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. Author manuscript; available in PMC: 2026 Jun 30.
Published in final edited form as: J Affect Disord. 2026 Jun 7;412:122082. doi: 10.1016/j.jad.2026.122082

Direct and indirect associations linking COVID-19 severity to internalizing disorders and symptoms among participants in New Haven, CT

David Davtian 1,2, Dan Qiu 1,2, Brenda Cabrera-Mendoza 1,2, Yaira Z Nunez 1,3, John H Krystal 1,4, Robert H Pietrzak 1,4,5, Joel Gelernter 1,3,6,7, Renato Polimanti 1,2,7,8,9
PMCID: PMC13312232  NIHMSID: NIHMS2185588  PMID: 42259487

Abstract

While COVID-19 has a negative impact on mental health, the understanding of its association with distinct psychiatric disorders and symptoms is still limited. Leveraging the PsychGenCOV19 cohort including 1,132 participants enrolled in New Haven, CT, we observed that moderate COVID-19 severity was associated with greater odds of internalizing disorders (major depressive disorder, MDD OR=3.74; generalized anxiety disorder, GAD OR=2.85; and post-traumatic stress disorder, PTSD OR=2.32) and with lower odds of panic disorder (OR=0.44). After modeling comorbidities among these mental health outcomes, the association between moderate COVID-19 severity and MDD remained statistically significant (OR=2.89, p=0.006). Investigating internalizing traits, we observed several associations with COVID-19 moderate severity even after accounting for MDD diagnosis (e.g., “lost interest in most things lasting two weeks or more” OR=3.84; “Feeling nervous, anxious or on edge” OR=1.82). In the multivariable model accounting for the co-occurrence of PTSD symptoms, moderate COVID-19 severity was also inversely related to “being super-alert or watchful or on guard” (OR=0.45). In addition to MDD symptoms, certain GAD and PTSD symptoms (e.g., “Feeling jumpy or easily startled”, “Feeling nervous, anxious or on edge”, “Worrying too much about different things”) mediated the association between COVID-19 severity and MDD (proportion mediated 9% to 27%). Finally, a latent class analysis identified PsychGenCOV19 participants characterized by severity patterns of COVID-19 and internalizing symptoms. These findings highlight the symptom-specific association of COVID-19 severity with mental health, underscoring possible transdiagnostic effects across the internalizing spectrum.

Keywords: COVID-19, symptoms, mental health, anxiety, depression, post-traumatic stress disorder

INTRODUCTION

Coronavirus disease 2019 (COVID-19) has had profound and far-reaching effects on physical and mental health globally. After the pandemic ended, a growing body of evidence highlighted the potential long-term mental health impacts of COVID-19 (Majolo et al., 2021), especially in the context of internalizing disorders. Indeed, major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD) have been associated with an increased risk of hospitalization, longer recovery times, and higher mortality following COVID-19 (Nemani et al., 2021). These findings align with existing evidence that individuals with psychiatric conditions are more vulnerable to adverse physical health outcomes following SARS-CoV-2 infection (Molero et al., 2023). Conversely, severe COVID-19 outcomes have been reported to increase the risk of negative mental health outcomes in individuals without prior psychiatric diagnoses, due to psychological stress (Di Blasi et al., 2021) and altered neuroimmune function (Raony et al., 2020).

While the association between COVID-19 and internalizing disorders and other mental illnesses has been reported in global cohorts with different characteristics (Xiong et al., 2020), limited information is available regarding the relationship between COVID-19 and specific psychiatric symptoms across diagnostic domains. Symptom-level analyses can lead to a more accurate characterization of psychopathology, especially with respect to highly heterogeneous conditions such as internalizing disorders (O'Driscoll et al., 2021). Recent studies have highlighted the importance of modeling symptom-level information to assess transdiagnostic factors of mental illnesses (Krueger and Eaton, 2015), their relationships with brain and behavior functions (Grisanzio et al., 2018), and their direct and indirect effects on individual well-being (Kist et al., 2023). With respect to COVID-19, multiple studies described neuropsychiatric symptoms as common and persistent after recovery (Badenoch et al., 2021), which is consistent with potential neuropathogenic mechanisms related to severe COVID-19 syndrome (Han et al., 2021). Regarding the possible dynamics differentiating COVID-19 relationship with internalizing disorders and symptoms, a genetically informed study highlighted a potential causal effect of COVID-19 on anxiety symptoms, while GAD may increase vulnerability to COVID-19 (Asgel et al., 2024).

