Research Letter | Psychiatry

Association of Acute Symptoms of COVID-19

and Symptoms of Depression in Adults
Roy H. Perlis, MD, MSc; Katherine Ognyanova, PhD; Mauricio Santillana, PhD; Matthew A. Baum, PhD; David Lazer, PhD; James Druckman, PhD; John Della Volpe, AB

Introduction Author affiliations and article information are

listed at the end of this article.
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.

Methods
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

Table. Demographic Information and Acute COVID-19 Symptoms Stratified

by PHQ-9 Depression Score

Patients by PHQ-9 Score, No. (%)

Total (n = 3904),
Characteristic <10 (n = 1858) ≥10 (n = 2046) No. (%) P value
Positive testa 1453 (78.9) 1399 (69.4) 2852 (74.0) <.001
Clinician diagnosisb 1586 (85.5) 1758 (86.0) 3344 (85.7) .62
Time since onset, mean (SD), moc 3.75 (2.61) 4.56 (2.80) 4.18 (2.74) <.001
Age, mean (SD), y 39.92 (13.59) 36.36 (10.92) 38.05 (12.39) <.001
Female gender 927 (49.9) 803 (39.2) 1730 (44.3) <.001
Income median (IQR), thousands of $d 70 (30-125) 75 (30-150) 75 (30-145) .002
Race/ethnicity
White 1320 (71.0) 1468 (71.7) 2788 (71.4)
Hispanic 195 (10.5) 221 (10.8) 416 (10.7)
Black 203 (10.9) 236 (11.5) 439 (11.2) .20
Asian 71 (3.8) 71 (3.5) 142 (3.6)
Other 69 (3.7) 50 (2.4) 119 (3.0)

(continued)
Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2021;4(3):e213223. doi:10.1001/jamanetworkopen.2021.3223 (Reprinted) March 12, 2021 1/4

Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 12/09/2022

 JAMA Network Open | Psychiatry Acute Symptoms of COVID-19 and Symptoms of Depression in Adults

Table. Demographic Information and Acute COVID-19 Symptoms Stratified

by PHQ-9 Depression Score (continued)

Patients by PHQ-9 Score, No. (%)

Total (n = 3904),
Characteristic <10 (n = 1858) ≥10 (n = 2046) No. (%) P value
Urbanicity
Rural 275 (14.8) 264 (12.9) 539 (13.8)
Suburban 1009 (54.3) 1071 (52.3) 2080 (53.3) .02
Urban 574 (30.9) 711 (34.8) 1285 (32.9)
Acute COVID-19 severitye
Not at all severe 317 (18.7) 153 (7.9) 470 (13.0) Abbreviations: COVID-19, coronavirus disease 2019;
Not too severe 553 (32.7) 398 (20.6) 951 (26.3) PHQ-9, Patient Health Questionnaire–9.
<.001 a
Somewhat severe 558 (33.0) 709 (36.8) 1267 (35.0) Missing in 17 participants (0.9%) with PHQ-9 scores
Very severe 263 (15.6) 669 (34.7) 932 (25.7) of less than 10 and 31 participants (1.5%) with PHQ-9
scores of 10 or greater.
Symptoms
b
Missing in 2 participants (0.1%) with PHQ-9 scores of
Fever 946 (50.9) 1083 (52.9) 2029 (52.0) .21
less than 10 and 2 participants (<0.1%) with PHQ-9
Chills 641 (34.5) 758 (37.0) 1399 (35.8) .10 scores of 10 or greater.
Shaking 590 (31.8) 714 (34.9) 1304 (33.4) .04 c
Missing in 249 participants (13.4%) with PHQ-9
Congestion 948 (51.0) 1051 (51.4) 1999 (51.2) .83 scores of less than 10 and 213 participants (10.4%)
Muscle pain 636 (34.2) 786 (38.4) 1422 (36.4) .007 with PHQ-9 scores of 10 or greater.
d
Cough 749 (40.3) 799 (39.1) 1548 (39.7) .42 Missing in 1 participant (<0.1%) with PHQ-9 scores of
Sore throat 813 (43.8) 925 (45.2) 1738 (44.5) .36 less than 10 and 3 participants (0.1%) with PHQ-9
scores of 10 or greater.
Headache 403 (21.7) 603 (29.5) 1006 (25.8) <.001
e
Shortness of breath 673 (36.2) 842 (41.2) 1515 (38.8) .002 Not asked in 167 participants (9.0%) with PHQ-9
scores of less than 10 and 117 participants (5.7%) with
Change in taste or smell 980 (52.7) 1122 (54.8) 2102 (53.8) .19
PHQ-9 scores of 10 or greater.

