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. 2023 Feb 14;20(2):e1004171. doi: 10.1371/journal.pmed.1004171

Suicidal ideation following self-reported COVID-19-like symptoms or serology-confirmed SARS-CoV-2 infection in France: A propensity score weighted analysis from a cohort study

Camille Davisse-Paturet 1,*, Massimiliano Orri 2, Stéphane Legleye 1,3, Aline-Marie Florence 4, Jean-Baptiste Hazo 5, Josiane Warszawski 6, Bruno Falissard 1, Marie-Claude Geoffroy 2,7, Maria Melchior 4, Alexandra Rouquette 1,6; the EPICOV study group
Editor: Toshiaki A Furukawa8
PMCID: PMC10072374  PMID: 36787340

Abstract

Background

A higher risk of suicidal ideation associated with self-report of Coronavirus Disease 2019 (COVID-19)-like symptoms or COVID-19 infection has been observed in cross-sectional studies, but evidence from longitudinal studies remains limited. The aims of this study were 2-fold: (1) to explore if self-reported COVID-19-like symptoms in 2020 were associated with suicidal ideation in 2021; (2) to explore if the association also existed when using a biological marker of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in 2020.

Methods and findings

A total of 52,050 participants from the French EpiCov cohort were included (median follow-up time = 13.7 months). In terms of demographics, 53.84% were women, 60.92% were over 45 years old, 82.01% were born in mainland France from parents born in mainland France, and 59.38% completed high school. COVID-19-like symptoms were defined as participant report of a sudden loss of taste/smell or fever alongside cough, shortness of breath, or chest oppression, between February and November 2020. Symptoms were self-reported at baseline in May 2020 and at the first follow-up in Autumn 2020. Serology-confirmed SARS-CoV-2 infection in 2020 was derived from Spike protein ELISA test screening in dried-blood-spot samples. Samples were collected from October 2020 to March 2021, with 94.4% collected in 2020. Suicidal ideation since December 2020 was self-reported at the second follow-up in Summer 2021. Associations of self-reported COVID-19-like symptoms and serology-confirmed SARS-CoV-2 infection in 2020 with suicidal ideation in 2021 were ascertained using modified Poisson regression models, weighted by inverse probability weights computed from propensity scores. Among the 52,050 participants, 1.68% [1.54% to 1.82%] reported suicidal ideation in 2021, 9.57% [9.24% to 9.90%] had a serology-confirmed SARS-CoV-2 infection in 2020, and 13.23% [12.86% to 13.61%] reported COVID-19-like symptoms in 2020. Self-reported COVID-19-like symptoms in 2020 were associated with higher risks of later suicidal ideation in 2021 (Relative Riskipw [95% CI] = 1.43 [1.20 to 1.69]), while serology-confirmed SARS-CoV-2 infection in 2020 was not (RRipw = 0.89 [0.70 to 1.13]). Limitations of this study include the use of a single question to assess suicidal ideation, the use of self-reported history of mental health disorders, and limited generalizability due to attrition bias.

Conclusions

Self-reported COVID-19-like symptoms in 2020, but not serology-confirmed SARS-CoV-2 infection in 2020, were associated with a higher risk of subsequent suicidal ideation in 2021. The exact role of SARS-CoV-2 infection with respect to suicide risk has yet to be clarified. Including mental health resources in COVID-19-related settings could encourage symptomatic individuals to care for their mental health and limit suicidal ideation to emerge or worsen.

Camille Davisse-Paturet and colleagues investigate whether self-reported COVID-19-like symptoms and SARS-CoV-2 infection were associated with suicidal ideation amongst the general population in France.

Author summary

Why was this study done?

  • There is a need to investigate suicide-related outcomes in individuals exposed to virus responsible for epidemics.

  • Coronavirus Disease 2019 (COVID-19) infection seems associated with a higher risk of suicidal ideation, but studies exploring the association over time are limited.

What did the researchers do and find?

  • We explored if COVID-19-like symptoms in 2020, as reported by participants, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in 2020, as confirmed by serological tests, were associated with a higher risk of suicidal ideation in 2021 in 52,050 participants from a French longitudinal study from the general population, followed three times from May 2020 to July 2021 in France.

  • Among these participants, reporting COVID-19-like symptoms in 2020 was associated with a higher risk of reporting suicidal ideation in 2021 (relative risk [95% confidence interval] 1.43 [1.20 to 1.69), while having a serologically confirmed SARS-CoV-2 infection in 2020 was not associated with a higher risk of reporting suicidal ideation in 2021 (0.89 [0.70 to 1.13]). These results account for sociodemographic and health-related factors.

What do these findings mean?

  • Individuals experiencing COVID-19-like symptoms in the first year of the pandemic were at higher risk of later suicidal ideation, but this association was not observed for serologically confirmed SARS-CoV-2 infection. Thus, further study is needed to confirm the role of the virus in relation to suicide risk.

  • From a public health perspective, short communication on what to do when someone is experiencing poor mental health, whether directly after the onset of symptoms or a few months later, may be beneficial to address increase in suicidal ideation.

Introduction

Since the beginning of the Coronavirus Disease 2019 (COVID-19) pandemic, mental health specialists have raised concerns regarding the possibility of an increase in the risk of suicidal behaviors among persons recovering from COVID-19 [1–3]. Moreover, as shown by a recent systematic review, exploration of suicide-related outcomes in individuals infected by infectious threat responsible for epidemics are needed [4].

Regarding potential biological pathways, the exact role of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) with regard to mechanisms involved in suicide risk has yet to be demonstrated. Nonetheless, the virus’s ability to invade the central nervous system through fixation on angiotensin-converting enzyme 2 receptors [5], or to inflict brain damage through hyperinflammation [6], are potential candidates.

From a public health point of view, suicide risk related to COVID-19 disease was first supported by findings from cross-sectional studies and case series [7,8], and evidence from longitudinal studies are now emerging. A systematic review ascertaining the risk of suicidal and self-harm thoughts and behaviors among persons recovering from SARS-CoV-2 infection identified 11 relevant studies conducted between January 2020 and July 2021 and representing eight separate samples [9]. Eight out of the 11 studies reported elevated risk of suicidal or self-harm thoughts after SARS-CoV-2 infection. Unfortunately, these studies were quite heterogenous in terms of suicide risk assessment, study population, or design. Of note, the only study with a longitudinal design found that self-reported suspicion or diagnosis of COVID-19 was associated with an elevated risk of self-harm thoughts or behaviors over 59 weeks since the end of March 2020 [10]. Additionally, a longitudinal study from Australia also reported an increased risk of suicidal ideation in the three months following exposure to COVID-19, even when controlling for the pandemic’s impact on employment and financial distress [11]. Yet, as explained by the authors, the situation in Australia at the time of assessment, between March and June 2020, was quite different from that in other parts of the world, including Europe. In a paper gathering data from seven longitudinal cohorts from six Northern-Europe countries, the number of days spent in bed due to SARS-CoV-2 infection was cross-sectionally associated with mental health outcomes in a dose-effect fashion [12]. Participants not bedridden by the infection were at lower risk of both depressive and anxiety symptoms than those who were not infected, while those bedridden for seven days or more were at higher risk. As depressive and anxiety symptoms are known trigger of suicidal behaviors [13], taking into account both the infection status and its associated symptoms might therefore be relevant when studying suicide risk. Moreover, as both COVID-19 disease and suicidal behaviors are related to individuals’ sociodemographic and health characteristics [13,14], comprehensive information regarding theses aspects are needed to address the association between COVID-19 disease and suicidal behavior. As causal inference is not possible in observational studies, the use of propensity scores weighting methods, which balance all selected covariates between exposure groups, can be a mean of getting closer to assessment of direct association between an exposure and an outcome [15].