To expand the characterization of COVID-19 relationships with psychiatric disorders and symptoms, we analyzed participants recruited in New Haven, CT. Specifically, we tested three hypotheses: (1) COVID-19 outcomes are associated with increased internalizing disorders; (2) internalizing symptoms are differentially associated with COVID-19 outcomes; and (3) the association between COVID-19 and internalizing disorders is mediated by specific symptoms. Leveraging a broad mental health assessment, we conducted a high-resolution analysis of the interplay between mental health and COVID-19, exploring transdiagnostic relationships across internalizing spectrum, possible mediated effects linking symptoms to disorders, and subgroups of participants with specific patterns of symptom co-occurrence.

METHODS

Study Population

The PsychGenCOV19 cohort was designed to investigate associations between COVID-19 severity and internalizing disorders. Participants were enrolled between January 2023 and January 2025 through advertisements within the Yale New Haven Health System and community events in the New Haven area. Within this period, COVID-19 testing was widely available in New Haven, CT and surrounding areas. Eligibility criteria included being older than 18 years of age, having experienced anxiety, depression, or post-traumatic stress symptoms, and/or having received a positive COVID-19 test. The PsychGenCOV19 study was conducted under protocol #2000033404 approved by the institutional review board of the Yale School of Medicine, New Haven, CT, USA. Written informed consent was obtained from each participant.

COVID-19 severity was based on self-reported information regarding COVID-19 symptoms assessed using the Coronavirus Health Impact Survey (Nikolaidis et al., 2021). Individuals were classified as having mild COVID-19 symptoms (i.e., fever, cough, sore throat, fatigue, loss of taste or smell, eye infection) but not shortness of breath. Moderate COVID-19 severity was defined by the presence of shortness of breath among reported COVID-19 symptoms.

A comprehensive mental health assessment integrating multiple screening instruments (Supplemental Table 1) was conducted. Information regarding internalizing disorders and symptoms was derived from the GAD-7 anxiety scale (Spitzer et al., 2006), the Patient Health Questionnaire-9 (PHQ-9) (Kroenke et al., 2001), and the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) (Blevins et al., 2015). Applying recommended thresholds, GAD-7, PHQ-9, and PCL-5 total scores were used to define GAD, MDD, and PTSD case-control status among PsychGenCOV19 participants. Because of its potential impact on mental health, the item “other unwanted or uncomfortable sexual experiences” assessed in Life Event Checklist for DSM-5 (LEC-5) was also included among events potentially related to PTSD. We calculated Cronbach’s alpha coefficients and observed high internal consistency in the PsychGenCOV19 cohort for MDD (α=0.9), GAD (α=0.8), and PTSD (α=0.9).

While 1,303 individuals started the enrollment process, we had complete information for a total of 1,132 PsychGenCOV19 participants. The excluded individuals (N=171) showed demographic characteristics (69% females, an age ranging from 18 to 69 years) similar to those of the sample analyzed (Table 1). The cross-sectional data available from 1,132 PsychGenCOV19 participants were used for the analyses described. No longitudinal information was available for this study.

Table 1:

Characteristics of the participants enrolled in the PsychGenCOV19 study.

Study Population N=1,132
Sex, Female N (%) 761 (67)
Age, mean±SD 35±13
Ethnicity, Hispanic N (%) 273 (24)
Race N (%) African American 278 (25)
Asian 75 (6)
Native American 6 (1)
Other 72 (6)
White 701 (62)
COVID-19 N (%) No 66 (6)
Mild 514 (45)
Moderate 556 (49)
Alcohol Use Disoder, N (%) 82 (7)
Ever Tobacco Smoker, N (%) 586 (52)
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Association Analysis