Figure. Logistic Regression Model for Association of Acute Coronavirus Disease 2019 (COVID-19) Symptoms
With Subsequent Patient Health Questionnaire–9 Depression Score

Participants,
Variable No. OR (95% CI) P value
Age by decade 3616 0.76 (0.72-0.81) <.001
Women 3616 0.72 (0.61-0.84) <.001
Race/ethnicity
White 2604 1 [Reference]
Hispanic 386 0.93 (0.73-1.18) .57
Black 382 0.93 (0.73-1.19) .57
Asian 131 0.76 (0.52-1.11) .16
Other 113 0.66 (0.44-0.98) .04
Income decile 3616 0.99 (0.96-1.03) .73
Location
Rural 490 1 [Reference]
Suburban 1924 1.07 (0.86-1.32) .55
Urban 1202 1.10 (0.88-1.39) .40
COVID-19 severity
Not at all 469 1 [Reference]
Not too 951 1.52 (1.20-1.94) <.001
Somewhat 1265 2.59 (2.04-3.30) <.001
Very 931 5.08 (3.93-6.59) <.001
Fever 3616 0.82 (0.70-0.97) .02
Chills 3616 0.98 (0.82-1.18) .84
Shaking 3616 0.95 (0.79-1.14) .57
Congestion 3616 0.89 (0.75-1.05) .18
Muscle pain 3616 1.00 (0.84-1.19) .99
Cough 3616 0.87 (0.74-1.03) .11
Sore throat 3616 0.98 (0.82-1.16) .79
Headache 3616 1.33 (1.10-1.62) .003
Shortness of breath 3616 1.19 (1.00-1.42) .05
Change of taste/smell 3616 1.07 (0.90-1.27) .43

0.3 0.5 1 2 5 7
OR (95% CI) OR indicates odds ratio.

JAMA Network Open. 2021;4(3):e213223. doi:10.1001/jamanetworkopen.2021.3223 (Reprinted) March 12, 2021 2/4

Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 12/09/2022

 JAMA Network Open | Psychiatry Acute Symptoms of COVID-19 and Symptoms of Depression in Adults

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.

Results
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.

Discussion
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.

JAMA Network Open. 2021;4(3):e213223. doi:10.1001/jamanetworkopen.2021.3223 (Reprinted) March 12, 2021 3/4

Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 12/09/2022

 JAMA Network Open | Psychiatry Acute Symptoms of COVID-19 and Symptoms of Depression in Adults

ARTICLE INFORMATION
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 (rperlis@mgh.harvard.edu).
Author Affiliations: Massachusetts General Hospital, Boston (Perlis); Harvard Medical School, Boston,
Massachusetts (Perlis, Santillana); Associate Editor, JAMA Network Open (Perlis); Rutgers University, New
Brunswick, New Jersey (Ognyanova); Harvard University, Cambridge, Massachusetts (Baum, Della Volpe);
Northeastern University, Boston, Massachusetts (Lazer); Northwestern University, Evanston, Illinois (Druckman).
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.

REFERENCES
1. Patient-Led Research for COVID-19. Report: what does COVID-19 recovery actually look like? Published May 11,
2020. Accessed September 8, 2020. https://patientresearchcovid19.com/research/report-1/
2. Ettman CK, Abdalla SM, Cohen GH, Sampson L, Vivier PM, Galea S. Prevalence of depression symptoms in US
adults before and during the COVID-19 pandemic. JAMA Netw Open. 2020;3(9):e2019686. doi:10.1001/
jamanetworkopen.2020.19686
3. Kroenke K, Spitzer RL. The PHQ-9: a new depression diagnostic and severity measure. Psychiatric Annals
2002;32(9):509-515. doi:10.3928/0048-5713-20020901-06
4. Speth MM, Singer-Cornelius T, Oberle M, Gengler I, Brockmeier SJ, Sedaghat AR. Mood, anxiety and olfactory
dysfunction in COVID-19: evidence of central nervous system involvement? Laryngoscope. 2020;130(11):
2520-2525. doi:10.1002/lary.28964
5. Peyton K, Huber G, Coppock A. The generalizability of online experiments conducted during the COVID-19
pandemic. SocArXiv. Preprint published November 28, 2020. doi:10.31235/osf.io/s45yg
6. Taquet M, Luciano S, Geddes JR, Harrison PJ. Bidirectional associations between COVID-19 and psychiatric
disorder: retrospective cohort studies of 62 354 COVID-19 cases in the USA. Lancet Psychiatry. 2021;8(2):130-140.
doi:10.1016/S2215-0366(20)30462-4

JAMA Network Open. 2021;4(3):e213223. doi:10.1001/jamanetworkopen.2021.3223 (Reprinted) March 12, 2021 4/4

Downloaded From: https://jamanetwork.com/ by a Mexico | Access Provided by JAMA User on 12/09/2022