Our aim was therefore to study the association of self-reported COVID-19-like symptoms in 2020 with suicidal ideation in 2021. We also aimed to explore if the association could be found when using serology-confirmed SARS-CoV-2 infection. We used data from a French cohort from the general population and accounted for a wide range of sociodemographic and health-related factors through inverse probability weighting.

Methods

Study population

The Epidémiologie et conditions de vie sous le COVID-19 (EpiCov) study is a longitudinal, French cohort from the general population, aiming to provide information on the virus’ dissemination and the pandemic’s consequences on the daily life and health of individuals [16]. Eligibility criteria were to be at least 15 years of age in 2020, to reside in mainland France or three oversea territories (Martinique, Guadeloupe, and Réunion), and to not live in a medical retirement home or a jail. A total of 371,000 individuals were randomly selected from France’s national tax database, with an expected participation rate of about 50% and a sampling design overrepresenting less densely populated and more socioeconomically disadvantaged areas [17].

Data collection methods included both self-computer-assisted web interviews (CAWIs) and computer-assisted telephone interviews (CATIs). From the 371,000 randomly selected individuals invited to participate, 36.22% (134,391) actually participated at baseline in May 2020 (02/05/2020 to 02/06/2020). The first follow-up took place in Autumn 2020 (26/10/2020 to 14/12/2020, 107,759 participants), and the second follow-up took place in Summer 2021 (24/06/2021 to 09/08/2021, 85,074 participants). The EpiCov study timeline as well as data collected and used are resumed in Fig 1.

Fig 1. The EpiCov study timeline and data used.

Fig 1

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The EpiCov study received approval from an ethics committee (Comité de Protection des Personnes Sud Méditerranée III 2020-A01191-38) and from France’s National Data Protection Agency (Commission Nationale Informatique et Libertés, CNIL, MLD/MFI/AR205138).

The present study does not have a registered prospective protocol. An unpublished, informal analysis plan was made and discussed among study authors prior to the implementation of statistical analyses.

Outcome: Suicidal ideation in 2021

At the second follow-up in Summer 2021, suicidal ideation were ascertained with the question, “Since December 2020, have you thought about ‘killing yourself by suicide’?” Killing oneself by suicide is the closest translation of the actual French word used in the questionnaire “se suicider.” The outcome of interest was a binary variable representing the occurrence of suicidal ideation at least once between December 2020 and July 2021 (yes versus no).

Exposures

Serology-confirmed SARS-CoV-2 infection in 2020

The exact methodology for serology testing has been described elsewhere [16]. Briefly, consent to participate to SARS-CoV-2 serology testing with blood sampling kit was collected at the first follow-up in Autumn 2020. A total of 63,524 dried-blood-spot samples were screened for antibodies against SARS-CoV-2’s spike protein S1 domain, with a commercial ELISA kit. Samples with a serology-confirmed SARS-CoV-2 infection had an optical density ratio of at least 0.7. We pooled suspicious serologies (i.e., with an optical density ratio between 0.7 and 1.1) with positive ones (i.e., optical density ratio >1.1) as a decline in circulating antibodies might occur with time [18]. Of note, 94.4% of blood samples were collected before January 2021 and the start of the vaccination campaign in France. Serology-confirmed SARS-CoV-2 infections were therefore unlikely to be due to vaccination.

Self-reported COVID-19-like symptoms in 2020

In this study, COVID-19-like symptoms were symptoms described as most suspicious in 2020 by the French Public Health Agency. They referred to any unusual episode of sudden loss of taste/smell or any unusual episode of fever alongside a cough, shortness of breath, or chest oppression. At baseline in May 2020, participants reported COVID-19-like symptoms since the 17th of March 2020. At first follow-up in Autumn 2020, they reported COVID-19-like symptoms since February 2020. Pooling the two, this study’s self-reported COVID-19-like symptoms (yes versus no) were self-report of COVID-19-like symptoms at least once from February 2020 to Autumn 2020.

Propensity score covariates

Covariate selection for propensity score modeling was based on current literature, including recommendations from the International COVID-19 Suicide Prevention Research Collaboration [19]. In accordance with propensity score methodology [20], included factors were related to both COVID-19 and suicidal ideation or only to suicidal ideation [8]. Directed acyclic graphs (DAGs) supported framework conceptualization for the assessment of suicidal ideation related to COVID-19 and minimize bias though appropriate covariate selection [21,22] (S3 Supporting Information).

Sociodemographic and health covariates

The following sociodemographic covariates were ascertained at baseline and included in propensity scores: gender (man, woman), age (years), participant’s and participant’s parents’ place of birth (participant and parents born in mainland France, participant or parents born in oversea territories, participant born in France of parents born abroad, participant born abroad), highest educational attainment (none, lower secondary school certificate, professional certificate, higher secondary school certificate, bachelor degree or equivalent, Master degree or more), occupational grade (employed, student, unemployed, retired, other including housemakers), perceived financial situation (comfortable, decent, short, difficult or unbearable without taking loans), physical space in participant’s usual accommodation (less than one room per person, yes or no), residence not in usual housing during the first lockdown (yes or no, the first lockdown lasted from the 17/03/2020 to the 11/05/2020), access to safe outdoor space during the first lockdown (balcony or garden, including common ones, yes or no), and usual living area, ranked according to the intensity of the first COVID-19 wave in France (less affected areas, Grand-Est, Hauts-de-France, Ile-de-France). More information regarding the first COVID-19 epidemic wave in France are available in S2 Supporting Information.

The following health-related covariates were also ascertained: perceived general health status at baseline (very good to good, quite good, poor to very poor), baseline body mass index (BMI; less than 18.5 kg/m2, between 18.5 and less than 25 kg/m2, between 25 and less than 30 kg/m2, 30 kg/m2 or more), pre-pandemic somatic conditions (yes or no), pre-pandemic mental health disorder (yes or no), baseline tobacco use (current, past, never), and baseline alcohol use (daily, often, occasional, rare, never). Pre-pandemic mental health disorder included self-reported anxiety, depression, and mental disability, assessed at baseline, history of at least one suicide attempt before November 2019, assessed at first follow-up, and self-report of at least one physician diagnosis of anxiety, mood, bipolar, eating, personality or substance use disorder, or schizophrenia before the pandemic, assessed at second follow-up. A detailed description of the pre-pandemic mental health disorder covariate is available in S1 Supporting Information.

Available indicators

The following indicators, made available by The National Institute for Statistics and Economic Studies (INSEE), were taken into account: deciles of household income per consumption unit studied as a five-category covariate (less resourceful, medium-low, medium, medium-high, wealthiest), household structure (single, couple without children, couple with children, single-parent, participant living with parents, complex household), urban density of living area (oversea territories, less than 2,000 urban units, between 2,000 and 1,999,999 urban units, Paris area), residence in a deprived neighborhood (yes or no), and hospitalization rates in place of residence during the first lockdown (lowest, medium-low, medium-high, highest quartile). An urban unit is a built area with less than 200 meters between two buildings, comprising at least 2,000 inhabitants. A deprived neighborhood is an administrative category, describing an area where particular budgetary efforts are made by the State to tackle inequalities regarding education, early life care, housing and living conditions, employment, social cohesion, security, and crime prevention.