Multinomial logistic regression was used to evaluate the relationship between COVID-19 severity and psychiatric disorders and symptoms, considering a three-level scale: no COVID-19 (denied having had COVID-19), mild COVID-19 severity, and moderate COVID-19 severity. In addition to demographic characteristics (age, sex, and race/ethnicity categories), we included tobacco smoking, income, and alcohol use disorder (AUD), because of their previously reported effect on COVID-19 (Cabrera-Mendoza et al., 2022; Wendt et al., 2021). Details regarding the distribution of these variables in the PsychGenCOV19 cohort are reported in Table 1. In the disorder-based analysis, each psychiatric disorder was tested individually with respect to COVID-19 severity. False discovery rate (FDR) multiple testing correction was applied to identify significant associations in the univariable analysis (FDR q<0.05). Then, a multivariable analysis was performed, entering the disorders into the same multinomial logistic regression model along with the covariates described above. In the symptom-based analysis, each internalizing symptom was tested individually with respect to COVID-19 severity including the covariates described above and MDD, because of the association observed in the disorder-based results. FDR multiple testing correction was applied to identify significant associations in the univariable analysis (FDR q<0.05). Then, a multivariable analysis was performed, entering them into the same multinomial logistic regression model including the covariates described above and MDD. Variance Inflation Factor (VIF) was computed to detect evidence of collinearity in the multivariable models. To test the Independence of Irrelevant Alternatives (IIA) assumption, we re-estimated the multinomial models after excluding specific outcome categories to compare the resulting regression coefficients.

Mediation Analysis

We used the R package mediation (Tingley et al., 2014) to test whether internalizing symptoms mediate the association between COVID-19 severity and MDD. The analysis focused on PHQ-9, GAD-7, and PCL-5 items that were associated with COVID-19 severity. Average Causal Mediated Effect (ACME) statistics were estimated through nonparametric bootstrapping (500 resamples). The medsens function was used to assess the robustness of mediation effects to potential unmeasured confounding.

Structural Equation Modeling

We constructed a structural equation model (SEM) using the R package lavaan (Rosseel, 2012) to quantify direct and indirect effects of COVID-19 severity on MDD and internalizing symptoms, while accounting for measurement error in symptom indicators. We used the Weighted Least Squares Means and Variance Adjusted (WLSMV) estimator to better account for binary and ordinal variables, as well as the non-normal distribution of the data. SEM fit was evaluated using the Comparative Fit Index (CFI), Root Mean Square Error of Approximation (RMSEA), and Standardized Root Mean Square Residual (SRMR). FDR multiple testing correction was applied to identify significant effects (FDR q<0.05).

Latent Class Analysis

Using the poLCA package (Linzer and Lewis, 2011), we performed a latent class analysis assessing whether distinct subgroups of participants could be identified based on the co-occurrence of COVID-19 severity, MDD status, and MDD symptoms. Models including between 2 and 10 classes were tested. Then, the best fit was defined considering Bayesian Information Criterion (BIC), entropy values, and class interpretability.

RESULTS

Among PsychGenCOV19 participants with complete data (N=1,132; Table 1), the mean age was 35 years (range 18–77), 67% were female, and 75% of reported being of non-Hispanic descent. With respect to self-reported race, the largest groups included White (61%) and African American (24%) individuals. Only 6% of the sample reported not having received a positive COVID-19 test by the time of their assessment. Among participants who screened positive before their assessment (N=1,070), 52% reported moderate COVID-19 severity.

Disorder- and Symptom-level Associations

Considering neuropsychiatric conditions with at least 100 cases (Supplemental Table 2), moderate COVID-19 severity was associated with increased odds of internalizing disorders (MDD OR=3.74, 95%CI=1.85–7.56; GAD OR=2.85, 95%CI=1.37–5.92; PTSD OR=2.32, 95%CI=1.30–4.16) and with reduced odds of panic disorder (OR=0.44, 95%CI=0.22–0.84; Figure 1) after FDR multiple testing correction. Mild COVID-19 severity showed an FDR-significant association only with MDD (OR=2.92, 95%CI=1.44–5.93; Figure 1, Supplemental Table 2). In the multivariable analysis modeling all significant neuropsychiatric conditions simultaneously, MDD remained associated with both moderate and mild COVID-19 severity (moderate OR=2.89, 95%CI=1.35–6.20; mild OR=2.74, 95%CI=1.28–5.89). Compared to models where MDD was tested individually, the association strength in the multivariable model was more consistent between moderate vs mild severity. No evidence of collinearity was observed among the terms included in the multivariable analysis (VIF<1.5, Supplementary Table 2). Sensitivity analyses demonstrated that associations between psychiatric disorders and COVID-19 outcome categories were consistent in direction across all models (Supplementary Table 2).

