with greater self-reported overall COVID-19 severity compared with those with lower severity.
We did not replicate a prior finding4 among 114 individuals with COVID-19 that loss of smell and taste were associated with greater near-term depressive and anxious symptoms. Instead, we found that those who reported headache during acute infection appeared to have an elevated risk of depressive symptoms. We note the important caveat that, as a cross-sectional study, we cannot exclude the possibility that individuals with current depression are more likely to recall or report headache. We might similarly expect other symptoms to also be reported more frequently, but this was not generally the case. Moreover, as a web-based survey, we cannot estimate a response rate as with more traditional survey designs; however, we note that surveys using similar methods have demonstrated replicable results during COVID-19.5 As respondents did not see the survey topic until entering the survey itself, it is unlikely our results are enriched for those with particular interest in, or impact from, COVID-19.
A further caveat is that we cannot attribute these symptoms to new onset of depression; individuals with acute infection could be less likely to recover from prior depressive episodes or those with preexisting depressive symptoms could have greater risk of contracting COVID-19. A 2021 claims-based study6 suggests a bidirectional association between COVID-19 and psychiatric illness.
Nevertheless, our results add to a growing body of evidence suggesting the importance of considering potential neuropsychiatric sequelae of COVID-19 infection. Our results also suggest the importance of considering strategies that might mitigate the elevated risk of depressive symptoms following acute infection.
Accepted for Publication: February 1, 2021.
Published: March 12, 2021. doi:10.1001/jamanetworkopen.2021.3223
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Perlis RH et al. JAMA Network Open.
Corresponding Author: Roy H. Perlis, MD, MSc, Massachusetts General Hospital, 185 Cambridge St, 6th Floor, Boston, MA 02114 (firstname.lastname@example.org).
Author Contributions: Dr Perlis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Perlis, Ognyanova, Lazer, Druckman, Della Volpe.
Acquisition, analysis, or interpretation of data: Perlis, Ognyanova, Santillana, Baum, Lazer, Della Volpe.
Drafting of the manuscript: Perlis, Santillana.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Perlis, Ognyanova, Santillana, Della Volpe.
Obtained funding: Ognyanova, Baum, Lazer.
Administrative, technical, or material support: Santillana, Lazer, Druckman, Della Volpe.
Conflict of Interest Disclosures: Dr Perlis reported receiving personal fees from RID Ventures, Outermost Therapeutics, Burrage Capital, Genomind, Psy Therapeutics, Takeda, and Belle Artificial Intelligence and holding equity in Outermost Therapeutics and Psy Therapeutics outside the submitted work. Dr Lazer reported receiving grants from the Knight Foundation and Steve Johnson, a donor to Northeastern, during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was supported by grant R01MH116270 from the National Institute of Mental Health to Dr Perlis and support from the National Science Foundation to Dr Baum.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: Dr Perlis is an associate editor for JAMA Network Open but was not involved in the editorial review or decision process for this manuscript.
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