Statistical analyses

Suicidal ideation in 2020 as well as life course suicide attempts were assessed at the first follow-up in Autumn 2020 (Fig 1). The related questions were, respectively, “In the last 12 months, have you thought about ‘killing yourself by suicide’?” and “In your lifetime, have you ever attempted suicide? If so, when was the last one?” Yet, mediators are not supposed to be included in propensity score calculation. Suicidal ideation and suicide attempts in 2020 could act as mediator in the association of self-reported COVID-19-like symptoms in 2020 and serology-confirmed SARS-CoV-2 infection in 2020 with suicidal ideation in 2021. But, in EpiCov, no data were available regarding the first occurrence of COVID-19-like symptoms in 2020 or date of SARS-CoV-2 infection in 2020. We could therefore not ascertain if suicidal ideation or suicide attempt in 2020 occurred before or after the two COVID-19 exposures. To ensure no mediator was included in propensity score calculation, participants reporting suicidal ideation or a history of suicide attempt in 2020 or who did not provide information on the timing of their last suicide attempt had to be removed from the statistical analyses. Participants who reported a last suicide attempt before 2020 were included in the pre-pandemic mental health disorder covariate. Excluded participants are detailed in Fig 2. Do not wish to answer modalities had to be removed because of small sample size.

Fig 2. Flow chart.

Fig 2

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Descriptive statistics

Study weights were applied to all descriptive statistics (Tables 1, 2, 3 and S1) in order to take EpiCov’s design and attrition bias into account. Briefly, the study weights accounted for demographic and socioeconomic indicators potentially linked to response probability and made available by INSEE from the tax data base. Study weights were also calibrated on margins of the general population according to census data and population projections [23]. The numerators and denominators for each descriptive table are available in the supporting tables file (S2, S3, S4 and S5 Tables). Because descriptive statistics were weighted by study weights the presented percentages do not reflect the division of numerators by denominators. Except for included/excluded comparison, all presented percentages were pooled from five imputed data sets (more details below, SAS MIANALYZE procedure).

Table 1. Prevalence of exposures and covariates according to suicidal ideation in 2021, weighted by study weights, pooled from five imputed data sets.
Suicidal ideation in 2021
No (% [95% CI]) Yes (% [95% CI])
Serology-confirmed SARS-CoV-2 infection in 2020
    No 90.42% [90.09–90.76] 90.65% [88.21–93.08]
    Yes 9.58% [9.24–9.91] 9.35% [6.92–11.79]
Self-reported COVID-19 symptoms in 2020
    No 86.93% [86.55–87.31] 77.39% [74–80.78]
    Yes 13.07% [12.69–13.45] 22.61% [19.22–26]
Gender
    Men 46.17% [45.59–46.75] 45.71% [41.48–49.94]
    Women 53.83% [53.25–54.41] 54.29% [50.06–58.52]
Age (years)
    15–25 11.03% [10.67–11.38] 24.42% [20.68–28.16]
    26–45 27.72% [27.22–28.23] 34.1% [30.14–38.07]
    46–65 35.02% [34.49–35.54] 29.09% [25.57–32.6]
    >65 26.23% [25.66–26.8] 12.39% [9.22–15.56]
Place of birth
    Participant and parents born in mainland France 82% [81.5–82.49] 82.96% [79.67–86.25]
    Participants or parents born in oversea territories 1.96% [1.8–2.11] 2.21% [0.6–3.82]
    Participants born in France from parents born abroad 8.6% [8.25–8.94] 9.31% [7.03–11.6]
    Participants born abroad 7.45% [7.07–7.82] 5.51% [3.4–7.63]
Highest academic level
    No diploma 8.26% [7.81–8.71] 4.69% [2.54–6.84]
    Certificate from junior high at most 13.32% [12.84–13.8] 12.35% [9.36–15.35]
    Professional certificate 19.21% [18.75–19.66] 13.61% [10.64–16.57]
    Baccalaureat 19.49% [19.05–19.92] 23.24% [19.54–26.93]
    2 to 4 years after bac 25.3% [24.86–25.75] 27.4% [23.93–30.87]
    At least 5 years after bac 14.42% [14.09–14.76] 18.71% [15.64–21.78]
Pooled weighted % [95% confidence interval]
Individuals in each cell in each of the imputed data sets are available in S3 Table
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Table 2. Prevalence of serology-confirmed SARS-CoV-2 infection and covariates according to self-reported COVID-19-like symptoms in 2020, weighted by study weights, pooled from five imputed data sets.
Self-reported COVID-19 Symptoms in 2020
No (% [95% CI]) Yes (% [95% CI])
Serology-confirmed SARS-CoV-2 infection in 2020
    No 93.67% [93.36–93.97] 69.19% [67.81–70.58]
    Yes 6.33% [6.03–6.64] 30.81% [29.42–32.19]
Self-reported COVID-19 symptoms in 2020
    No
    Yes
Gender
    Men 46.79% [46.17–47.41] 42.03% [40.51–43.55]
    Women 53.21% [52.59–53.83] 57.97% [56.45–59.49]
Age (years)
    15–25 10.59% [10.21–10.96] 15.62% [14.51–16.72]
    26–45 26.32% [25.8–26.85] 37.72% [36.24–39.2]
    46–65 35.02% [34.46–35.58] 34.24% [32.85–35.63]
    >65 28.07% [27.45–28.69] 12.42% [11.27–13.58]
Place of birth
    Participant and parents born in mainland France 82.51% [81.99–83.03] 78.78% [77.37–80.19]
    Participant or parents born in oversea territories 1.99% [1.82–2.15] 1.81% [1.43–2.19]
    Participant born in France from parents born abroad 8.3% [7.94–8.66] 10.62% [9.6–11.64]
    Participant born abroad 7.2% [6.81–7.6] 8.79% [7.69–9.88]
Highest academic level
    No diploma 8.41% [7.92–8.89] 6.84% [5.72–7.95]
    Certificate from junior high at most 13.77% [13.25–14.29] 10.26% [9.13–11.38]
    Professional certificate 19.72% [19.23–20.22] 15.1% [13.97–16.22]
    Baccalaureat 19.31% [18.84–19.77] 21.16% [19.95–22.36]
    2 to 4 years after bac 24.77% [24.3–25.24] 29.06% [27.78–30.34]
    At least 5 years after bac 14.02% [13.67–14.37] 17.59% [16.6–18.58]
Weighted % [95% confidence interval]
Individuals in each cell in each of the imputed data sets are available in S4 Table
First LD: first lockdown (17/03/2020–11/05/2020)
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Table 3. Prevalence of self-reported COVID-19-like symptoms and covariates according to serology-confirmed SARS-CoV-2 infection in 2020, weighted by study weights, pooled from five imputed data sets.
Serology-confirmed SARS-CoV-2 infection in 2020
No (% [95% CI]) Yes (% [95% CI])
Self-reported COVID-19 symptoms in 2020
    No 89.87% [89.52–90.23] 57.41% [55.63–59.19]
    Yes 10.13% [9.77–10.48] 42.59% [40.81–44.37]
Gender
    Men 46.34% [45.73–46.95] 44.44% [42.62–46.26]
    Women 53.66% [53.05–54.27] 55.56% [53.74–57.38]
Age (years)
    15–25 10.77% [10.41–11.14] 15.78% [14.44–17.12]
    26–45 27.19% [26.67–27.71] 33.87% [32.15–35.6]
    46–65 35.16% [34.61–35.71] 32.61% [30.99–34.23]
    >65 26.87% [26.27–27.47] 17.74% [16.18–19.29]
Place of birth
    Participant and parents born in mainland France 82.81% [82.3–83.31] 74.52% [72.76–76.29]
    Participant or parents born in oversea territories 1.89% [1.72–2.05] 2.7% [2.14–3.25]
    Participant born in France from parents born abroad 8.22% [7.87–8.57] 12.25% [10.96–13.54]
    Participant born abroad 7.08% [6.71–7.46] 10.53% [9.12–11.94]
Highest academic level
    No diploma 8.23% [7.76–8.7] 7.94% [6.51–9.38]
    Certificate from junior high at most 13.56% [13.06–14.06] 10.92% [9.58–12.26]
    Professional certificate 19.56% [19.08–20.04] 14.89% [13.64–16.14]
    Baccalaureat 19.38% [18.92–19.83] 21.19% [19.71–22.66]
    2 to 4 years after bac 25.05% [24.59–25.51] 28.03% [26.52–29.54]
    At least 5 years after bac 14.23% [13.88–14.57] 17.03% [15.88–18.18]
Weighted % [95% confidence interval]
Individuals in each cell in each of the imputed data sets are available in S5 Table
First LD: first lockdown (17/03/2020–11/05/2020)
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Inverse probability weighting and modified Poisson regression models