Figure 1:

Figure 1:

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Association of neuropsychiatric conditions with COVID-19 severity. Full results are reported in Supplemental Table 2. Odds ratios (95% CI) are shown for univariable models. Significance after false discovery rate correction is indicated by dot fill (solid dot: FDR q<0.05; open dot FDR q≥0.05). Abbreviations: MDD, Major Depressive Disorder; GAD, Generalized Anxiety Disorder; PTSD, Post-traumatic Stress Disorder; OCD, Obsessive-Compulsive Disorder.

To follow up on the disorder-level associations, we conducted a symptom-level analysis, testing the association between COVID-19 severity and individual items available from the GAD-7, PHQ-9, and PCL-5 (Supplemental Tables 3, 4, and 5). To identify symptom-level associations independent of MDD status, we included this disorder as an additional covariate together with those included in the disorder-level analysis (i.e., age, sex, race/ethnicity categories, tobacco smoking, income, and AUD). No collinearity was observed among most terms included in these multivariable models (all VIF values <5; Supplementary Tables 3, 4, and 5). Mild multicollinearity was observed for “feel empty or hopeless lasting 2 weeks or longer” (VIF=5.2) in the PHQ-9 model and for “not being able to stop or control worrying” (VIF=5.4) and “worrying too much about different things” (VIF=5.6) in the GAD-7 model. Perfect multicollinearity was detected for “this period lasted for 6 months or more” in the GAD-7 multivariable model (Supplementary Table 4), and therefore, this item was excluded from further analyses.

Ten PHQ-9 items showed FDR-significant associations with both moderate and mild COVID-19 severity, after accounting for MDD status (Figure 2A, Supplemental Table 3). The strongest association was observed for “lost interest in most things lasting two weeks or more” (moderate OR=3.84, 95%CI=2.13–6.94; mild OR=2.37, 95%CI=1.31–4.27). When entering PHQ-9 items into a multivariable model to account for their co-occurrence, this symptom remained associated with moderate COVID-19 severity (OR=11.58, 95%CI=2.28–58.95). Conversely, “take little or no interest or pleasure in things during low mood” was associated with increased moderate and mild COVID-19 severity when tested individually (moderate OR=1.61, 95%CI=1.21–2.14; mild OR=1.37, 95%CI=1.03–1.82), but this relationship was reversed in the multivariable model including the other PHQ-9 items (moderate OR=0.22, 95%CI=0.09–0.53; mild OR=0.25, 95%CI=0.10–0.61).

Figure 2:

Figure 2:

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Association of PHQ-9 and GAD-7 items (left panel for PHQ-9 items and right panel for GAD-7). Full results are reported in Supplemental Tables 3 and 4. Odds ratios (95% CI) are shown for univariable models. Significance after false discovery rate correction is indicated by dot fill (solid dot: FDRR q<0.05; open dot: FDR q≥0.05). Abbreviations: PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder-7; PCL-5, PTSD Checklist for DSM-5.

After FDR multiple testing correction, three GAD-7 items were associated with moderate COVID-19 severity, and two with mild COVID-19 severity (Figure 2B; Supplemental Table 4). Interestingly, the only two GAD-7 items associated with both moderate and mild COVID-19 severity showed inverse relationships (“usually worry about one particular thing” moderate beta=−8.72±0.76, mild beta=−9.6±0.75; “keyed up or on edge” moderate beta=−8.75±0.98, mild beta=−9.33±0.98). These associations remained significant in the multivariable model, accounting for the co-occurrence of GAD symptoms (Supplemental Table 4).

No association of PCL-5 items with COVID-19 severity survived FDR multiple testing correction (Supplemental Table 5). However, mild COVID-19 severity showed nominally significant inverse association with “being super-alert or watchful or on guard” in both univariable and (univariable-OR=0.65, 95%CI=0.47–0.89; multivariable OR=0.38, 95%CI=0.21–0.69).