First, propensity scores associated with (a) reporting COVID-19-like symptoms or (b) having a serology-confirmed SARS-CoV-2 infection were computed using logistic regression models based on the covariates described above. Then, propensity scores were included in statistical models using inverse probability weights (IPWs; S5 Supporting Information). Balance after IPWeighting was considered satisfactory if (1) absolute standardized mean differences (SMDs) between each covariate, as well as each modality of each covariate were below 10%, and (2) variance ratios of propensity scores computed after weighting were between 0.5 and 2 [15,20]. Covariates distribution after weighting was also assessed with chi-squared and Student t tests. Lastly, IPWeighted modified Poisson regression models with robust error variance were used to assess the association between both COVID-19 exposures in 2020 and suicidal ideation in 2021 [24]. If after IPWeighting residual distribution differences remained for some covariates, regression models were further adjusted for these incompletely balanced covariates. Models were therefore further adjusted for highest educational attainment for the self-reported COVID-19-like symptoms in 2020 model, and for highest educational attainment, perceived financial situation, household income, and residence in deprived neighborhood for the serology-confirmed SARS-CoV-2 infection in 2020 model.

Sensitivity analyses

To test the robustness of our results, we also estimated relative risks (RRs) by weighting the reference groups (no self-reported COVID-19-like symptoms; SARS-CoV-2-negative serology) to match the covariates’ distribution in the exposed groups (respectively, self-reported COVID-19-like symptoms; serology-confirmed SARS-CoV-2 infection). This method, called average treatment effect on the treated (ATT; S5 Supporting Information), assesses what would have happened to participants who reported COVID-19-like symptoms, or who had a serology-confirmed SARS-CoV-2 infection, if they had not reported symptoms and been infected. The more consistent the estimated RRs in IPWeighted and ATTWeighted analyses, the more robust the results.

Interactions between gender, or age, and the two COVID-19 exposures in 2020 with respect to later suicidal ideation in 2021 were assessed but did not reached statistical significance (all p-value above 0.20).

In response to peer review comments, the following four sets of sensitivity analyses were also performed.

As pre-pandemic mental health disorder were partly assessed at the second follow-up, a memory bias cannot be ruled out. A sensitivity analysis removing the variable from propensity scores calculation was therefore performed.

As occurrence of COVID-19-like symptoms since December 2020, ascertained at the second follow-up in Summer 2021, can be associated with suicidal ideation between December 2020 and Summer 2021, a sensitivity analysis (i.e., propensity score calculation and IPWeighted Poisson regression model) was performed, removing participants who reported COVID-19-like symptoms between December 2020 and Summer 2021 (n = 4,564).

Time between self-reported COVID-19-like symptoms and suicidal ideation was also explored. We therefore conducted three sensitivity analyses ascertaining the association of self-reported COVID-19-like symptoms in 2020 with suicidal ideation in 2021, where COVID-19 symptoms were defined as follows: (1) self-reported COVID-19-like symptoms with last onset in the two months before first follow-up in Autumn 2020; (2) self-reported COVID-19-like symptoms with last onset four to six months before first follow-up in Autumn 2020; (3) self-reported COVID-19-like symptoms with last onset more than six months before first follow-up in Autumn 2020. In all three sensitivity analyses, the reference group reported no COVID-19-like symptoms.

Lastly, to explore the intersection of both COVID-19 exposures with respect to suicidal ideation, association of self-reported COVID-19-like symptoms before December 2020 with subsequent suicidal ideation in 2021 was separately assessed according to the SARS-CoV-2 serological status.

All the analyses were performed using SAS V9.4. Tests were two-sided and considered statistically significant at p < 0.05. Missing data on covariates (up to 4.84%) were handled using the fully conditional specification method and assuming that data were missing at random (SAS MI procedure, FCS statement, five imputed data sets; S4 Supporting Information). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Strobe Checklist).

Results

Main analysis

Among the 52,050 participants, 1.7% [1.5 to 1.8] (n = 863) reported suicidal ideation between December 2020 and Summer 2021, 9.6% [9.2 to 9.9] (n = 5,091) had a serology-confirmed SARS-CoV-2 infection in 2020 and 13.2% [12.9 to 13.6] (n = 7,043) reported COVID-19 symptoms between February and November 2020. Of note, among participants who reported COVID-19-like symptoms, 30.8% [29.4; 32.2] had a serology-confirmed SARS-CoV-2 infection (Table 2). Among participants with a serology-confirmed SARS-CoV-2 infection, 42.6% [40.8; 44.4] reported COVID-19-like symptoms (Table 3). Using unadjusted modified Poisson regression model, self-reported COVID-19 symptoms were associated with a higher risk of suicidal ideation (RR [95% CI]: 1.90 [1.63 to 2.23]), while the same association was not observed for serology-confirmed SARS-CoV-2 infection (0.98 [0.78 to 1.23]).

As shown in Fig 3, after IPWeighting, self-reported COVID-19-like symptoms in 2020 were associated with a higher risk of suicidal ideation in 2021 (RRipw: 1.43 [1.20 to 1.69]), while serology-confirmed SARS-CoV-2 infection were not (RRipw: 0.89 [0.70 to 1.13]).

Fig 3. Relative risk of suicidal ideation following self-reported COVID-19-like symptoms or SARS-CoV-2 infection in the EpiCov cohort.

Fig 3

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Sensitivity analyses

Sensitivity ATTWeighted analyses yielded similar results as the IPWeighted ones. Self-reported COVID-like symptoms in 2020 were associated with a higher risk of suicidal ideation in 2021 (RRwatt: 1.43 [1.22 to 1.68]), while serology-confirmed SARS-CoV-2 infection in 2020 was not associated with suicidal ideation in 2021 (RRwatt: 0.93 [0.75 to 1.18]) (Fig 3).

When removing the pre-pandemic mental health disorder variable from propensity scores calculation, self-reported COVID-19-like symptoms in 2020 were associated with subsequent suicidal ideation in 2021 (RRipw [95% CI]: 1.51 [1.27 to 1.79]), while serology-confirmed SARS-CoV-2 infections were not (RRipw: 0.87 [0.69 to 1.11]).

In line with main analyses, among participants who reported no COVID-19-like symptoms between December 2020 and Summer 2021, self-reported COVID-19-like symptoms in 2020 were associated with a higher risk of suicidal ideation in 2021 (RRipw: 1.40 [1.14 to 1.71]) (S6 Supporting Information).

Regarding the sensitivity analyses accounting for the period of the last symptom onset, among participants who reported COVID-19-like symptoms in 2020, 27.2% [25.9 to 28.6] reported a last onset in the two months before first follow-up in Autumn 2020, 25.8% [24.5 to 27.1] reported a last onset four to six months before first follow-up in Autumn 2020, and 47.0% [45.4 to 48.5] reported a last onset more than six months before first follow-up in Autumn 2020. A total of 19 participants had missing data on timing of the last COVID-19 symptoms onset. In line with main analyses, self-reported COVID-19-like symptoms with last onset in the two months before first follow-up were associated with a higher risk of later suicidal ideation in 2021 (RRipw [95% CI]: 1.82 [1.39 to 2.39]). However, when the last onset of self-reported COVID-19-like symptoms was four to six months or more than six months before first follow-up, no association was found with suicidal ideation in 2021 (RRipw: 1.24 [0.91 to 1.67] and 1.24 [0.95 to 1.62], respectively) (S6 Supporting Information).

Lastly, the sensitivity analysis exploring the association of self-reported COVID-19-like symptoms with later suicidal ideation according to SARS-CoV-2 serology yielded similar results, although statistical significance was reached in one group but not the other (RRipw: 1.49 [0.95 to 2.32]), in the serology-confirmed SARS-CoV-2 infection group; RRipw: 1.49 [1.22 to 1.83], in the negative SARS-CoV-2 serology group) (S6 Supporting Information).

Discussion

Summary of findings

In a large French cohort from the general population, self-reported COVID-19-like symptoms in 2020, as defined by self-reports of sudden loss of taste/smell or fever alongside cough or shortness of breath or chest oppression, were associated with a higher risk of later suicidal ideation in 2021. Associations persisted after adjusting for a wide range of sociodemographic and health-related factors, using inverse probability weighting. Sensitivity analyses showed that participants with more recent symptoms were the most at-risk ones. When using serology-confirmed SARS-CoV-2 infection in 2020, as confirmed by circulating antibodies in dried-blood-sport samples collected for the cohort, no association was found with suicidal ideation in 2021. To the best of our knowledge, it is the first time the associations of self-reported COVID-19-like symptoms and serology-confirmed SARS-CoV-2 infection in 2020 with suicidal ideation in 2021 are assessed in a large, randomly selected, longitudinal study, using propensity score weighting methods.

Serology-confirmed SARS-CoV-2 infection and suicidal ideation

Our findings suggest that SARS-CoV-2 is not likely to be involved in suicidal ideation. Although misclassification of infected individuals with very low levels of circulating antibodies cannot be ruled out, misclassification due to a new variant impairing effective detection of antibodies in blood samples seems unlikely as the first known variant of concern, the Alpha variant, was first observed in France at the very end of 2020 [25].

A recent study using two propensity score-matched cohorts from health databases found that the higher risk of mood and anxiety disorders seen after a SARS-CoV-2 infection was transient, with no evidence of a greater risk about 100 days (three months) after the infection, as compared with other respiratory infection [26]. The SARS-CoV-2 infection definition used was the International Classification of Disease 10th edition (ICD-10) code 07.1, i.e., COVID-19 confirmed by laboratory testing irrespective of severity of clinical signs or symptoms. Similar results were also found in the meta-analysis of five European cohorts were a higher risk of depressive symptoms was found in the first two months following a SARS-CoV-2 infection diagnosis (self-reported positive polymerase chain reaction (PCR) or antibody test), but not after [12]. In the present study, time between SARS-CoV-2 infection and suicidal ideation could not be assessed. Nonetheless, the two COVID-19 waves in 2020 in France occurred in early Spring 2020 and Autumn 2020, while consultation in emergency department for suicide attempt in the first half of 2021 were on the rise in March and June. It is therefore possible that, in our study, the mean time between the SARS-CoV-2 infection detected by serology testing and suicidal ideation in 2021 exceeded two months, possibly explaining the absence of association found. Although we acknowledge that depressive symptoms do not always lead to suicidal ideation and that the link between suicidal ideation and suicidal attempt is not linear, our results seem in line with current findings.

Self-reported COVID-19-like symptoms and suicidal ideation

Several hypotheses can explain the association between self-reported COVID-19-like symptoms and subsequent suicidal ideation. First are the consequences of a symptomatic illness on the quality of life. Symptomatic COVID-19 may require hospitalization or may have long-lasting symptoms, which both can affect mental health, whether directly or indirectly by, for example, affecting employment or financial outcome first [27–29]. A possible way of preventing symptomatic individuals to experience suicidal ideation could therefore be through policies aiming at mitigating the socioeconomical impact of the pandemic [30]. Second, anxiety and depressive symptoms could act as mediators of the relationship between COVID-19 and suicidal ideation [10,12,29]. Third, Paul and Fancourt showed that COVID-19 illness or death among friends/family or closed ones was associated with a higher risk of self-harm thoughts and behaviors [10]. This was also true for worries about relatives in the preceding week. As COVID-19 is a communicable disease, individuals with symptomatic COVID-19 could be more likely to have symptomatic cases among their relatives, increasing their risk of suicidal ideation, especially if they feel responsible for their relatives’ infection.

In our sensitivity analyses, we found that participants with more recent onset of COVID-19-like symptoms in 2020 were at higher risk of suicidal ideation in 2021. But the association was not found in participants with older onset. In lines with other findings [12,26], the first few months after the infection seem to be a critical window for the onset of mental health disorders. The difference seen in statistical significance for the association of COVID-19-like symptoms with later suicidal ideation according to SARS-CoV-2 serological status is likely to be due a lack of statistical power to assess such association in the serology-confirmed SARS-CoV-2 infection group.

Strengths and limitations

A main limitation of our study is the lack of prospectively collected pre-pandemic information as the EpiCov study was initiated in 2020. Nonetheless, many pre-pandemic characteristics were collected retrospectively and could be considered. Specific attention was given to reports of previous mental health disorders, as they are key predictors of suicidal behaviors [13]. We considered participants’ history of anxiety, depression, or mental impairment, history of suicide attempt before November 2019, and self-report of a physician diagnosis of psychiatric disorders. Although less accurate than prospectively collected or health record data, these information give valuable insights of pre-pandemic mental health conditions.

A second limitation of our study is the use of a single question to assess suicidal ideation, which did not specifically explore whether suicidal ideation was active or passive, or whether the participants had an explicit suicidal plan. Scales specifically designed to assess suicidal ideation and behaviors [31–33] would have given a more accurate picture of the severity, chronicity, and intentionality of these thoughts and their association with COVID-19-like symptoms.

Regarding propensity scores, balance between persons who did or did not experience COVID-19 is only achieved for covariates included in propensity score estimations. Definition of relevant factors to assess COVID-19 disease and suicidal ideation was based on the existing scientific literature and availability of information in study questionnaires. The probability of imperfect balance due to unmeasured factors cannot be ruled out.

Lastly, although the EpiCov cohort is based on a randomly selected sample, attrition overtime as well as successive steps of participant selection for analyses purpose limit the generalizability of our results. Difference between included and excluded participants can be found in S1 Table. Of note, included participants were less likely to report suicidal ideation in 2021 but more likely to report COVID-19-like symptoms, potentially leading to an underestimation of the association between the two. Such difference was, however, not found for serology-confirmed SARS-CoV-2 infection.

Conclusions

Self-reported COVID-19-like symptoms in 2020, especially recent ones, but not serology-confirmed SARS-CoV-2 infection in 2020 were associated with a higher risk of subsequent suicidal ideation in 2021 while adjusting for a wide range of sociodemographic and health-related factors using inverse probability weighting. In a pandemic context, bringing awareness on mental health in the first few months following a symptom onset could limit an increase in suicidal ideation. Mental health resources could, for example, be made available in COVID-19-related settings such as family doctors waiting room, pharmacies, or COVID-19 screening places. Examples of mental health resources include help lines numbers and websites, or brief and accessible description of what a deteriorated mental health can look like, and guidance on what to do when experiencing it.

Supporting information

S1 STROBE checklist. STROBE checklist for cohort studies.

(DOCX)

Click here for additional data file. (34.2KB, docx)
S1 Acknowledgements. Membership of the EpiCoV study group.

(DOCX)

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S1 Supporting information. Detailed description of the pre-pandemic mental health disorders variable construction.

(DOCX)

Click here for additional data file. (12.7KB, docx)
S2 Supporting information. Evolution of total number of deaths by French departments during the first COVID-19 epidemic wave.

(DOCX)

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S3 Supporting information. Directed acyclic graph.

(DOCX)

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S4 Supporting information. Multiple imputation information.

(DOCX)

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S5 Supporting information. Propensity score methodology.