Mediation Analysis

Considering the associations observed with respect to GAD-7, PHQ-9, and PCL-5, 17 items showed statistically significant ACME estimates (FDR q<0.05) for mediating the association between COVID-19 severity and MDD (Figure 3A; Supplemental Table 6). As expected due to their relationship with MDD status, PHQ-9 items accounted for most of these effects (71%), with mediated proportions ranging from 28% (“think a lot about death”) to 80% (“trouble concentrating or making day-to-day decisions because of your low mood”). Four GAD-7 items showed mediation effects in the association between COVID-19 and MDD: “feeling nervous, anxious or on edge” (mediated proportion=24%), “worrying too much about different things” (mediated proportion=22%), “trouble relaxing” (mediated proportion=21%), and “being so restless that it is hard to sit still” (mediated proportion=10%). Among PCL-5 items, only “feeling jumpy or easily startled” showed a significant mediation effect in the association between COVID-19 severity and MDD (mediated proportion=27%). For most symptoms, ACME estimates remained non-zero up to moderate levels of confounding (ρ≈0.3–0.4). However, the low sensitivity thresholds observed for other symptoms (ρ≤0.2) indicate that their mediation effects may be influenced at least partially by weak unmeasured confounders.

Figure 3:

Figure 3:

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PHQ-9, GAD-7, and PCL-5 items mediating the association between COVID-19 severity and MDD (Left Panel). Full results are reported in Supplemental Table 6. Structural equation modeling statistics related to the paths among COVID-19 severity, MDD status, and internalizing symptoms (Right Panel). Full results are reported in Supplementary Table 7. Abbreviations: PHQ-9, Patient Health Questionnaire-9; GAD-7, Generalized Anxiety Disorder-7; PCL-5, PTSD Checklist for DSM-5; ACME, Average Causal Mediation Effect.

Structural Equation Modeling

We observed good fit statistics (CFI=0.995, RMSEA=0.045, SRMR=0.108) when modeling the relationship between COVID-19 severity and MDD as mediated by internalizing symptoms (Figure 3B). Specifically, we observed a direct effect of COVID-19 severity on GAD-7, PHQ-9, and PCL-5 items (FDR q<0.05), but not on MDD status (p=0.8; Supplemental Table 7). As expected, PHQ-9 items showed a direct effect on MDD status (Estimate=0.48±0.05).

Latent Class Analysis

In the latent class analysis including COVID-19 severity, MDD status, and internalizing symptoms, we observed the best fit with respect to a four-class model (Supplemental Table 8) with comparable sizes (ranging from N=221 to N = 373). Across them, we observed correlated gradients of probabilities of being an MDD case, reporting internalizing symptoms, and experiencing a certain degree of COVID-19 severity, where latent class #1 showed the highest probabilities across these domains, while lower estimates were observed for the other classes (Supplemental Table 9).

DISCUSSION

The intersection between COVID-19 and psychiatric disorders has emerged as a pressing public health concern, necessitating careful examination of potential pathways and risk factors. Common psychiatric disorders are highly heterogeneous, with individuals receiving the same diagnosis often presenting different symptom patterns (Olbert et al., 2014). This heterogeneity poses major challenges for both treating affected patients and investigating risk factors and consequences contributing to morbidity and mortality of psychiatric disorders (Nguyen et al., 2023). In this context, symptom-level analyses can provide greater resolution to assess transdiagnostic features across psychopathology spectrum and their association with other health domains ( O'Driscoll et al., 2021). With respect to COVID-19, a number of studies have reported a range of neuropsychiatric symptoms in individuals infected by SARS-CoV-2 virus (Frontera and Simon, 2022). However, there is very limited information regarding COVID-19 relationship with diagnostic criteria across psychopathology spectrum. To address this issue, we leveraged novel data from a cohort recruited specifically to investigate the interplay between COVID-19 and mental health. We analyzed information collected from multiple instruments (Supplementary Table 1), including items screened by PHQ-9, GAD-7, and PCL-5.

In line with previous evidence (Young et al., 2023), we observed that moderate COVID-19 severity was associated with increased odds of MDD, PTSD, and GAD. However, only MDD was associated with mild COVID-19 severity. Interestingly, moderate COVID-19 severity showed an inverse relationship with respect to panic disorder. While previous studies have described a link between COVID-19 infection and exacerbated symptoms in patients affected by panic disorder (Dennis et al., 2025), our findings suggest that individuals with panic disorder were less likely to contract COVID-19, potentially due to behaviors that reduced exposure risk. Multivariable modeling of these neuropsychiatric conditions simultaneously suggested that MDD was the primary driver of the associations with both moderate and mild COVID-19 severity.