(DOCX)

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S6 Supporting information. Graphic representation of sensitivity analyses results.

(DOCX)

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S1 Table. Comparison of EpiCov participants included versus excluded from analyses using two-sided chi-squared tests.

(XLSX)

Click here for additional data file. (15.6KB, xlsx)
S2 Table. Numerators and denominators of S1 Table.

(XLSX)

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S3 Table. Numerators and denominators of the exposures and covariates, according to the onset of suicidal ideation in 2021, in each of the five imputed data sets.

(XLSX)

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S4 Table. Numerators and denominators of covariates according to the COVID-19 symptoms variable in each imputed data set.

(XLSX)

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S5 Table. Numerators and denominators of covariates according to the SARS-CoV-2 variable in each imputed data set.

(XLSX)

Click here for additional data file. (16.5KB, xlsx)
S6 Table. Covariates name and definition for multiple imputation.

(XLSX)

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S7 Table. Parameters of the propensity scores balance for COVID-19-like symptoms.

(XLSX)

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S8 Table. Parameters of the propensity scores balance for COVID-19-like symptoms for each covariate.

(XLSX)

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S9 Table. Parameters of the propensity scores balance for SARS-CoV-2 serology.

(XLSX)

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S10 Table. Parameters of the propensity scores balance for SARS-CoV-2 serology for each covariate.

(XLSX)

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Abbreviations

ATT

average treatment effect on the treated

BMI

body mass index

CATI

computer-assisted telephone interview

CAWI

computer-assisted web interview

COVID-19

Coronavirus Disease 2019

DAG

directed acyclic graph

INSEE

The National Institute for Statistics and Economic Studies

IPW

inverse probability weight

PCR

polymerase chain reaction

RR

relative risk

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

SMD

standardized mean difference

Data Availability

All anonymous aggregated data regarding the results presented in this paper are available online and on supporting information files. The non-aggregated individual data cannot be shared publicly because of European Regulation 2016/679. Nonetheless, these data can be made available after submission to approval of French Ethics and Regulatory Committee procedure (Comité du Secret Statistique, CESREES and CNIL). The access procedure is available on the Centre of Secured Access to Data website (https://www.casd.eu/).

Funding Statement

The present work was supported by a research grant from the department of research, studies, evaluation and statistics (Direction de la Recherche, des Etudes, de l’Evaluation et des Statistiques, Drees) of the French Ministry for Research attributed to AR (grant number R21094LL). The EpiCov study received institutional fundings from Inserm (Institut National de la Santé et de la Recherche Médicale), the French Ministry for Research and its department of research, studies, evaluation and statistics (Direction de la Recherche, des Etudes, de l’Evaluation et des Statistiques, Drees), the French Ministry for Health, and the Région Ile de France. https://drees.solidarites-sante.gouv.fr/article/observatoire-national-du-suicide https://www.inserm.fr/ https://www.enseignementsup-recherche.gouv.fr/fr https://drees.solidarites-sante.gouv.fr/ https://solidarites-sante.gouv.fr/ https://www.iledefrance.fr/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Callam Davidson

1 Jul 2022

Dear Dr Davisse-Paturet,

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Decision Letter 1

Callam Davidson

24 Aug 2022

Dear Dr. Davisse-Paturet,

Thank you very much for submitting your manuscript "COVID-19 illness, SARS-CoV2 infection, and subsequent suicidal ideation in the French nationwide population-based EpiCov cohort: a propensity score analysis of more than 50,000 individuals." (PMEDICINE-D-22-02146R1) for consideration at PLOS Medicine for our upcoming Special Issue.

Your paper was evaluated by an associate editor and discussed among all the guest editors. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

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In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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Comments from the Academic Editor

1) First I have some logical difficulty in understanding the examined cause-effect relationship. The outcome is the suicidal ideation between Dec 2020 and June 2021, based on a single question “Have you thought about committing suicide in the past year” (and then excluding those who said they did so in Nov 2020). The exposure is self-reported COVID-19 symptoms or serology-confirmed SARS-COV2 infection at the 2nd wave, hence between the beginning of the pandemic and Nov 2020.

Can one expect to have an increase (or decrease) in thinking about committing suicide in, say, May 2021 when they had COVID-19 symptoms or SARS-COV2 infection in May 2020? If any such cause-effect is present, would it not be more natural to expect such in June-November 2021 but how are such possibilities accounted for or not accounted for in the present analyses?

In a similar vein, if someone had symptoms or infection in Jan 2021, it could have had an effect on suicidal ideation between Jan and June 2021 (this is a hypothesis that the study is examining), but where are such possibilities accounted for in the present analyses?

2) As suggested by Reviewer #3, I think the timeline of the study is essential to understanding all these and an expanded version of their Supplementary Fig 1 must be included in the main text.

3) Like Reviewer #2, I also have a difficulty calling this study as nationally representative, when only 16% of the originally nationally representative population is analyzed.

4) Looking at their Supplementary Fig 1, the variables (pre-pandemic diagnoses measured at the 3rd wave) are included in calculating the IPW. Sure, they are supposed to be pre-baseline but they are subjectively recalled at the same time as the outcome measurement. I wonder if the authors need not report at least a sensitivity analysis excluding this variable in the IPW calculation.

5) Although the statistical reviewer is basically OK with the analyses, I am not sure if the authors have done their best to impute the missing data. When the authors can use multiple imputation, is it justified to exclude almost 30000 (so amounting to some 60% of the final sample) for missing that variable (while they must have had other data because these 30000 did respond in principle to the surveys). Likewise some 2400 people are excluded because they had missing data on suicidality (but apparently had other data): in this situation, could they also not impute the missing outcome, using some auxiliary variables?

6) I agree with Reviewer #3 that the relationship (overlaps) between those with self-reported COVID-19 symptoms and those with serologically confirmed SARS-COV2 infection. Could they be non-overlapping? If so, what could each mean, especially the former? Could some further analysis focusing on those with self-reported symptoms but without serological confirmation shed some more light?

Requests from the editor

Throughout: Consider whether the term ‘COVID-19 illness’ ought to be updated to ‘COVID-19 symptoms’ to describe more accurately what was assessed in the study.

Title: Related to the above, please revise your title to “COVID-19 symptoms, SARS-CoV2 infection, and suicidal ideation in France: A population-based propensity score–matched cohort study”, or similar.

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions).

Abstract Methods and Findings:

* Please include the length of follow up.

* In the last sentence of the Abstract Methods and Findings section, please describe the main limitations of the study's methodology.

The Data Availability Statement (DAS) requires revision. If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Citations should be preceding punctuation.

Please include paragraphs in your Introduction.

The terms gender and sex are not interchangeable (as discussed in https://www.who.int/health-topics/gender); please use the appropriate term.

Ethics: Please specify whether informed consent was written or oral.

Please remove the Role of the Funding Source section.

Please remove the Authors contribution and Data Sharing, and Acknowledgements section from the main text as all the relevant information is captured as metadata via the Submission Form. You are welcome to still include an Acknowledgements section but it should not contain details of study funders.

Please remove italic formatting in the References and include the first six author names before et al.

Please do not report P<0.0001, report instead as P<0.001 (Supporting Information).

Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

Comments from the reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

Davisse-Paturet et al present an impressive analysis of data from a national cohort study, looking at the association between COVID-19 and subsequent suicidal ideation. This review considers the use of statistics in the paper.

The basic method of deriving models to predict the propensity of having COVID-19 illness or SARS-Cov-2 infection, and using these to weight the analysis of each exposure variable and the outcome, is good. I thought the paper was clearly written, and the results are well presented and interpreted, so my comments are fairly minor.

One exception is the use of the E-value. Whilst I think it is a nice idea, the more I read about it, the less convinced I am that it really adds very much. Ultimately, it is simply a transformation of the estimated association between exposure and outcome, so I think it could be excluded without affecting the paper.

Lines 184-188 describe the methods for dealing with missing covariate data. Personally, I think if you are going to that much trouble, it is worth doing multiple imputation of the missing data, so as to allow for the additional uncertainty due to the missingness.

Lines 213-214 say that the estimated association between COVID-19 illness and suicidal ideation was unchanged after IPW. I would disagree. The estimate reduces from 1.90 to 1.43, so it had roughly halved after reweighting. In Figure 2, there is a visible reduction in the estimated association. The authors describe the adjusted association of 1.43 as "an almost 1.5 higher risk", which I think is a slight exaggeration. I would just say "a 43% higher risk".

Did the authors consider a combined model, adjusting for both COVID-19 illness and SARS-Cov-2 infection? Was there a big overlap between the two? Could there be an interaction?

Line 234: These sorts of analysis have come to be known as "causal" analyses, but I think this is a misleading term. These methods are a good way to adjust an analysis of the association between an exposure and an outcome, but the final estimated association cannot be described as "causal". As with any observational study, the possibility of unobserved confounders will always remain.

In Figure 1, the final set of exclusions are described as having "Insufficient 'Do not wish to answer' to be analysed". Is the word "Insufficient" correct here?

I would rather see Table 1 with separate columns for those with and without the outcome, and for those who are exposed/unexposed. The "by-outcome" table is given in table S2, but could "by-exposure" tables also be shown?

Finally, and I hope this is just a typo, but in the supplement, the weights for the exposed group are given as 1/(1-p), and for the unexposed as 1/p. I believe it should be the other way round. Those who were exposed, despite having a low probability of being exposed (i.e. small p) should be up-weighted in the analysis, as should those who were unexposed, despite a high probability of being exposed (high p, small 1-p).

Also, I prefer "exposed/unexposed" over "case/control" in this context, since this is not a case-control study.

Reviewer #2: I read the manuscript "COVID-19 illness, SARS-CoV2 infection, and subsequent suicidal ideation in the French nationwide population-based EpiCov cohort: a propensity score analysis of more than 50,000 individuals" with great interest and would like to share the following few thoughts with the authors.

1. The authors found that self-reported COVID-19 symptoms are indicative of suicidal ideation whereas serology-confirmed SARS-CoV2 infection was not. Before we speculate the underlying reasons for such disparity, I wonder if the authors could clarify the number of participants with both self-reported symptoms and serology-confirmed infection. Namely, among the 9.57% with a SARS-CoV2 infection in 2020 and 13.23% that reported COVID-19 symptoms, how many had both?

2. Related to this, can the authors provide a comparison between the above two groups, something similar as the Supplementary table 2? This will likely help us to understand the differences between these two groups of participants.

3. According to Supplementary Table 1, the participants included in the final analysis are rather different from the participants excluded from the analysis. Specifically, there seems to be a higher prevalence of self-reported COVID-19 symptoms, but a lower prevalence of suicidal ideation, among the included participants, compared with excluded participations. This will likely lead to an underestimated association between self-reported symptoms and suicidal ideation. This is however not the case for serology-determined infection.

4. Related to the above, I think the authors cannot claim their data as population-based, because the study participants included in the analyses are not representative of the underlying source population. This should rather be discussed as a limitation of the study.

Reviewer #3: This manuscript examines the impact of COVID-19 illness and SARS-CoV2 infection on suicidal ideation in a cohort, EpiCOV, which is a longitudinal nationwide French cohort aimed at examining the impact of the pandemic on daily life and health of individuals. The study consisted of three waves of data collection. The sample size analyzed was 52,050 participants aged 15 years and older who had participated in the second wave of follow-up and participated in dried-blood-spot sampling kit to test for antibodies against SARS-COV2's spike protein S1 domain and answered questions regarding suicidal ideation. The survey asked the following question at the 3rd wave of the study: "Since December 2020, have you thought about committing suicide (yes/no)?". There were also questions about thoughts of suicide in the last 12 months and lifetime suicide attempts. Self-reported symptoms of COVID-19 were assessed and defined as a self-report of any unusual episode of sudden loss of taste/smell or any unusual episode of fever alongside a cough, shortness of breath, or chest oppression. The study is timely and addresses an important research question that has not been studied yet. The large sample size, longitudinal design, examining serology to test for COVID-19 antibodies, and the use of propensity scores to control for covariates and potential confounders are all major strengths. Below are some concerns that if addressed, it would strengthen the study.

- The manuscript is not clear on the temporality of assessments between exposure and outcome. It would help to include a figure to describe the waves of the study and when questions were asked about exposure and outcome. The outcome is described at multiple points in the manuscript with questions about suicidal ideation since the pandemic and in the last 12 months.

- The authors do not describe the baseline characteristics of the sample analyzed vis-a-vis the rest of the sample who were not included in the analyses. It is difficult to determine potential ascertainment biases without this comparison.

- It is not clear how the authors assessed prior history of suicidal behavior and mental disorders. It would help to include more details and whether there were screens for depression and anxiety symptoms.

- It is not clear why the authors excluded those with prior history of suicidal behavior between November 2019 and 2020 when someone could reattempt and those with a prior history are at highest risk for re-attempt.

- It would be important to include more details about the study weights and how they were computed.

- The description of the sample's characteristics is based on some subgroups when there's variability (e.g., non-smokers when there were a good proportion of the sample who were past or current smokers).

- One of the limitations of the study is the assessment of ideation and attempt using individual items. The questions do not differentiate between passive and active suicidal ideation; and whether the suicide attempts were actual vs. gestures and/or preparatory behaviors. The authors need to refer to suicide attempt as suicidal behavior as the latter is often referring to actual suicide attempt, which was not assessed here.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Callam Davidson

24 Nov 2022

Dear Dr. Davisse-Paturet,

Thank you very much for re-submitting your manuscript "Suicidal ideation following self-reported COVID-19 like symptoms or serology-confirmed SARS-CoV2 infection in France: a propensity score weighted analysis from a cohort study" (PMEDICINE-D-22-02146R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

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We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 01 2022 11:59PM.   

Sincerely,

Callam Davidson,

Associate Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editor:

Please address the comment from the statistical reviewer.

The Data Availability Statement (DAS) requires revision. For each data source used in your study:

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address).

Please correct 'SARS-CoV2' to 'SARS-CoV-2' throughout.

Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions). Please combine the Methods and Findings sections into one section, “Methods and findings”.

Please update the beginning of your abstract to read: 'A higher risk of suicidal ideation associated with self-reported COVID-19 like symptoms or COVID-19 infection has been observed in cross sectional studies, but evidence from longitudinal studies remains limited. This study's aims...'

In the last sentence of the Abstract Methods and Findings section, please describe the main limitations of the study's methodology (the sentence that currently finishes the abstract 'Methods' can be relocated).

In the Abstract Conclusions, please avoid vague statements such as those in the concluding sentence of the abstract. Instead, mention specific implications substantiated by the results.

Please include a basic demographic summary of your sample in the Methods and Findings of your Abstract.

Please structure your author summary using 2-3 single sentence bullet points for each of the three questions. Bullet points should be objective, brief, succinct, specific, accurate, and avoid technical language.

Line 46: 'dose-response fashion'.

The terms gender and sex are not interchangeable (as discussed in https://www.who.int/health-topics/gender); please consider whether sex (and thus male/female) would be the more appropriate term dependent on how this covariate data was collected.

Please cite your Supporting Information as outlined here: https://journals.plos.org/plosmedicine/s/supporting-information

For international readers unfamiliar with how residential areas in France were affected during the pandemic, it may be useful to provide further details regarding this categorisation (i.e., brief overview of Grand-Est, Hauts-de-France-Ile-de-France).