To further evaluate the relationship between COVID-19 severity and MDD, we examined internalizing symptoms screened by the PHQ-9, GAD-7, and PCL-5 instruments. After accounting for MDD status and covariates also included in the disorder-level analysis (age, sex, income, AUD, and tobacco smoking), we identified several symptom-level associations. With respect to PHQ-9 items, the strongest effect was observed with respect to “lost interest in most things lasting two weeks or more”. This was also the one that remained significant in the multivariable model accounting for co-occurrence of other MDD symptoms assessed by the PHQ-9. Conversely, in the multivariable model, “take little or no interest or pleasure in things during low mood” showed an inverse relationship with moderate COVID-19 severity. Previous reports highlighted how focusing on pleasurable activities has been useful in coping with the COVID-19 pandemic, but little is known on how anhedonia among people with MDD may be related to COVID-19. It is possible that loss of interest could have reduced the participation of the individuals in social or outdoors activities, which could have reduced their exposure to COVID-19. Our findings suggest a complex interplay that may have implications for other MDD comorbidities.

Among GAD-7 items, we observed a strong inverse relationship between COVID-19 severity with “usually worry about one particular thing” and “keyed up or on edge when worried or anxious”. They remained significant also when accounting for the co-occurrence of GAD-7 items. These are features also shared with other anxiety disorders and may reflect similar dynamics to those implicated in the inverse associations observed with respect to panic disorder and OCD. Conversely, moderate COVID-19 severity was associated with increased odds of “more irritable than usual”, which remained significant in the multivariable analysis. Irritability has been frequently reported as a symptom associated with COVID-19 (de Amorim Macedo et al., 2023). Our results suggest that irritability, which is commonly associated with GAD, may be positively linked to COVID-19, while features shared with other anxiety disorders, such as heightened worry or vigilance, may be associated with behaviors, such as social withdrawal, that reduce exposure to the virus. This finding is also consistent for “being super-alert or watchful or on guard” in the PCL-5, which was inversely associated with COVID-19 severity, and this association remained significant in the multivariable analysis. These findings support that certain internalizing symptoms, such as hypervigilance, associated either with GAD or PTSD, may be protective factors against COVID-19 by reducing exposure to COVID-19 risk factors.

Results of our mediation analysis highlighted that the association between MDD and COVID-19 may be mediated by internalizing symptoms. Among PHQ-9 items, the largest mediated proportion was observed for “have trouble concentrating or making day-to-day decisions because of your low mood” and “feel tired out, low on energy, easily fatigued”. These symptoms are characteristic of long-COVID-19 syndrome (van der Feltz-Cornelis et al., 2024). Accordingly, our findings suggest a contribution of certain MDD domains to long-term consequences of COVID-19 infection. We also observed that GAD and PTSD symptoms partially mediate the association between MDD and COVID-19 severity. The role of internalizing symptoms across diagnostic boundaries in mediating this relationship was also confirmed by the SEM model. As highlighted also by other studies ( Verdejo-Garcia et al., 2024), these results support the need for symptom-level analyses to investigate trans-diagnostic features and their relationship with comorbid conditions.

While we expanded the understanding of direct and indirect effects linking internalizing spectrum to COVID-19, our study has several limitations. The lack of longitudinal data prevents us from establishing the temporal sequence of COVID-19 infection and psychiatric symptoms. Accordingly, the results obtained from mediation and SEM analyses should be interpreted as exploratory and do not imply causality. Furthermore, reliance on self-reported information may introduce reporting biases, and the specific characteristics of our sample (including recruitment methods and inclusion criteria) may limit the generalizability of our findings. Similarly, the online recruitment process may introduce assessment bias in our study. In this context, non-probability sampling is susceptible to self-selection bias, and as a result, the prevalence and severity of mental health symptoms in this study may be overestimated compared to those observed in the general population. Because most individuals in the New Haven area had COVID-19 at least once at the time of the recruitment (January 2023-January 2025), our cohort included a small proportion of COVID-19 controls. While this may have reduced the statistical power of our analyses, this case-control imbalance is expected to bias the results toward the null, but they should not generate false positive results. Finally, while we conducted appropriate sensitivity analyses to ensure the reliability of the analyses performed, we cannot completely exclude assumption violations of the models used.

In conclusion, our study suggests that the relationship between COVID-19 severity and mental health is largely driven by MDD and symptom patterns across the internalizing spectrum. The design of the study did not allow us to address the direction of causality, i.e., whether COVID19 infection caused some of these symptoms, or whether symptoms already present at the time of infection modified COVID risk or severity. Across the internalizing spectrum, we observed differences where certain features may be more directly related to COVID-19, while others may reduce the probability of being exposed to COVID-19 risk factors. Further studies will be needed to assess how different dynamics underlying internalizing spectrum can influence the comorbidity of physical health outcomes, also investigating the interplay between brain and peripheral biological systems.