Line 226: 'sensitivity analysis'

Lines 229-241: This reads as a description of the sensitivity analysis results. Please only describe methodology in the Methods section and relocate description of findings to the Results section.

Please update your STROBE checklist to use section names and paragraph numbers, as page/line numbers are likely to change.

Table 1 does not appear to be cited anywhere in the main text.

Please present numerators and denominators for percentages, at least in the Tables.

Please define the abbreviation DOM in Table legends.

The term 'mental health behaviour' may present a translation issue as the meaning is ambiguous. Please provide a definition of this term.

Please update 'associated to' to 'associated with' throughout.

Please consider tabulating the results of your sensitivity analyses and presenting these in the Supporting Information.

Lines 359-361: I feel this should be in the Limitations section.

Your concluding sentence (line 395-396) introduces the concept of socioeconomic involvement, despite this not being a key finding of your study. I would suggest moving this sentence earlier in the Discussion.

Please carefully check your references for formatting issues, I noted problems with references 5, 12, and 22.

Reference 23 is a preprint and ought to be identified as such (see https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references for further guidance).

Comments from Reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

I thank Davisse-Paturet et al for their responses to my original comments, and I am mostly happy with these.

The one exception is their handling of the association between COVID-19 illness and suicidal ideation separately in those with and without confirmed SARS-Cov-2 infection. The authors state that there was an association in the uninfected subgroup, but not the infected subgroup. However, the RRs are identical in the two groups. The fact that the p-value is significant for one but not the other is not the correct way to assess these associations. It would be better to fit a single model and test the interaction between illness and infection; given the results presented, this will be non-significant, meaning that there is no evidence to suggest that the association between COVID-19 illness and suicidal ideation is any different in those with or without confirmed infection.

Reviewer #2: Thank you for the responses to my comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Callam Davidson

3 Jan 2023

Dear Dr. Davisse-Paturet,

Thank you very much for re-submitting your manuscript "Suicidal ideation following self-reported COVID-19 like symptoms or serology-confirmed SARS-CoV-2 infection in France: a propensity score weighted analysis from a cohort study" (PMEDICINE-D-22-02146R3) for review by PLOS Medicine.

Before we can accept the paper for publication in the journal, we require that you address a few remaining issues.

The remaining issues that need to be addressed are listed at the end of this email. Please take these into account before resubmitting your manuscript.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Jan 10 2023 11:59PM.   

Sincerely,

Callam Davidson,

Associate Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Please update your abstract introduction such that the first sentence reads: 'A higher risk of suicidal ideation associated with self-reported COVID-19 like symptoms or COVID-19 infection has been observed in cross sectional studies, but evidence from longitudinal studies remains limited. The aims of this study were twofold...'.

The final sentence of the abstract introduction (‘Propensity scores…’) can be deleted as this information is already present in the abstract methods and findings.

The additional demographic data included in the abstract can be moved to the beginning of the abstract methods and findings, i.e., ‘52,050 participants from the French EpiCov cohort were included (median follow-up time = 13.7 months). In terms of demographics, 53.84% were women…’ etc.

Please update your abstract conclusions such that the first sentences read: ‘Self-reported COVID-19-like symptoms in 2020, but not serology-confirmed SARS-CoV-2 infection in 2020, were associated with a higher risk of subsequent suicidal ideation in 2021. The exact role of SARS-CoV-2 infection with respect to suicide risk has yet to be clarified’.

In the interest of brevity, please delete the two final sentences in the Abstract (beginning ‘In France…’).

In the Author Summary, please expand your response to the second question (‘What Did the Researchers Do and Find?’) slightly to include brief details of the study design as well as headline numbers relating to the key findings.

I think that the first bullet point under the question ‘Who do these findings mean’ should be rephrased to avoid misinterpretation. Please update to ‘Individuals experiencing COVID-19 like symptoms in the first year of the pandemic were at higher risk of later suicidal ideation, but this association was not observed for serologically confirmed SARS-CoV-2 infection, thus further study is needed to confirm the role of the virus in relation to suicide risk.’

Line 20: Please update ‘distress’ to ‘poor mental health’.

The term ‘sensibility analysis’ appears several times throughout the text – please review and correct to ‘sensitivity analysis’ where appropriate.

Comments from Reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

Thank you once again for considering my comments. I had not considered the implications of fitting an interaction model whilst using IPTW. Whilst I am sure there are ways around this, I am happy with the changes that the authors have made, and have no further comments.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 4

Callam Davidson

10 Jan 2023

Dear Dr Davisse-Paturet, 

On behalf of my colleagues and the Academic Editor, Dr Toshi Furukawa, I am pleased to inform you that we have agreed to publish your manuscript "Suicidal ideation following self-reported COVID-19 like symptoms or serology-confirmed SARS-CoV-2 infection in France: a propensity score weighted analysis from a cohort study" (PMEDICINE-D-22-02146R4) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

When making the formatting changes, please also make the following editorial changes:

* Please format your Author Summary using bullet points (see previously published PLOS Medicine articles for an idea of the expected format).

* Please update 'Summer 2021' to 'July 2021' in your Author Summary.

* Please update the second bullet under question two of your Author Summary to read ‘Among these participants, reporting COVID-19 like symptoms in 2020 was associated with a higher risk of reporting suicidal ideation in 2021 (relative risk [95% confidence interval] 1.43 [1.20 – 1.69]) while having a serologically confirmed SARS-CoV-2 infection in 2020 was not associated with a higher risk of reporting suicidal ideation in 2021. These results account for sociodemographic and health-related factors.’

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper and will be in touch soon with further information regarding the planned publication window for the Special Issue. 

Sincerely, 

Callam Davidson 

Associate Editor 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 STROBE checklist. STROBE checklist for cohort studies.

    (DOCX)

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    S1 Acknowledgements. Membership of the EpiCoV study group.

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    S1 Supporting information. Detailed description of the pre-pandemic mental health disorders variable construction.

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    S2 Supporting information. Evolution of total number of deaths by French departments during the first COVID-19 epidemic wave.

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    S3 Supporting information. Directed acyclic graph.

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    S4 Supporting information. Multiple imputation information.

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    S5 Supporting information. Propensity score methodology.

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    S6 Supporting information. Graphic representation of sensitivity analyses results.

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    S1 Table. Comparison of EpiCov participants included versus excluded from analyses using two-sided chi-squared tests.

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    S2 Table. Numerators and denominators of S1 Table.

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    S3 Table. Numerators and denominators of the exposures and covariates, according to the onset of suicidal ideation in 2021, in each of the five imputed data sets.

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    S4 Table. Numerators and denominators of covariates according to the COVID-19 symptoms variable in each imputed data set.

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    S5 Table. Numerators and denominators of covariates according to the SARS-CoV-2 variable in each imputed data set.

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    S6 Table. Covariates name and definition for multiple imputation.

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    S7 Table. Parameters of the propensity scores balance for COVID-19-like symptoms.

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    S8 Table. Parameters of the propensity scores balance for COVID-19-like symptoms for each covariate.

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    S9 Table. Parameters of the propensity scores balance for SARS-CoV-2 serology.

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    S10 Table. Parameters of the propensity scores balance for SARS-CoV-2 serology for each covariate.

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    Attachment

    Submitted filename: Response to reviewer.docx

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    Attachment

    Submitted filename: Response to reviewer.docx

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    Data Availability Statement

    All anonymous aggregated data regarding the results presented in this paper are available online and on supporting information files. The non-aggregated individual data cannot be shared publicly because of European Regulation 2016/679. Nonetheless, these data can be made available after submission to approval of French Ethics and Regulatory Committee procedure (Comité du Secret Statistique, CESREES and CNIL). The access procedure is available on the Centre of Secured Access to Data website (https://www.casd.eu/).

    Articles from PLOS Medicine are provided here courtesy of PLOS

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