Supplementary Material

Supplemental Tables

HIGHLIGHTS.

  • Major depressive disorder is the primary mental outcome related to COVID-19

  • Internalizing symptoms are associated with COVID-19 independently of MDD

  • MDD is not directly associated with COVID-19 severity

  • Internalizing symptoms mediate the association between MDD and COVID-19

ACKNOWLEDGMENTS

The authors acknowledge the important work done by the personnel refining the assessment and the recruitment team in enrolling the PsychGenCOV19 participants.

FUNDING

This study was supported by a grant from the National Institutes of Mental Health (RF1 MH132337).

DECLARATION OF COMPETING INTEREST

RP and JG are paid for their editorial work on the journal Complex Psychiatry. RP received a research grant outside the scope of this study from Alkermes. The remaining authors declare that they have no competing interests. JK is a scientific advisor to Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), PsychoGenics, Inc., Stanley Centre for Psychiatric research at the Broad Institute of MIT and Harvard, Lohocla Research Corporation. JK owns stock and/or stock options in Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Inc., BlackThorn Therapeutics, Inc., Terran Biosciences, Inc. JK reports income <$10 000 per year from: AstraZeneca Pharmaceuticals, Biogen, Idec, MA, Biomedisyn Corporation, Bionomics, Limited (Australia), Boehringer Ingelheim International, Concert Pharmaceuticals, Inc., Epiodyne, Inc., Heptares Therapeutics, Limited (UK), Janssen Research & Development, L.E.K. Consulting, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc. Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, Taisho Pharmaceutical Co., Ltd. JK reports income >$10 000 per year from Biological Psychiatry (Editor). JK received the drug, Saracatinib from AstraZeneca and Mavoglurant from Novartis for research related to NIAAA grant ‘Centre for Translational Neuroscience of Alcoholism [CTNA-4]’ from AstraZeneca Pharmaceuticals. JK holds the following patents: 1) Seibyl JP, Krystal JH, Charney DS. Dopamine and noradrenergic reuptake inhibitors in treatment of schizophrenia. US Patent #:5447948. September 5, 1995; 2) Vladimir, Coric, Krystal, John H, Sanacora, Gerard - Glutamate Modulating Agents in the Treatment of Mental Disorders US Patent No. 8778979 B2 Patent Issue Date: July 15, 2014. US Patent Application No. 15/695164: Filing Date: 09/05/2017; 3) Charney D, Krystal JH, Manji H, Matthew S, Zarate C, - Intranasal Administration of Ketamine to Treat Depression United States Application No. 14/197767 filed on March 5, 2014; United States application or Patent Cooperation Treaty (PCT) International application No. 14/306382 filed on June 17, 2014; 4): Zarate, C, Charney, DS, Manji, HK, Mathew, Sanjay J, Krystal, JH, Department of Veterans Affairs ‘Methods for Treating Suicidal Ideation’, Patent Application No. 14/197.767 filed on March 5, 2014 by Yale University Office of Cooperative Research; 5) Arias A, Petrakis I, Krystal JH. - Composition and methods to treat addiction. Provisional Use Patent Application no. 61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research.; 6) Chekroud, A., Gueorguieva, R., Krystal, J.H. ‘Treatment Selection for Major Depressive Disorder’ [filing date June 3, 2016, USPTO docket number Y0087.70116US00]. Provisional patent submission by Yale University; 7) Gihyun, Yoon, Petrakis I., Krystal J.H. - Compounds, Compositions and Methods for Treating or Preventing Depression and Other Diseases. U.S. Provisional Patent Application No. 62/444552, filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; and 8) Abdallah, C., Krystal, J.H., Duman, R., Sanacora, G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62/719935 filed on August 20, 2018 by Yale University Office of Cooperative Research OCR 7451 US01.

DATA AVAILABILITY

The data generated from the present study are included in the manuscript and its supplemental material.

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Associated Data

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

Supplementary Materials

Supplemental Tables
NIHMS2185588-supplement-Supplemental_Tables.xlsx (45.3KB, xlsx)

Data Availability Statement

The data generated from the present study are included in the manuscript and its supplemental material.

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